MANKANN UT HIDUS009890195B2 ONMUUTUNUT (12 ) United States Patent ( 10) Patent No. : US 9 ,890 , 195 B2 Panitch et al. (45 ) Date of Patent: * Feb . 13, 2018

(54 ) MK2 INHIBITOR COMPOSITIONS AND 2300 /434 ; A61L 2430 /32 ; A61L 29 / 048 ; METHODS TO ENHANCE NEURITE A61L 29 / 16 ; A61L 31 /047 ; A61L 31 / 16 ; OUTGROWTH , NEUROPROTECTION , AND CO7K 14 /001 ; CO7K 7 /06 ; CO7K 7 / 08 REGENERATION See application file for complete search history . ( 75 ) Inventors : Alyssa Panitch , W . Lafayette , IN (US ) ; ( 56 ) References Cited Kevin Otto , West Lafayette , IN (US ) ; U . S . PATENT DOCUMENTS Nnadozie Onunkwo, West Lafayette, IN (US ) ; Andrew Woolley , Lafayette , 4 ,105 , 027 A 8/ 1978 Lundquist 4 , 192 , 309 A 3 / 1980 Poulsen IN (US ) 4 , 227 , 522 A 10 / 1980 Carris 4 ,627 , 432 A 12/ 1986 Newell et al . ( 73 ) Assignee: Purdue Research Foundation , West 4 , 778 ,054 A 10 / 1988 Newell et al. Lafayette , IN (US ) 4 ,811 , 731 A 3 / 1989 Newell et al. 5 , 035 , 237 A 7 / 1991 Newell et al. 5 , 175 , 144 A 12 / 1992 Walser ( * ) Notice : Subject to any disclaimer, the term of this 5 ,415 , 864 A 5 / 1995 Kopecek et al . patent is extended or adjusted under 35 5 , 565 ,350 A 10 / 1996 Kmiec et al . U . S . C . 154 (b ) by 872 days . 6 , 855, 693 B2 2 /2005 Mochly -Rosen et al. 6 , 921 , 527 B2 7 / 2005 Platz et al . This patent is subject to a terminal dis 7 , 041 , 814 B1 5 / 2006 Weinstock et al. claimer . 7 , 135 , 453 B2 11/ 2006 Brophy et al. 7 , 361, 352 B2 4 / 2008 Birkett et al. 8 , 536, 303 B2 9 / 2013 Panitch et al . (21 ) Appl. No. : 12 /844 ,815 8 , 741 , 849 B2 6 / 2014 Panitch et al. 2002 / 0009491 A1 1 / 2002 Rothbard et al. ( 22 ) Filed : Jul. 27 , 2010 2002 / 0041899 Al 4 / 2002 Chudzik et al. 2002 / 0128444 Al 9 / 2002 Gingras et al. 2003 /0134810 Al 7 / 2003 Springate et al . (65 ) Prior Publication Data 2003 / 0187232 Al 10 / 2003 Hubbell et al. 2003/ 0190364 Al 10 / 2003 Panitch et al . US 2011 /0052658 A1 Mar . 3 , 2011 2005 /0153372 Al 7 /2005 Greengard et al . 2006 / 0024264 Al 2 / 2006 Kuroda et al. 2006 / 0035814 Al 2 /2006 Brophy et al. Related U . S . Application Data 2006 /0115453 A1 6 / 2006 Yaffe et al. 2006 /0193920 Al 8 / 2006 Bosch et al . (60 ) Provisional application No. 61 / 228 , 738 , filed on Jul. 2006 / 0293234 Al 12 / 2006 Schroeder 27 , 2009 . 2007 /0026518 AL 2 / 2007 Healy et al . (Continued ) (51 ) Int. Ci. CO7K 7 / 06 ( 2006 .01 ) FOREIGN PATENT DOCUMENTS CO7K 14 /00 ( 2006 .01 ) CA 2689296 * 2 / 1927 A61L 15 / 32 ( 2006 .01 ) CN A61K 38 / 16 ( 2006 .01 ) 17479493 / 2006 A61K 38 /00 ( 2006 . 01 ) (Continued ) A61K 38 /04 ( 2006 .01 ) CO7K 7 / 08 ( 2006 .01 ) OTHER PUBLICATIONS A61L 15 /44 ( 2006 .01 ) Burgess et al . J of Cell Bio . 1990 , 111 :2129 - 2138. * A61L 27/ 22 ( 2006 .01 ) Bowie et al. Science , 1990 , 247 : 1306 - 1310 . * A61L 27 /54 ( 2006 .01 ) Pawson et al. 2003 , Science 300 : 445 -452 . * A61L 29 /04 ( 2006 .01 ) Abergel et al. , “ Biochemical composition of the in A61L 29 / 16 keloids and analysis of collagen metabolism in keloid fibroblast ( 2006 . 01 ) cultures, ” J Invest Dermatol, vol. 84 , pp . 384 - 390 , May 1985 . A61L 31/ 04 ( 2006 .01 ) Achari et al ., 1997 , J Polym Sci A : Polym Chem , 35 : 2513 - 2520 . A61L 31/ 16 ( 2006 .01 ) Allaire et al. ( 1997) Ann Thorac Surg 63 ( 2 ): 582 - 91. (52 ) U . S . CI. Altschul et al. , Nucleic Acids Res . 25 : 3389 - 3402 ( 1997 ). CPC . CO7K 7/ 08 (2013 . 01 ); A61L 15 / 32 (Continued ) ( 2013 .01 ) ; A61L 15 /44 ( 2013 .01 ) ; AGIL 27 /227 ( 2013 .01 ); A61L 27 /54 ( 2013 .01 ) ; Primary Examiner — Chang - Yu Wang A61L 29 / 048 ( 2013 .01 ) ; A61L 29 / 16 ( 74 ) Attorney, Agent, or Firm - McCarter & English (2013 . 01 ) ; A61L 31 /047 (2013 .01 ) ; AGIL LLP 31 / 16 ( 2013 .01 ) ; CO7K 7 /06 ( 2013 . 01 ); COOK 14 /001 ( 2013 .01 ) ; A61K 38 /00 ( 2013. 01 ) ; (57 ) ABSTRACT A61L 2300/ 252 ( 2013 .01 ) ; A61L 2300 / 41 The described invention provides compositions comprising (2013 .01 ) ; A61L 2300 /412 ( 2013 .01 ) ; A61L at least one peptide of formula I for enhancing neurite 2300 / 434 ( 2013 .01 ) ; A61L 2430 / 32 (2013 .01 ) outgrowth , neuroprotection , and nerve regeneration , and (58 ) Field of Classification Search methods of use thereof. CPC .. . . A61L 15 / 32 , A61L 15/ 44 ; A61L 2300 / 252 ; A61L 2300 /41 ; A61L 2300 /412 ; A61L 29 Claims, 16 Drawing Sheets US 9, 890 , 195 B2 Page 2

( 56 ) References Cited Brennan et al. , “ Cylokine Expression in Chronic Inflammatory Disease ,” British Medical Bulletin , 1995, 51( 2 ), 368 - 384 . U . S . PATENT DOCUMENTS Brophy et al, ( 1998 ) J Reprod Fertil 114 (2 ) : 351- 355 . Buckenmaier , C . C . , 3ra, et al. , " Comparison of antiadhesive treat 2007 /0078092 A1 4 / 2007 Livnah et al. ments using an objective rat model, ” Am . Surg ., 1999 , 65 ( 3 ) :274 2007 /0154448 Al 7 /2007 Reid et al. 82 . 2007 /0202189 A1 8 / 2007 Ahlfors 2008 / 0038352 A1 2 / 2008 Simpson et al . Butler et al ., “ Use of organotypic coculture to study keloid biology, " 2008 /0113971 Al 5 / 2008 Hanau et al. Am J Surg, 195 ( 2 ): 144 -148 , Feb . 2008 . 2008 /0132443 A1 6 / 2008 Brophy et al . Calderon et al. , “ Increased proliferation in keloid fibroblasts 2008 /0293640 AL 11/ 2008 Brophy et al . wounded in vitro ,” J Surg Res, vol. 61, pp . 343 -347 , Mar. 1996 . 2009 /0149389 A1 * 6 / 2009 Panitch et al . 514 / 13 Carpino et al. , 1972 , J. Org . Chem ., 37 : 3403 - 3409 . 2009/ 0176694 Al 7 / 2009 Brophy et al . Carroll et al ., “ Heparin stimulates production of bFGF and TGF 2009 /0176695 A1 7 / 2009 Brophy et al. beta 1 by human normal, keloid , and fetal dermal fibroblasts, ” Med 2009 /0179638 AL 7 / 2009 Barker et al. Sci Monit , vol. 9, pp . BR97 - 108 , Mar. 2003 . 2009 /0196927 A1 * 8 / 2009 Panitch et al. 424 / 484 Carroll et al. , " Triamcinolone stimulates bFGF production and 2009 / 0258819 A1 10 / 2009 Brophy et al. inhibits TGF -beta 1 production by human dermal fibroblasts ." 2009 /0269406 Al 10 / 2009 Panitch et al . 2010 /0004165 A1 1 /2010 Brophy et al. Dermato Surg , vol. 28 , pp . 704 - 709, Aug . 2002 . 2010 /0009903 A11 / 2010 Brophy et al. Chiu et al. , “ Photodynamic therapy on keloid fibroblasts in tissue 2010 /0098760 A1 * 4 /2010 Panitch ...... 424 /484 engineered keratinocyte - fibroblast co -culture ,” Lasers Surg Med , 2010 / 0158968 A1 * 6 / 2010 Panitch et al...... 424 /422 vol. 37 , pp . 231 -244 , Sep . 2005 . 2011 / 0052658 AL 3 / 2011 Whitekettle et al. Choi , et al. , 2005, Angewandte Chemie , 44 (41 ) : 6685 -6689 . 2011/ 0288036 AL 11 / 2011 Lander et al. Glaverie et al ., Comput. Chem ., 17 : 191 - 201 ( 1993 ) . 2012 / 0263680 A1 10 / 2012 Lander et al . Clowes et al. ( 1991 ) J Vasc Surg , 13 ( 6 ) :885 - 91. 2014 /0112947 A1 4 /2014 Panitch et al. Corpet, et al. , Nucleic Acids Research , 16 : 10881 -90 ( 1988 ). Coumans et al. ( 2001) . “ Axonal regeneration and functional recov ery after complete spinal cord transection in rats by delayed with FOREIGN PATENT DOCUMENTS transplants and neurotrophins. ” The Journal of Neuroscience , JP 2002 -505077 2 / 2002 21( 23 ) : 9334 - 9344 . JP 2006 -515159 2 /2004 Dalkowski et al ., " Cryotherapy modifies synthetic activity and wo WO 1991/ 16038 10 / 1991 differentiation of keloidal fibroblasts in vitro ,” Exp Dermatol , vol. WO WO 1993 /022443 11 / 1993 12, pp . 673 -681 , Oct. 2003. WO WO 2002 /083933 10 / 2002 Davies et al. (2000 ) Biochem J 351( Pt 1) : 95 - 105 . WO WO 2003 /018758 3 / 2003 DeGrado et al. ( 1999 ) Annual Review of Biochemistry 68 :779 - 819 . WO WO 2003 /076333 9 / 2003 DeMarzo et al ., “ Prostate stem cell compartments : expression of the WO WO 2004 /075914 9 / 2004 cell cycle inhibitor p27Kipl in normal , hyperplastic , and neoplastic WO WO 2004 / 110337 12 / 2004 WO WO 2005 /037236 4 / 2005 cells ” , Am . J . Pathol. , Sep . 1998 , vol. 153 , No. 3 , 911 -919 . WO WO 2005 /114221 12 / 2005 Dreiza et al. , “ Transducible heat shock protein 20 phosphopeptide WO WO 2006 /053315 5 / 2006 alters cytoskeletal dynamics, " FASEB J . 19 : 261- 263 ; 2004 . wo WO 2006 /071456 7 / 2006 Dreiza et al. (2005 ) FASEB J 19 ( 2 ) : 261- 3 . wo WO 2007 /053512 5 / 2007 Duncan et al . ( 1999 ) FASEB J 13 ( 13 ) : 1774 - 86 . WO WO 2008 /008772 1 / 2008 Fawell et al . , Proc Natl Acad Sci USA , 1994 , 91( 2 ) : 664 -668 . W0 2689296 7 / 2008 Feldmann et al. , “ Role of cytokines in rheumatoid arthritis, ” Annual WO WO 2008 / 085191 7 / 2008 Review of Immunology, 1996 , 14 , 397 - 440 . WO WO2008085191 7 / 2008 CO7K 7 /08 Feldmann et al. , “ The role of cytokines in the pathogenesis of WO WO 2009 /021137 2 / 2009 WO WO 2009 / 123759 10 / 2009 rheumatoid arthritis, " Rheumatology , 1999 , 38 , 3 - 7 . WO WO 2010 /065206 6 / 2010 Fields et al ., 1990 , Int. J. Pept. Protein Res. , 35 : 161- 214 . WO WO 2010 /068692 6 / 2010 Firestein et al. , “How important are Y cells in chronic rheumatoid WO WO 2011 /017132 2 / 2011 synovitis ? II . T cell - independent mechanisms from beginning to end ,” Arthritis and Rheumatism 2002 , 46 , ( 2 ) , 298 - 308 . Fisher et al ., 1994 , Macromol Chem Phys . 195 : 679 -687 . OTHER PUBLICATIONS Fragonas et al. , Aricular cartilage repair in rabbits by using suspen Arnano et al. , “ Formation of Actin Stress Fibers and Focal Adhe sions of allogenic chondrocytes in alginate , Biomaterials, 2000 , sions Enhanced by RhoKinase” , Science, Feb . 28 , 1997, vol. 275 , 21( 8 ) : 795 - 801. No. 5304 , 1308 - 1311 . Frankel et al. , Cell, 55 (6 ) : 1189 - 1193 , 1988 . Andrew et al ., “ Spinothalamic lamina I selectively sensitive Fuchs et al . ( 1997 ) J Hypertens 15 ( 3 ) : 301 -307 . to histamine : a central neural pathway for itch , ” Nature Neurosci Fuchs et al. (2000 ) Am J Physiol Regul Integr Comp Physiol 279 (2 ): ence , 2001 4 ( 1 ) : p . 72 -77 . R492 - 8 . Andrews et al . ( 1993 ) “ Report of the AVMA panel on Euthanasia , ” Gaestel et al. , “ Protein kinases as small molecule inhibitor targets in Journal of the American Veterinary Association , 202 ( 2 ) : 229 - 249 . inflammation , ” Current Medicinal Chemistry , 2007 , 14 (21 ) : 2214 Auwerx . “ The Human Leukemia - Cell Line, Thp - 1 - a Multifaceted 2234 . Model for the Study of Monocyte -Macrophage Differentiation ," Gaestel, Nat . Rev . Mol. Cell . Biol . 7 , 120 - 130 , 2006 . Experientia , 1991 , 47 , 22 - 31 . Gerthoffer et al. ( 2001 ) J Appl Physiol 91: 963 - 972 , 2001 . Bareyre et al ., “ Inflammation , degeneration and regeneration in the Green et al . , Cell, 1988 , 55 (60 : 1179 - 1188 . injured spinal cord : insights from DNA microarrays, " Trends Gu et al. , 2002 , J Appl Poly Sci, 86 : 3412 - 3419 . Neurosci, 2003 , 26 ( 10 ) : p . 555 -63 . Haapasalo et al. , “ Truncated trkB , T1 is dominant negative inhibitor Beutler, 1999 ; J. Rheurnatol. , 26 : 16 - 21 . of trkB , TK + -mediated cell survival” , Biochem Biophys Res Biomol International (online ), Kinase Inhibitors, 2006 , retrieved Comun , Feb . 9, 2001, vol. 280 , No . 5 , 1352 - 1358 (Abstract only ). from www .biomol .com /Online _ Catalog /Online _ Catalog / Prod Hanasono et al . , “ Autocrine growth factor by fetal , keloid , and ucts /36 / ? search = & mode = product & lastSort = & all = true & normal dermal fibroblasts ,” Arch Facial Plast Surg . vol . 5 , pp . categoryId = 714 . 26 - 30 , Jan . - Feb . 2003 . Biomol International (online ) , Kinases, 2006 , retrieved from www . Hayess et al ., “ Effect of protein kinase inhibitors on activity of biomol. com / Online _ Catalog/ Online _ Catalog /Products / 36 / ? mammalian small heat -shock protein (HSP25 ) kinase ” , Biochemical search = & mode = product & lastSort = & all = true & categoryId = 713 . Pharmacology , May 9 , 1997 , vol. 53 , No . 9 , 1239 - 1247 . US 9, 890 , 195 B2 Page 3

( 56 ) References Cited McCormack et al. , “ The effect of copper tripertide and tretinoin on growth factor production in a serum - free fibroblast model .” Arch OTHER PUBLICATIONS Facial Plast Surg , vol. 3 , pp . 28 - 32 , Jan . -Mar . 2001. McLemore et al. (2005 ) J Am Coll Surg 201( 1) : 30 -6 . Hedges et al. , J Biol. Chem . 274 , 24211 - 24219 , 1999 . Merrifield , 1963 , J . Am . Chem . Soc ., 85 : 2149 - 2154 . Hegen et al. , “ MAPKAP kinase 2 -deficient mice are resistant to Myers et al ., Computer Applic . Biol . Sci ., 4 : 11 - 17 ( 1988 ) . collagen - induced arthritis, " Journal of Immunology 2006 , 177 ( 3 ) , Mosse et al . ( 1985 ) Lab Invest 53 ( 5 ) :556 -62 . 1913 - 1917 . Needleman et al. , J. Mol. Biol. , 48 : 443 ( 1970 ) . Henikoff et al . ( 1989 ) Proc . Natl. Acad . Sci . USA 89 : 10915 ) . Neidigh et al. ( 2002 ) Nature Structural Biology 9 (6 ) : 425 -430 . Higgins et al. , CABIOS, 5 : 151 - 153 ( 1989 ). Pearson et al. , Methods in Molecular Biology , 24 : 307 -331 ( 1994 ). Higgins et al. , Gene , 73 :237 - 244 ( 1988 ). Pearson et al ., Proc . Natl. Acad . Sci ., 85: 2444 ( 1988 ). Hirano et al. , Journal of Surgical Research 102 , 77 -84 , 2002 . Pincus et al. , “ What is the Natural -History of Rheumatoid Arthri Ho et al . , “ Synthetic Protein Transduction Domains: Enhanced tis, ” Rheumatic Disease Clinics of North America , 1993 , 19 , ( 1) , 123 - 151 . Transduction Potential in Vitro and in Vivo ," Cancer Research , Pineau et al . , Proinflaminatory cytokine synthesis in the injured 2001 , 61: 474 - 477 . mouse spinal cord : mulipphasic expression pattern and identifica Hong et al. , " Growth of keloid -producing fibroblasts in commer tion of the cell types involved , : J Comp Neurol , 2007 , 500 ( 2 ) : pp . cially available serum - free media, ” Otolaryngol Head Neck Surg , 267 - 285 . vol. 121, pp . 469 -473 , Oct. 1999 . Pinol et al. , “ Effect of minoxidil on DNA synthesis in cultured Hruby, V . J . ( 2002 ) Nat Rev Drug Discov 1 ( 11) : 847 -58 . fibroblasts from healthy skin or keloids, " Med Cutan Ibero Lat Am , Huang , et al. , Computer Applications in the Biosciences 8 : 155 -65 vol. 18, pp . 13 -17 , 1990 . ( 1992) . Podolin et al. , “ Altenuation of murine collagen - induced arthritis by Iwasaki et al. , “ Effect of transformig growth factor beta 1 on spinal a novel , potent , selective small molecule inhibitor of I kappa B motor neurons after axotomy, ” J Neurol Sci, 1997 , 147 ( 1 ) : 9 - 12 . kinase 2 , TPCA - 1 ( 2 - [ ( aminocarbonyl) amino ] - 5 - ( 4 - fluorophenyl) Jaccvella , Long - lasting results with hydroxylapatide (Radiesse ) 3 - thiophenecarboxamide ) , occurs via reduction of proinflammatory facial filler, Plastic and Reconstructive Surgery , 2006 , 118 ( 3S ) : 15S cytokines and antigen - induced T cell proliferation ,” Journal of 21S . Pharmacology and Experimental Therapeutics , 2005 , 312 , ( 1 ) . Jenkins et al ., “ The pathogenesis of rheumatoid arthritis : A guide to 373 - 381 . therapy, ” American Journal of the Medical Sciences, 2002 , 323 ( 4 ) , Polo et al. , “ Effect of TGF- beta2 on proliferative scar fibroblast cell 171 - 180 . kinetics, ” Ann Plast Surg , vol. 43, pp . 185 - 190 , Aug . 1999 . Jobanputra et al. , Colorectal Dis . Oct . 2007 : 9 Suppl 2 : 54 -9 . Seal et al ., Biomacromolecules, 2003 ,4 : 1572 - 1582 . Johnson et al. ( 2004 ) Nature Biotech 22 ( 9 ) : 1093 - 1094 . Sestier et al . , “ In vitro toxicity of magnetic fluids evaluated for Karlin et al ., Proc . Natl . Acad . Sci . USA 90 : 5873 -5787 ( 1993 ) . macrophage cell lines, " Journal of Magnetism and Magnetic Mate Kent et al . (2000 ) Ann Vasc Surg 18( 2 ) : 135 - 7 . rials , 2002 , 252 , ( 1 - 3 ) , 403- 405 . Knoepp et al . ( 2000 ) J Vasc Surg 31: 343 - 353 . Shi et al. (2002 ) Biol Chem 383: 1519 - 1536 , 2002. Koch et al. “ Serum - free keloid fibroblast cell culture: an in vitro Silver et al ., “ Regeneration beyond the glial scar, " Nature Reviews model for the study of aberrant wound healing, ” in Plast Reconstr Neuroscience , 2004 . 5 ( 2 ) : p . 146 - 156 . Sur. , vol . 99 , 1997 , pp . 1094 - 1098 . Smith and Waterman , Adv . Appl. Math . , 2 : 482 ( 1981) . Koonin et al . , “ Origin and evolution of eukaryotic apoptosis : the Sousa et al . (2007 ) J Cell Biochem 100 ( 6 ) : 1581 - 1592 . bacterial connection ” , Cell Death Differ, Apr. 2002 , vol. 9 , No. 4 , Stokoe , Biochem . J ., 1993 , 296 (pt 3 ) : 843 -849 . 394 -404 . Takemura et al. , “ Evaluation of a human monobytic cell line THP - 1 Kossi et al. , “ Different metabolism of hexose sugars and sucrose in model for assay of the intracellular activities of antimicrobial agents wound fluid and in . fibroblast cultures derived from granulation against Legionella pneumophlia , ” Journal of Antimicrobial. tissue, hypertrophic scar and keloid .” Pathobiology ; vol. 68, pp . Tanaka et al ., 1976 , Bulletin of the Chemical Society of Japan , 29 - 35 , Jan . - Feb . 2000 . 49 ( 10 ) :2821 - 2823 . Kotlyarov et al. , “ MAPKAP kinase 2 is essential for LPS - induced Tang et al ., Synthesis of urea oligomers and their antibacterial TNF - alpha biosysnthesis ,” Nature Cell Biology, 1999 , 1 ( 2 ): 94 - 97 . activity , Chem Commun . 2005 , 1537 - 1539 . Kumar et al . , " p38 map kinases: Key signaling molecules as Terashima et al. ( 2002 ) J Am Coll Cardiol 39 :228A . therapeutic targets for inflammatory diseases , ” Nature Reviews Tessier et al . (2004 ) J Vasc Surg 40 ( 1 ) : 106 - 14 . Drug Discovery, 2003 , 2 , ( 9 ), 717 -726 . Tew et al. , De novo design of biomimetic antimicrobial polymers , Kwon et al. , “ The cdk2 Binding Domain of p27Kip Correlates with PNAS , 2002 , 99 ( 8 ): 5110 -5114 . the Inhibition of the Kinase Activity of pdk2/ Cyclin Complexes” , Tapash et al. , Transdermal and Tropical Drug Delivery , pp . 249 - 297 Biochem Biophys Res Comm . 1996 , vol . 220 , 703 -709 . ( 1997 ) . Langer, 1990 Science 249 , 1527 - 1533 . Tyagi et al. , J Biol Chem , 2001, 276 (5 ): 3254 -3261 . Lavoie et al. , J Biol. Chem . 268 , 24210 - 24214 . 1993 . Vassalli , 1992 , Annu . Rev . Immunol. , 10 :411 -452 . Lavoie et al. , Mol Cel Biol . 15 : 505 -516 , 1995 . Verlardo et al. , “ Patterns of Gene Expression Reveal a Temporarally Liu et al ., De novo design , synthesis , and characterization of Orchestrated Wound Healing Response in the Injured Spinal Cord ,” antimicrobial beta -peptides , J Am Chem Soc , 2001 , 123 ( 31 ) :7553 J . Neurosci. : 2004 , 24 ( 39 ) : p . 8562 - 8576 . 7559 . Vincent et al. , “ Human Skin Keloid Fibroblasts Display Bioener LoGerto et al, ( 1984 ) Arch Surg 119 : 1212 - 1214 . getics of Cancer Cells , ” J . Invest Dermatol. 128 ( 3 ) : 702 - 709 , Mar. Lopes et al. , “ Inhibition of HSP27 phosphorylation by a cell 2008 . permeantMAPKAP Kinase 2 inhibitor ” . Biochemical and Biophysi Violette et al. , Mimicking hetical antibacterial peptides with cal Research Communications, May 8, 2009 , vol. 382 , No . 3 , nonpeptidic folding oligomers, Chemistry and Biology , 2006 , 13 (5 ): 535 -539 . 531 - 538 . Macomson et al. (2002 ) Neurosurgery 51 ( 1 ) : 204 - 10 : discussion Wang et al. , " Construction of animal models of keloid by tissue 210 - 1 . engineering ," Di Yi Jun Yi Da Xue Xue Bao , vol. 25 , pp . 815 - 819 , Mann et al. ( 1999 ) Lancet 354 ( 9189 ): 1493 - 8 . 832 , Jul. 2005 . ( Japanese language with English Abstract provided ) . Manjnissen et al. , Tissue - engineered cartilage using serially pas Wang et al ., " p27Kipl overexpression causes apoptotic death in saged articular chondrocytes. Chrondrocytes in alginate , combined mammallan cells ” , Oncogene , Dec . 11, 1997 , vol. 15 , No . 24 , in vivo with a synthetic ( E210 ) or biologic degradable carrier 2991 - 2997 . (DBM ) , Biomaterials , 2000 . Ward et al. , “ Design of a bioactive cell -penetrating peptide : when a Matsuoka et al . , “ Ultrastuctural characteristics of keloid fibro transduction domain does more than transduce ” , Journal of Peptide blasts . ” Am J Dermatopathol, vol. 10 , pp . 505 -508 , Dec . 1988 . Science , Oct, 2009 , vol. 15 , No. 10 , 668 -674 . US 9, 890 , 195 B2 Page 4

( 56 ) References Cited Babapulle , Mohan N . et al: “ A hierarchial bayesian meta analysis of randomized clinical trials of drug eluting stents .” Lancet (2004 ) 364 OTHER PUBLICATIONS p . 583 - 91. Cyrus, Tillmann et al ; “ Effect of low dose aspirin on vascular Weibel et al ., Am . J . Surg . 1973 ; 126 : 345 -53 . Woerly et al, (2001 ) “ Spinal cord reconstruction using NeurogelTM inflammation , plaque stability , and atherogenesis in low density Implants and functional recovery chronic injury, " Journal of Neu lipoprotein receptor deficient mice, ” Circulation (2002 ) 106 p . roscience Research , 66 : 1187 -1197 . 1282 - 1287 . Wooten et al. , Comput. Chem ., 17 : 149 - 163 ( 1999 ) . Dinarello , C . A .; “ The IL - 1 family and inflammatory diseases. " Worm et al . , “ Abberant p27kipl promoter methylation in malignant Clin . Exp . Rheumatol. (2002 ) 20 ( suppl. 27 ) p . S1 - S13 . melonama” , Oncogene, Oct . 19 , 2000 , vol . 19 , No. 44 , 5111 -5115 . Tourneau Christophe Le et al; “ Dose escalation methods in phase I Xia et al. , “ Increased CCN2 transcirption in keloid fibroblasts cancer clinical trials . " J . Natl . Cancer. Inst . (2009 ) 101 ( 10 ) p . requires cooperatively beween AP - 1 and SMAD binding sites .” Ann 708 -720 , publication date May 20 , 2009 . Surg . vol. 246 , pp . 886 - 895 , No. 2007 . Schneider et al. , 1998 , In Vivo Evaluation of hsp27 as an Inhibitor Xia et al. , “ P38 MAP kinase mediates transforming growth factor of Actin Polymerization : Hsp27 Limits Actin Stress Fiber and Focal beta2 transcription in human keloid fibrolasts , ” Am J Physiol Regul Adhesion Formation After Heat Shock , Journal of Cellular Physi Integr Comp Physiol . vol . 290 , pp . R501 - R508, Mar. 2006 . ology , 177 : 575 -584 . Xu et al ., Oncogene 25 , 2987 - 2998 , 2006 . Beck et al. , 2000 , Molecular chaperones in the kidney : distribution , Yamanishi et al ., “ Regulation of joint destruction and inflammation putative roles , and regulation , Am J Physiol Renal Physiol, 279 : by p53 in collagen - induced arthritis, ” American Journal of Pathol 203 -215 . ogy 2002. 160 . ( 1) , 123 - 130 . Keezer et al . , Andiogenesis inhibitors Target the Endothelial Cell Yamboliev et al. , Am . J Physiol. Heart Circ Physiol. , 278 , H1899 Cystoskeleton through Altered Regulation of Heat Shock Protein 27 1907 , 2000 . and Cofilin , Cancer Res . 63 : 6405- 6412 . Yang et al ., “ Establishment of an animal model of human hyperplastic scar in nude mice ,” Zhonghua Shao Shang Za Zhi, vol. Cheek S ., et al. , “ Sequence and structure classification of kinases” , 20 , pp . 82 - 84 . Apr. 2004 . (Japanese language with English Abstract J . Mol . Biol . , 2002 , vol. 320 , pp . 855 - 861. provided ) Cagnello M ., et al. , " Activation and function of the MAPKs and Yang et al. , “ Early expression and cellular localization of proinflam their substrates, the MAPK - activated protein kinases" , Microbiol matory cytokines interleukin - 1 beta , interleukin - 6 , and tumor necro ogy adn Molecular Biology Reviews, 2011 , vol. 75 , pp . 50 - 83 . sis factor -alpha in human traumatic spinal cord injury , " Spine , 2004 . Ward B . , et al. , “ Design of a bioactive cell -penetrating , peptide : Zong, X . , et al ., “ Prevention of postsurgery - induced abdominal when a transduction domain doesmore than transduce ” , J Pept Sci. , adhesions by electrospun bioabsorable nanofibrous poly ( lactide -co 2009 , vol. 15 , pp . 668 -674 . clucolide ) -based membranes ,” Am . Surg. , 2004 , 240 ( 5 ) : p . 910 - 5 . Powell et al. ( 2003) Moelcular and Cellular Biology, 23 ( 15 ) 5376 Colomer, Sub -Cellular Biochemistry , 2007 , 45 : 169 - 214 . 5387 . Barone et al . , “ Inhibition of p38Mitogen -Activated Protein Kinase Ridley et al. , “ Actions of 11 - 1 are Selectively controlled by P38 Provides Neuroprotection in Cerebral Focal Ischemia ” , Med Res . Mitogen -Activated Protein Kinase : regulation of prostaglandin H Rev. , 2001, vol . 21, No . 2 , 129 - 145 . synthase - 2 , Metalloproteinases, and IL - 6 at different levels ” , J . Schindler et al ., Examination of the kinetic mechanism of mitogen immunol. , 1997 , vol. 158 , 3165- 31373 . activated protein kinase activated protein kinase - 2 , Biochimica et Ross et al. , " High -content screening analysis of the p38 pathway : Biophysica Acta, Jul. 29 , 2002 , 1598 ( 1 -2 ) : 88 -97 . Profiling of structurally related p38 alpha kinase inhibitors using Burgess et al. , J of Cell Bio ., 1990 , 11 : 2129 - 2138 . cell- based assays, ” Assay and Drug Development Technologies , Bowie et al. , Science , 1990 , 247 : 1306 - 1310 . 2006 , 4 , ( 4 ) , 397 - 409 . Pawson et al. , Science 2003 , 300 : 445 -452 . Russel et al ., “ The effect of histamine on the growth of cultured Zhongshu Song et al ., “ Fusarin C biosynthesis in Fusarium monil fibroblasts isolated from normal and keloid tissue , " J Cell Physiol, liforme and Fusarium venenatum ” , Chembiochem , 2004 , vol . 93 , pp . 389 - 393 , Dec . 1977 . 5 ( 9 ) : 1196 - 1203 . Sahara et al ., “ Suppression of in vitro proliferative scar fibroblast Morrison et al. , “ Combinatorial alaine - scanning, ” Current Opinion contraction by interferon alfa -2b ,” Wound Repair Regen , vol. 1, pp . in Chemical Biology , 2001, 5 : 302 - 307. 22 - 27 , Jan . 1993. Del Gaizon et al, A Novel TAT- Mitochondrial Signal Sequence Saklatvala , “ The p38 MAP kinase pathway as a therapeutic target in Fusion Protein Is Processed , Stays in Mitochondria , and Crosses the inflammatory disease, ” Current Opinion in Pharmacology, 2004 , 4 , Placenta , Molecular Therapy , 2003 , 7 (6 ): 720 - 730 ( 4 ) , 372 - 377 . Yu , Pey - Jen et al ; “ Vascular injury and modulation of MAPKs: A Sawhney et al. , Macromolecules ( 1993 ) 26 , 581- 587 . targeted approach to therapy of restenosis ,” Cell , Signai, (2007 ) 19 Schenk et al, Signal perception and transduction : the role of protein pp . 1359 -1371 . kinases , Biochemica et Biophyica Acta , 1999 , vol. 1449 , 1 - 24 . Tucker, Erik I . et al : " Prevention of vascular graft occlusion and Schwarze et al ., Science, 1999, 285 (54339 : 1569 -1572 . thrombus -associated thrombin generation by inhibition of factor XI, ” Blood ( 2009 ) 113 ( 4 ) p . 936 - 944 . * cited by examiner atent Feb . 13 , 2018 Sheet 1 of 16 US 9 ,890 , 195 B2

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UNIT/GPROTEIN US 9 ,890 , 195 B2 MK2 INHIBITOR COMPOSITIONS AND usually degenerates and dies . Large are sur METHODS TO ENHANCE NEURITE rounded by a fatty insulating sheath called , which is OUTGROWTH , NEUROPROTECTION , AND essential for high -speed conduction of action potentials . The NERVE REGENERATION myelin sheath is interrupted at very regular intervals. These points of interruption are called nodes of Ranvier. CROSS REFERENCE TO RELATED Near its end , the axon divides into many fine branches , APPLICATIONS which have specialized endings called presynpatic termi nals . The presynaptic terminals are the transmitting elements This application claims the benefit of U . S . Provisional of the . By means of its terminals , one neuron Application No. 61/ 228 .738 , filed Jul. 27 , 2009, the contents 10 contacts and transmits information about its own activity to of which are incorporated by reference in their entirety . the receptive surfaces of another neuron , a muscle or other kinds of effector cells . The point of contact is the . STATEMENT OF GOVERNMENT FUNDING It is formed by the presynaptic terminal of one cell (the presynpatic cell ), the receptive surface of the other ( the This invention was made with government support under 15 postsynaptic cell ) , and the space separating them ( the syn Grant 00014975 awarded by the Indiana State Department aptic cleft ) . The terminals of the presynaptic neuron some of Health . The government has certain rights in the inven times contact the postsynpatic neuron on its cell body , but tion . more commonly the contacts occur on . Less often , are located on the initial or on the terminal portions FIELD OF THE INVENTION 20 of axons . On the basis of the number of processes that arise from the The invention relates to cell biology, peptides for enhanc cell body, neurons are classified into three groups : unipolar, ing neurite outgrowth , methods of use thereof, neuroprotec bipolar and multipolar. tion , and nerve regeneration . Unipolar cells have one primary process that may give 25 rise to many branches . Some branches serve as dendritic BACKGROUND receiving structures , and other branches as axons and ter minal structures. Unipolar cells predominate in the nervous Neurons systems of invertebrates in collections of nerve cells located Neurons or nerve cells are excitable cells in the nervous near the spinal cord in the sensory ganglia of the dorsal system that respond to stimuli . They are the core compo - 30 roots . nents of the brain , the vertebrate spinal cord , the invertebrate Bipolar neurons have an ovoid that gives rise to one ventral nerve cord , and the peripheral . Neurons do process at each end : a or peripheral process (which not go through mitosis , and usually cannot be replaced after picks up information from the periphery ) , and an axon or being destroyed . central process (which carries information toward the central Neurons are highly specialized for the processing and 35 nervous system ). The bipolar cells of the retina are examples transmission of cellular signals . Their wide variety in shape , of this class . size and electrochemical properties is reflective of the diver - Multipolar neurons predominate in the vertebrate nervous sity of functions they perform in different parts of the system . These cells have one or more dendritic branches and nervous system . A number of specialized types of neurons a single axon . In a typicalmultipolar cell, dendrites emerge exist . For example , sensory neurons ( afferent) respond to 40 from all parts of the cell body ; variants are the touch , sound , light and numerous other stimuli affecting of the cerebral cortex and the , a class of cells of the sensory organs that then send signals to the GAGAergic neurons located in the cerebellar cortex . spinal cord and brain , while motor neurons ( efferent ) receive Even within the category of multipolar neurons, the size signals from the brain and spinal cord , cause muscle con - and shape of different cells vary greatly . Different types of tractions and affect glands . 45 multipolar cells account for nearly all of the distinguishable The typical neuron has four morphologically defined neuronal cell types , which number between 1 , 000 and regions: ( 1 ) the cell body ( also called the soma or perik - 10 , 000 . The morphological differences among multipolar aryon ) , ( 2 ) the dendrites , ( 3 ) the axon and ( 4 ) the presynaptic cells are due largely to variations in two features : the number terminals of the axon . Nerve cells generate active electrical and length of the dendrites, and the length of the axon . The signals , and each region has distinctive signaling functions . 50 number and extent of dendritic processes in a given cell The cell body is the metabolic center of the neuron . Three correlate with the number of synaptic contacts that other organelles are characteristic of the cell body : the nucleus, neurons make on that cell . For example , a spinal motor cell , which in neurons often is quite large ; the endoplasmic whose dendrites are moderate in both number and extent, reticulum , upon which membrane and secretory proteins are receives roughly 10 , 000 contacts, while the large dendritic synthesized ; and the Golgi apparatus , which carries out the 55 tree of the Purkinje cell of the cerebellum receives approxi processing of secretory and membrane components . The cell mately 150 , 000 contacts . body usually gives rise to several fine arborizing outgrowths The length of the axon reflects the signaling function of a or extensions called dendrites , which serve as the chief neuron . Neurons with long axons (“ Golgi type I cells” ) carry receptive apparatus for the neuron . The cell body also gives information from one brain region to another; they serve as rise to the axon , a tubular process that can extend consid - 60 projection or relay neurons . Neurons with short axons erable distances (up to 1 m in humans ) . (“ Golgi type II cells ” ) primarily process information within The axon constitutes the conducting unit of the neuron . a small, limited region of the brain . These nerve cells serve Axons lack ribosomes and therefore cannot synthesize pro - as local in various nuclei of the brain and in teins . Newly synthesized macromolecules are assembled reflex pathways . into organelles within the cell body and are moved along the 65 The movement of axons is determined by their growth axon to the presynaptic terminals by a process called axo - cones , expansions of the tip of the growing axon that plasmic transport. When severed from the cell body , the generate the mechanical force that pulls the axon forward . US 9 ,890 , 195 B2 The has a broad sheet - like extension ( lamelli cord and resembles the spinal cord in aspects of its organi podia ) which contain protrusions ( filopodia ) . The motility of Zation . The pons, which lies rostral to the medulla , contains growth cones is punctuated by cycles of protrusion , adhe a massive set of neurons that relay information from the sion , and contraction . Actin plays a major role in the cerebral hemispheres to the cerebellum . The cerebellum is mobility of this system . 5 not part of the brain stem , but because of its position dorsal The direction pursued by the growth cones of an out - to the pons, it is commonly grouped together with the pons . growing axon is influenced by a variety of cues that range The midbrain lies rostral to the pons , and is important in the from ( 1 ) simple differences in the texture and stickiness of control of eye movement. The midbrain also contains an the substrate , to (2 ) rather precise molecular cues from essential relay in the auditory pathway and several structures recognition molecules imbedded in the surface membrane of 10 critically involved in motor control of skeletal muscles . the cells over which the growth cone crawls , to ( 3 ) diffusible The diencephalon contains two key subdivisions : the gradients set up by a distant source . Further, guidepost cells , and the hypothalamus . The thalamus processes and which typically are other neurons , may assist in the guidance relays most of the information coming from the lower of neuronal axon growth . regions of the CNS en route to the cerebral cortex . The It is likely that the physical substrate over which an axon 15 hypothalamus is important for integration in the autonomic grows out contributes cues that guide the growth cone to its nervous system and for regulating hormonal secretion by the target. Substrates vary in adhesiveness, and that selective pituitary gland . adhesion can guide the direction of the outgrowing process . The cerebral hemispheres consist of the cerebral cortex Variations in the texture and shape of the available surfaces and the basal ganglia . Collectively termed the “ ” , on which processes grow may produce regional differences 20 these structures are concerned with perceptual, cognitive , in the adhesion between the growth cone and the substrate and higher motor functions . The cerebral cortex is further that determine the direction of growth . Environments with subdivided into four lobes : frontal, parietal, temporal and high levels of cell adhesion molecules (CAM ' s) create an occipital . Large regions of the cerebral cortex are committed ideal environment for axonal growth . Generally , it is to movement and sensation . Areas that are directly commit believed that this provides a " sticky ” surface along which 25 ted are called primary , secondary , and tertiary sensory or axons can grow . Examples of CAM ' s specific to neural motor areas . Surrounding the primary areas are higher order systems include the immunoglobulins N -CAM , neuroglial (secondary and tertiary ) sensory and motor areas . These CAM (NgCAM ) , TAG - 1 , MAG , and DCC . Extracellular areas process more complex aspects of a single sensory matrix adhesion molecules (ECMs ) also provide a sticky modality or motor function than primary areas . The purpose substrate along which axons can grow . Examples of ECMs 30 of the higher order sensory areas is to achieve greater include laminin , fibronectin , tenascin , and perlecan . Some analysis and integration of information coming from the ECMs are surface -bound to cells and thus act as short range primary sensory areas . In contrast , the flow of information attractants or repellents . Others are diffusible ligands and from the motor areas is in the opposite direction . Higher thus can have long range effects . order motor areas distill complex information about a poten In addition to adhesiveness, growth cones also might also 35 tial motor act and relay it to the primary motor cortex , which sense more specific recognition molecules. For example , is the site from which voluntary movement is initiated . specific receptors on the surface of outgrowing growth cones Peripheral Nervous System ( PNS ) might recognize molecules on the surface of cells forming The peripheral nervous system (PNS ) resides or extends the substrate . Alternatively , a signal molecule might be outside the CNS . The main function of the PNS is to connect secreted by a substrate cell and internalized by the outgrow - 40 the CNS to the limbs and organs . The PNS is divided by ing cell; the molecule then could act from within the second function into the somatic nervous system , the autonomic cell to influence the direction of neurite outgrowth . nervous system and the enteric nervous system . Nervous System The somatic nervous system is responsible for coordinat The nervous system is divided into two parts : the central ing the body movements , and also for receiving external nervous system (CNS ) , which consists of the brain and 45 stimuli . It regulates activities that are under conscious con spinal cord , and the peripheral nervous system (PNS ), which trol . consists of cranial and spinal nerves along with their asso - The autonomic nervous system (or autonomic motor ciated ganglia . system ) provides the innervation for the endocrine and ( CNS ) exocrine glands, for the viscera , and for smooth muscles in The CNS consists of six main regions : ( 1 ) the spinal cord ; 50 all organs of the body. The autonomic nervous system has ( 2 ) the medulla ; ( 3 ) the pons ; ( 4 ) the midbrain ; ( 5 ) the two major divisions: the sympathetic and parasympathetic . diencephalon ; and ( 6 ) the cerebral hemispheres. The sympathetic system often mediates the response of the The spinal cord , the most caudal part of the CNS , receives body to stress ; it speeds up heart rate , increase blood information from the skin , joints , and muscles in the trunk pressure , mobilizes the body ' s energy stores for emergency , and limbs, and it is the final way station for issuing com - 55 and prepares for action . In contrast , the parasympathetic mands for movement . In the spinal cord there is an orderly system acts to conserve the body ' s resources and restore arrangement of motor and sensory nucleic controlling the homeostasis ; it slows the heart , reduces blood pressure , and limbs and trunk . In addition to nuclei, the spinal cord prepares the body for relaxation and rest . The two divisions contains afferent pathways for sensory information to flow are segregated anatomically. The cell bodies that give rise to to the brain and efferent pathways for commands necessary 60 the sympathetic division lie in the thoracic and lumbar for motor control to descend from the brain to the motor regions of the spinal cord . The neurons that give rise to the neurons. The spinal cord also receives sensory information parasympathetic division lie above this region of the spinal from the internal organs and controls many autonomic cord in several brain stem nuclei associated with cranial functions. nerves, and below it in the sacral region of the spinal cord . The spinal cord continues rostrally as the brain stem , 65 The autonomic nuclei in the brain stem and spinal cord which comprises the medulla , the pons and the midbrain . contain neurons (preganglionic cells ) that send their axons to The medulla is the most direct rostral extension of the spinal synapse on a second set of neurons ( postganglionic cells ) US 9 ,890 , 195 B2 that lie in peripheral collections of nerve cell bodies ( auto via the synapse ). These influencesmay be mild , or they can nomic ganglia ) . the postganglionic cells in turn innervate b e drastic and cause degeneration of the affected neurons. viscera , glands , and smooth muscle . Transneuronal changes of various kinds are important in The main control center for the autonomic motor system explaining why a lesion at one site in the CNS can have is the hypothalamus , which also is critically involved in the 5 effects on sites distant to the lesion , sites that are distributed regulation of feeding and drinking. The hypothalamus sends according to the connections that the lesion interrupts . out descending fibers that regulate sympathetic and para Glial Cells sympathetic nuclei in the spinal cord and brain stem , axons In addition to neurons, contains glial cells that control the release of hormones by the anterior pituitary ( , , ependymal cells , Schwann gland , and axons that release hormones directly into the 10 cells and ) . Some of these cells play an important posterior pituitary gland . The hypothalamus receives infor role in healing. Certain types of supporting cells absorb the mation from many other structures, including higher levels cellular debris that results from neuronal injury by taking up of the motivational systems: the cerebral cortex and the and destroying ( phagocytosing ) toxic products of degenera reticular formation . tion , while other supporting cells sometimes can interfere The enteric nervous system controls the gastrointestinal 15 with healing if their proliferation blocks the restoration of system . The enteric nervous system is capable of autono - severed synaptic connections within the brain and spinal mous functions , such as the coordination of reflexes , and cord . Therefore , the healing processes that are activated in may contain as many as 100 ,000 ,000 neurons. The neurons the CNS by neuronal injury can be both helpful ( e . g . of the enteric nervous system are collected into two types of phagocytosis ) and troublesome ( e . g . blocked regeneration ) . ganglia : myenteric ( Auerbach ' s ) and submucosal (Meiss - 20 Two types of glial cells , astrocytes and oligodendrocytes , ner ' s ) plexuses. Myenteric plexuses are located between the vastly outnumber neurons . Astrocytes predominate in gray inner and outer layers of the muscularis externa . Submu - matter. They have small cell bodies ( 3 - 5 um ) that are packed cosal plexuses are located in the submucosa ( the layer of with bundles of glial filaments about 100 nm in diameter. dense irregular connective tissue that supports the mucosa ). Numerous processes radiate from the cell body in various In vertebrates, the enteric nervous system includes efferent 25 directions, and many of these come into close contact with neurons, afferent neurons, and interneurons , all of which blood vessels The term “ sclerosis ” often is used to describe make the enteric nervous system capable of carrying reflexes disease states , such as multiple sclerosis , that affect popu and acting as an integrating center in the absence of CNS lations of axons in the brain , and refers to the palpably hard input. scar of astrocytes that replaces phagocytosed debris result Nerve Injury and Disorders 30 ing from the disease process . Damage to nervous tissue is particularly serious because Oligodendrocytes, which form myelin in the CNS , pre most neurons in the adult mammalian CNS have withdrawn dominate in . They have smaller cell bodies ( 1 - 3 from the mitotic cycle and no longer are capable of cell u m in diameter ) and give off fewer processes than astro division . Consequently , any physical injury that causes cytes ; each process appears to participate in forming myelin neurons to die will not be followed by regeneration of cells 35 for a single axon . In the CNS , each con but will bring about a permanent change in the structure of tributes to the myelin sheath of several ( as many as 20 ) the nervous system . This structural change usually is accom - axons by means of its different processes . panied by long -lasting alterations in the functions of the Glial cells proliferate around chromatolytic neurons and affected areas. assume the appearance of phagocytes. The term " chroma The term “ axotomy” refers to the cutting or severing of a 40 tolysis ” ( and its various grammatical forms) is used herein neuron ’ s axon . Cutting an axon interrupts both rapid axonal to refer to reorganizational changes in the cell body of a transport and slower axoplasmic flow , the two mechanisms damaged neuron . Glial cells have been observed displacing that carry materials synthesized in the neuronal cell body to presynaptic terminals along the proximal dendrites and cell the axon terminals . The axon and the synaptic terminals bodies of axonotomized motor neurons . The pre - and post degenerate when deprived of their normal metabolic inter - 45 synaptic elements of the synapse appear to be pushed apart action with the cell body. The term “ anterograde ” or “ Walle - by the invading glial cells. Damaged neurons receive rian ” degeneration as used herein refers to degeneration of reduced synaptic inputs , and the evoked excitatory postsyn that part of the axon disconnected from the cell body which aptic potentials are smaller in amplitude , as if synapses on would be considered distal relative to the lesion . The term the cell body and proximal dendrites were removed by " retrograde ” degeneration refers to changes proximal to the 50 encroachment of glial cells . Even though somatic synapses lesion site in the part of the axon that remains connected to are displaced , chromatolysing motor neurons still can be the cell body . Retrograde changes are found quite frequently activated because remote synapses on their dendritic tree after axotomy ; in some instances they are severe and can that normally are ineffective begin to excite the cell . After result in death of the neuron . the normal input to the soma is removed , new trigger zones Synapses mediate not only electrical signals but also 55 develop on the cell body and along the axon . A reorganiza nutritive ( trophic ) interactions between neurons . Trophic t ion of this type may enable the cell to maintain normal factors are crucial for the normal maintenance of these cells . number of synapses . If appropriate connections with Like synaptic interactions , trophic interactions are thought muscles are established by the regenerating motor axons , to occur via a neuron ' s synaptic contacts. Deprived of its then the normal input to the cell body of the synaptic terminals , a neuron may shrink , atrophy or degen - 60 returns . erate . Therefore , if a bundle of axons in the CNS is severed , If a bundle of axons is cut, either by sectioning of a tract degenerative changes may be found not only in the damaged within the brain or by sectioning of a peripheral nerve , the neurons but also in neurons that receive synapses from the site where the lesion is located is termed the “ zone of damaged neurons . In some injuries , the presynaptic neurons trauma. ” The part of the axon still connected to the cell body that synapse on the damaged cells also are affected ( these 65 is the “ proximal segment, ” and the part isolated from the rest reactions are referred to as “ transsynpatic ” or “ transneu - of the cell is the distal segment. ” The cut ends of both parts ronal” meaning that they cross from one neuron to the next of the axon lose immediately after injury, but the US 9 ,890 , 195 B2 ends soon become sealed off by fusion of the axon mem - Neuroregeneration brane, retract from one another, and begin to swell. The The term “ neuroregeneration ” ( or " nerve regeneration " ) swollen reaction bulbs that result are formed largely by refers to the growth or repair of nervous tissues, cells or cell materials carried along the axon by axonal transport and products . Repair mechanisms may include , but are not axoplasmic flow . Mitochondria , vesicles , multivesicular 5 limited to , remyelination and generation of new neurons , bodies and much unidentified membranous material pile up g lia , axons, myelin and synapses . in the sealed end of each axon segment. Although both the While the PNS has an intrinsic ability for repair and proximal and the distal segments swell (because fast axonal regeneration , the CNS is , for the most part , incapable of transport occurs in two directions ), the proximal end swells self -repair and regeneration . Currently, there is no treatment more , because newly synthesized , microtu - 10 for recovering human nerve function after injury to the CNS . bules , and microfilaments , traveling by slow axoplasmic Neuroregeneration in the CNS flow , come from the cell body only . Unlike PNS injury, injury to the CNS is not followed by Types of Nerve Injury extensive regeneration . Several factors may contribute to Nerve injury may be classified into three types : this inactivity . The environment within the CNS , especially neurapraxia ; axonotmesis ; and neurtmesis . 15 following trauma, hinders the repair of myelin and neurons , In neurapraxia , the least severe form of nerve injury with and , generally , growth factors are not expressed or re complete recovery , the actual structure of the nerve remains expressed ( for example , the extracellular matrix lacks lami intact, but there is an interruption in conduction of the nins) . Additionally , the axons themselves lose the potential impulse down the nerve fiber. Most commonly, this involves for growth with age . Further , a distal segment in the CNS compression of the nerve or disruption to the blood supply 20 degenerates slower than in the PNS ; the slower removal of ( ischemia ). There is a temporary loss of function which is myelin and axonal debris contributes to the inhibitory envi reversible within hours to months of the injury ( the average ronment. All these factors contribute to the formation of is 6 - 8 weeks ) . Wallerian degeneration ( a process that results what is known as a glial scar, across which axons cannot when a nerve fiber is cut or crushed in which the part of the grow . Several families of molecules are released that pro axon separated from the neuron ' s cell nucleus degenerates ) 25 mote and drive glial scar formation . Transforming growth does not occur, so recovery does not involve actual regen - factors B - 1 and B - 2 , interleukins, and cytokines all are eration . There frequently is greater involvement of motor believed to play a role in the initiation of scar formation . The than sensory function with autonomic function being further produce factors that inhibit remyelination and retained . axon repair , such as , for example , NOGO and NI- 35 . Axonotmesis , a more severe nerve injury with disruption 30 At a zone of trauma in the CNS, the axon and myelin of the neuronal axon , but with maintenance of the myelin sheath undergo rapid local degeneration . Because blood sheath , results in loss of the relative continuity of the axon vessels usually are interrupted by a lesion , macrophages and its covering of myelin , but preservation of the connec - from the general circulation can enter the area and phago tive tissue framework of the nerve (i . e , the encapsulating cytose axonal debris . Glial cells ( astrocytes and microglia ) tissue, the and , are preserved ) lead - 35 also proliferate and act as phagocytes . In the CNS , however, ing to Wallerian degeneration . Loss in both motor and the proliferation of fibrous astrocytes leads to the formation sensory spines is more complete with axonotmesis than with of a glial scar around the zone of trauma. Scarring can block neurapraxia , and recovery occurs only through regenerations the course taken by regenerating axons and establish an of the axons. There usually is an element of retrograde effective barrier against the reformation of central connec proximal degeneration of the axon , and for regeneration to 40 tions. occur, this loss first must be overcome. The regeneration Degeneration spreads in both directions along the axon fibers must cross the injury site , and regeneration through from the zone of trauma, but only for a short distance in the the proximal or retrograde area of degeneration may require proximal segment, usually up to the point of origin of the several weeks ; then the neuritic tip progresses down the first axon collateral. After 2 - 3 days , a retrograde reaction is distal site . The proximal lesion may grow distally as fast as 45 seen in the cell body . If the entire cell body dies , then 2 mm to 3 mm per day and the distal lesion as slowly as 1 . 5 degeneration spreads from the ( the conical area mm per day. Regeneration may take several weeks or years. of origin of the axon from the nerve cell body ) down along Neurotmesis , the most severe lesion with potential of the remainder of the proximal segment. In the distal seg recovery , occurs on severe contusion , stretch , laceration or ment, outside the zone of trauma, degeneration first appears local anesthetic toxicity . Not only the axon but also the 50 in the about 1 day after the occurrence of the encapsulating connective tissue lose their connectivity . The lesion . In approximately 2 weeks , the synapses formed by last ( extreme) degree of neurotmesis is transection . Most the distal segment degenerate completely ( terminal degen neurotmetic injuries do not produce gross loss of continuity eration ) . Degeneration of the distal axon itself takes place of the nerve but rather internal disruption of the architecture over a period of 1 - 2 months (Wallerian degeneration ) . of the nerve sufficient to involve the perineurium one of the 55 Eventually , cells that are either pre - or postsynaptic to the supporting structures of peripheral nerve trunks , consisting injured neuron also may be affected ( “ transneuronal degen of layers off lattened cells and collagenous connective tissue , eration ” ) . Thus , in anterograde transneuronal degradation , which surround the nerve fasciculi and form the major neurons deprived of major input from axons that have been diffusion barrier within the nerve ] and [ the destroyed may atrophy . In retrograde transneuronal degra innermost connective tissue supportive structure of nerve 60 dation , similar changes may occur in neurons that have lost trunks that surrounds both myelinated and unmyelinated the main recipient of their outflow . nerve fibers, consisting principally of ground substance, The axon terminal is very sensitive to interruption of collagen , and fibroblasts ] as well as axons and their cover contact with the parent cell body . If the axon of a motor ing . There is a complete loss of motor , sensory and auto - neuron to a skeletal muscle is severed by cutting a peripheral nomic function . If the nerve has been completely divided , 65 nerve , within a matter of hours degenerative changes begin axonal regeneration causes a neuroma ( swelling or to occur at the presynaptic terminals of the motor axon pseudoneuroma) to form in the proximal stump. because the maintenance of its integrity is critically depen US 9 ,890 , 195 B2 10 dent on fast axonal transport . Synaptic transmission fails upon the nature of the injury , the proximal segment of a soon after the axon is cut, even before the first morphologi- severed axon can regenerate and reconnect to its previous cal signs of degeneration become evident in the synaptic synaptic sites as long as its cell body remains alive . The terminal. The onset of transmission failure is very rapid if regenerating axons run along the connective tissue sheath , the axon is cut close to the synaptic terminal region , and 5 which acts as a conduit leading the growing axons back to slower if the axon is cut close to the cell body . This indicates the peripheral target. Conversely , if the centrally directed that axonal transport continues for some time in the distal branches of cells are cut, the glial scar segment until the entire axon is depleted of metabolic that forms around the degenerating axons in the dorsal products required for synaptic transmission . aspect of the spinal cord prevents any axons that might The degenerative changes that occur in the synaptic 10 regenerate from reaching their central targets . terminal itself are similar to the changes that take place in There are two major ways in which the cell bodies of degenerating synapses in the CNS . Within one day after different classes of neurons respond to axotomy. After an axotomy, the terminal and its mitochondria begin to swell . In axon is severed , some neurons undergo distinctive regen some cases the terminal becomes filled with swirls of erative changes as they prepare metabolically for the neurofilaments surrounding a central packet of disrupted 15 regrowth of a new axon . For example , cutting the peripheral mitochondria . Alternatively , the terminalmay become filled axon of a dorsal root ganglion cell or a spinal motor neuron with more homogeneous electron - dense products of degen - causes characteristic changes in the parent neuron within 2 - 3 eration . After 6 or 7 days the terminal is pushed away from days . The cell body first begins to swell ( it may double in its contacts with postsynaptic neurons by invading glial size ). The nucleus moves to an eccentric position , usually cells . At the neuromuscular synapse , eventually the 20 opposite the axon hillock , and also begins to swell. Finally , Schwann cells around the synaptic terminal of the motor the rough endoplasmic reticulum ( ER ) breaks apart and axon de - differentiate and proliferate to form phagocytes that moves to the periphery of the swollen cell body . For 1 - 3 absorb the degenerating terminal . Soon afterward , the whole weeks, the number of free polysomes in the cell body, the distal axon breaks up into short , beaded segments that then total amount of protein , and RNA synthesis in the nucleus are phagocytosed by Schwann cells . 25 increases ( chromatolysis ) , suggesting that a massive synthe About one week after the initial degenerative changes sis of proteins necessary for regenerating the severed parts appear in the axon terminal, degeneration begins in the of the axon occurs . If the proper connections are restored entire distal axon . The myelin sheath draws away from the after regeneration of the axon , this buildup ceases and the axon and breaks apart. The axon swells and then becomes cell body usually regains its normal appearance . If the beaded . Neurofilaments and neurotubules ( collectively neu - 30 proper connections are not restored , the cell will atrophy or rofibrils ) soon fill the axon . Fragments of the axon and the degenerate totally . The age of the animal, the site of the myelin sheath are absorbed by local phagocytes derived lesion , and the nature of the injury are important consider from the glial cell population in the CNS or from Schwann ations in judging the potential for functional recovery after cells in the PNS. In the CNS , macrophages from the generalnerve section . circulation do not absorb the debris produced by Wallerian 35 Neuroprotection degeneration , as they do in the zone of trauma. Neuroprotection refers to the mechanisms and /or strate Neuroregeneration in the PNS gies used to guard or defend against neuronal injury or Neuroregeneration in the PNS occurs to a significant degeneration in the CNS following acute disorders ( such as, degree . Injury to the PNS immediately elicits the migration for example , stroke, nervous system injury or trauma ) or as of phagocytic cells , Schwann cells , and macrophages to the 40 a result of chronic neurodegenerative diseases (such as , for lesion site in order to clear away debris, such as damaged example , Parkinson 's disease , Alzheimer ' s disease ,Multiple tissue . After injury , the proximal end swells and experiences Sclerosis ) . Neuroprotectives (products or compounds with some retrograde degeneration , but once the debris is cleared , neuroprotective effects ) can be grouped into several catego it begins to sprout axons and the presence of growth cones ries including, but not limited to , the following: free radical can be detected . The proximal axons are able to regrow as 45 scavengers ; anti - excitotoxic agents ; apoptosis inhibitors ; long as the cell body is intact, and they have made contact anti -inflammatory agents ; neurotrophic factors ; metal ion with the neurolemmocytes in the endoneurial channel. chelators ; and ion channel modulators . Human axon growth rates can reach 2 mm per day in small Free Radical Scavengers nerves and 5 mm per day in large nerves. The distal segment, A free radical is a highly reactive and usually short -lived however, experiences Wallerian degeneration within hours 50 molecular fragment with one or more unpaired electrons . of the injury ; the axons and myelin degenerate , but the Free radicals are highly chemically reactive molecules . endoneurium ( a delicate connective tissue around individual Because a free radical needs to extract a second electron nerve fibers in a nerve bundle ) remains . In the later stages of from a neighboring molecule to pair its single electron , it regeneration , the remaining endoneurial tube directs axon often reacts with other molecules , which initiates the for growth back to the correct targets. During Wallerian degen - 55 mation of many more free radical species in a self - propa eration , Schwann cells grow in ordered columns along the gating chain reaction . This ability to be self -propagating endoneurial tube , creating a band of Bungner (boB ) that makes free radicals highly toxic to living organisms. protects and preserves the endoneurial channel. Also , mac Reactive oxygen species (“ ROS ” ) , such as free radicals rophages and Schwann cells release neurotrophic factors and peroxides , represent a class of molecules that are that enhance re - growth . 60 derived from the metabolism of oxygen and exist inherently The sequence of axonal degeneration in the PNS differs in all aerobic organisms. The term " oxygen radicals ” as used from the sequences that occurs in the CNS . If the periph - herein refers to any oxygen species that carries an unpaired erally directed process of a dorsal root ganglion cell is cut, electron ( except free oxygen ). The transfer of electrons to or if a motor axon is cut, then the distal segment of the oxygen also may lead to the production of toxic free radical severed axon will degenerate . However , the connective 65 species . The best documented of these is the superoxide tissue sheath that surrounds the nerve in which the severed radical. Oxygen radicals , such as the hydroxyl radical axon ran may remain intact. In many instances, depending (OH - ) and the superoxide ion (O2 -) are very powerful US 9 ,890 , 195 B2 12 oxidizing agents that cause structural damage to proteins, on caspase proteases ( a class of cysteine proteases) and lipids and nucleic acids . The free radical superoxide anion , others that are caspase independent . It can be triggered by a product of normal cellular metabolism , is produced mainly many different cellular stimuli, including cell surface recep in mitochondria because of incomplete reduction of oxygen . tors, mitochondrial response to stress, and cytotoxic T cells , The superoxide radical, although unreactive compared with 5 resulting in activation of apoptotic signaling pathways many other radicals , may be converted by biological sys - The caspases involved in apoptosis convey the apoptotic tems into other more reactive species , such as peroxyl signal in a proteolytic cascade , with caspases cleaving and (ROO — ), alkoxyl (RO ) and hydroxyl (OH - ) radicals. activating other caspases that then degrade other cellular Oxidative injury may lead to widespread biochemical targets that lead to cell death . The caspases at the upper end damage within the cell . The molecular mechanisms respon - 10 of the cascade include caspase - 8 and caspase - 9 . Caspase - 8 sible for this damage are complex . For example , free radi- is the initial caspase involved in response to receptors with cals may damage intracellular macromolecules , such as a death domain (DD ) like Fas. nucleic acids ( e . g ., DNA and RNA ) , proteins , and lipids . Receptors in the TNF receptor family are associated with Free radical damage to cellular proteins may lead to loss of the induction of apoptosis , as well as inflammatory signal enzymatic function and cell death . Free radical damage to 15 ing . The Fas receptor (CD95 ) mediates apoptotic signaling DNA may cause problems in replication or transcription , by Fas - ligand expressed on the surface of other cells . The leading to cell death or uncontrolled cell growth . Free radical damage to cell membrane lipids may cause1. Free the Fas- FasL interaction plays an important role in the immune damaged membranes to lose their ability to transport oxy system and lack of this system leads to autoimmunity , gen , nutrients or water to cells . indicating that Fas- mediated apoptosis removes self -reactive Free radical scavengers with a neuroprotectivee effect -20 lymphocytes . Fas signaling also is involved in immune include, but are not limited to , 3 -methyl - 1 -phenyl - 2 -pyra surveillance to remove transformed cells and virus infected zolin - 5 - one ( edaravone ) , and a - phenyl- n - tert- butyl- nitrone cells . Binding of Fas to oligimerized FasL on another cell (PBN ) , N -tert - butyl - ( 2 - sulfophenyl) - nitrone ( S -PBN ) . activates apoptotic signaling through a cytoplasmic domain Anti - Excitotoxic Agents termed the death domain (DD ) that interacts with signaling Excitatory acidic amino acids (EAAS ) constitute the 25 adaptors including FAF , FADD and DAX to activate the major group of exitatory neurotransmitters in the mamma caspase proteolytic cascade . Caspase - 8 and caspase - 10 first lian brain . They serve a multitude of defined physiological are activated to then cleave and activate downstream cas functions, which are the subject of several studies . It gen pases and a variety of cellular substrates that lead to cell erally is believed that EAAS play a critical role in neuronal death . development, learning processes and motor control. Their 30 Mitochondria participate in apoptotic signaling pathways actions are mediated by membrane receptors, which are through the release of mitochondrial proteins into the cyto classically divided into three pharmacologically distinct plasm . Cytochrome c , a key protein in electron transport , is subtypes : N -methyl - D - aspartate (NMDA ) , quisqualate , and released from mitochondria in response to apoptotic signals , kainate receptors . Further, EAAS can produce selective and activates Apaf- 1 , a protease released from mitochondria . Activated Apaf- 1 activates caspase - 9 and the rest of the "“ excitotoxicityaxon - sparing ” ” refersneuronal to the lesions pathological in the processCNS. Theby which term 35 caspase pathway . Smac /DIABLO is released from mito nerve cells are damaged and killed by glutamate and similar chondria and inhibits IAP proteins that normally interact substances . This occurs when receptors for the excitatory with caspase - 9 to inhibit apoptosis . Apoptosis regulation by neurotransmitter glutamate ( glutamate receptors (NMDA Bcl- 2 family proteins occurs as family members form com receptors , a - amino - 3 - hydroxy - 5 -methyl - 4 - isoxazolepropi plexes that enter the mitochondrial membrane, regulating onic acid receptor (AMPA or quisqualate receptor ) ) ) are 40 the release of cytochrome c and other proteins . TNF family overactivated . Excitotoxins , such as, but not limited to , receptors that cause apoptosis directly activate the caspase NMDA and kainic acid , which bind to these receptors , and cascade, but can also activate Bid , a Bcl - 2 family member, pathologically high levels of glutamate , can cause excito which activates mitochondria -mediated apoptosis. Bax , toxicity by allowing high levels of calcium ions ( Ca2 + ) to another Bcl- 2 family member, is activated by this pathway enter the cell . Ca2 + influx into cells activates a number of 45 to localize to the mitochondrial membrane and increase its enzymes, including , but not limited to , phospholipases , permeability , releasing cytochrome c and other mitochon endonucleases, and proteases, such as, for example, calpain . drial proteins. Bcl- 2 and Bcl- xL prevent pore formation , These enzymes go on to damage cell structures including , blocking apoptosis . Like cytochrome c , AIF (apoptosis but not limited to , components of the cytoskeleton , the cell inducing factor) is a protein found in mitochondria that is membrane , and DNA . Anti -excitotoxic agents include , but 50 released from mitochondria by apoptotic stimuli . While not are limited to , NMDA antagonists , phencyclidine , ket cytochrome C is linked to caspase -dependent apoptotic amine , ( + ) - SKF 10 , 047 , pentazocine , d - aminophosphon signaling , AIF release stimulates caspase -independent apop ovalerate , d - aminophosphonoheptanoate , d - a -aminoadi tosis , moving into the nucleus where it binds DNA . DNA pate , OH -quinoxaline carboxylate , kynurenate . ( + ) -cis - 2 . 3 - binding by AIF stimulates chromatin condensation , and piperidine dicarboxylate, secobarbital, amobarbital and 55 DNA fragmentation , perhaps through recruitment of nucle pentobarbital. rbital and 55 ases. Apoptosis Inhibitors The mitochondrial stress pathway begins with the release The terms “ apoptosis ” or “ programmed cell death ” refer of cytochrome c from mitochondria , which then interacts to a highly regulated and active process that contributes to with Apaf- 1 , causing self- cleavage and activation of cas biologic homeostasis comprised of a series of biochemical pase - 9 . Caspase - 3 , - 6 and - 7 are downstream caspases that events that lead to a variety of morphological changes 60 are activated by the upstream proteases and act themselves including blebbing , changes to the cell membrane, such as to cleave cellular targets . loss of membrane asymmetry and attachment, cell shrink Granzyme B and perforin proteins released by cytotoxic age , nuclear fragmentation , chromatin condensation , and T cells induce apoptosis in target cells , forming transmem chromosomal DNA fragmentation , without damaging the brane pores, and triggering apoptosis , perhaps through organism . 65 cleavage of caspases , although caspase- independent mecha Apoptotic cell death is induced by many different factors nisms of Granzyme B mediated apoptosis have been sug and involves numerous signaling pathways , some dependent gested . US 9 ,890 , 195 B2 13 14 Fragmentation of the nuclear genome by multiple nucle - flammatory response includes activation of microglia , resi ases activated by apoptotic signaling pathways to create a dent tissue macrophages in the CNS and the principle nucleosomal ladder is a cellular response characteristic of mediators of neuroinflammation , resulting in phagocytosis apoptosis . One nuclease involved in apoptosis is DNA and the release of inflammatory mediators such as cytokines fragmentation factor (DFF ) , a caspase - activated DNAse 5 and chemokines . Chronic neuroinflammation includes long (CAD ) . DFF /CAD is activated through cleavage of its standing activation of microglia and subsequent sustained associated inhibitor ICAD by caspases proteases during release of inflammatory mediators , which perpetuate the apoptosis . DFF /CAD interacts with chromatin components inflammatory cycle , activating additionalmicroglia , promot such as topoisomerase II and histone H1 to condense chro - ing their proliferation , and resulting in further release of matin structure and perhaps recruit CAD to chromatin . 10 inflammatory factors . Several anti - inflammatory agents are Another apoptosis activated protease is endonuclease G generally believed to provide a neuroprotective effect (EndoG ) . EndoG is encoded in the nuclear genome but is including, but not limited to , non -steroidal anti- inflamma localized to mitochondria in normal cells . EndoG may play tory drugs (NSAIDS ) , such as , but not limited to , aspirin , a role in the replication of the mitochondrial genome, as well ibuprofen , indomethacin , sulindac , and flurbiprofen ; estro as in apoptosis . Apoptotic signaling causes the release of 15 gen ; and peroxisome proliferator - activated receptor - y EndoG from mitochondria . The EndoG and DFF /CAD path - (PPARs ) agonists , such as, but not limited to , thiazolidin ways are independent since the EndoG pathway still occurs ediones (TZDs ) . in cells lacking DFF . Neurotrophic Factors Hypoxia , as well as hypoxia followed by reoxygenation Neurotrophic factors are important regulators of the can trigger cytochrome c release and apoptosis . Glycogen 20 development and maintenance of vertebrate nervous sys synthase kinase (GSK - 3 ) a serine - threonine kinase ubiqui - tems. Neurotrophins are a unique family of polypeptide tously expressed in most cell types , appears to mediate or growth factors that influence the proliferation , differentia potentiate apoptosis due to many stimuli that activate the tion , survival, and death of neuronal and nonneuronal cells . mitochondrial cell death pathway . Loberg , R D , et al ., J . The effects of neurotrophins depend upon their level of Biol. Chem . 277 (44 ) : 41667 -673 ( 2002 ). It has been dem - 25 availability , their binding affinity to transmembrane recep onstrated to induce caspase 3 activation and to activate the tors , and the downstream signaling cascades that are stimu proapoptotic tumor suppressor gene p53 . It also has been lated after receptor activation . Neurotrophins have multiple suggested that GSK - 3 promotes activation and translocation roles in the adult nervous system including, but not limited of the proapoptotic Bcl - 2 family member , Bax , which , upon to , regulating synaptic connections and synapse structure , agregation and mitochondrial localization , induces 30 neurotransmitter release and potentiation , mechanosensa cytochrome c release . Akt is a critical regulator ofGSK - 3 , tion , and pain and synaptic plasticity . and phosphorylation and inactivation of GSK - 3 may medi Many growth factors and neurotrophins can promote ate some of the antiapoptotic effects of Akt. neuronal survival. These factors can activate several intra It generally is believed that apoptosis contributes to cellular signaling transduction systems including , but not neuronal cell death in a variety of neurodegenerative con - 35 limited to , the extracellular signal- regulated kinase ( ERK ) texts . Activation of cysteine protease caspase - 3 appears to be and the phosphatidyl - inositol - 3 - OH kinase ( PI 3 - kinase ) a key event in the execution of apoptosis in the CNS. pathways. Studies have reported that activation of the PI Caspase - 3 activation has been observed in stroke , spinal 3 -kinase pathway is required for ( 1 ) NGF -mediated survival cord trauma, head injury and Alzheimer ' s disease . Some of ( a ) the rat pheochromocytoma cell line PC12 (Greene and studies have shown that peptide -based caspase inhibitors can 40 Tischler, 1976 ) (an in vitro cell culture system for studying prevent neuronal loss in animal models of head injury and the mechanism of NGF action ) and ( b ) rat superiorcervical stroke . Further , failed caspase inhibition may have a role in ganglion (SCG ) neurons ; ( 2 ) insulin - like growth factor - 1 spinal muscular atrophy (SMA ) ( a hereditary neurodegen mediated survival of (a ) cerebellar granule neurons, (b ) erative disorder) . In severe SMA , the neuronal specific oligodendrocytes , and ( c ) PC12 cells; and ( 3 ) for membrane inhibitor of apoptosis ( IAP ) family member known as NAIP 45 depolarization -mediated survival of cerebellar granule neu often is dysfunctional due to missense and truncation muta - rons . Neuroprotective neurotrophic factors include , but are tions . IAPs such as NAIP potently block the enzymatic not limited to , brain - derived neurotrophic factor ( BDNF) , activity of group II caspases ( 3 and 7 ) ; NAIP mutations may nerve - growth factor (NGF ) , neurotrophins 3 and 4 / 5 , glial permit unopposed developmental apoptosis to occur in sen derived neurotrophic factor (GDNF ) , and ciliary neuro sory and motor systems resulting in lethal muscular atrophy 50 trophic factor (CNTF ) . ( see , for example , Robertson , G . S . , et al ., Brain Pathology. Metal Ion Chelators 2006 . 10 ( 2 ) :283 - 292 ) . Neuroprotective apoptosis inhibitors Metal ions are associated with metabolic processes ( such include , but are not limited to , boc - aspartyl( Ome ) - fluorom - as, for example , protein aggregation and oxidative stress ) ethylketone , erythropoietin , and (R , S ) - ( { (2S ) - 2 - [ 5 - tert - bu - that are involved in several neurodegenerative disorders. tyl- 3 - { [ ( 4 -methyl - 1 , 2 , 5 -oxadiazol - 3 -yl ) methyl ) amino } - 2 - 55 Several chelators have been studied for their potential in the oxopyrazin - 1 ( 2H ) - yl] butanoyl } amino ) - 5 - [ hexyl( methyl ) treatment of neurodegenerative diseases including, but not amino ] - 4 -oxopentanoic acid bis - hydrochloride (M826 ) . limited to , (1 ) hexadentate chelators , such as , for example , Anti- Inflammatory Agents desferrioxamine , and a synthetic amino - carboxylate ligand A sustained inflammatory reaction is present in acute (DP - 109 ); (2 ) tridentate chelators , such as, for example , neurodegenerative disorders ( such as , for example , stroke ) 60 isonicotinoyl picolinoyl hydrazine; and ( 3 ) bidentate chela and chronic neurodegenerative disorders ( such as , for tors , such as , for example , bathocuproine, feralex , and example, Alzheimer ' s disease , Parkinson ' s disease and mul - 8 -hydroxyquinoline analogues . tiple sclerosis ) . Inflammation , which is fostered by both One of the dominant properties of any therapeutic chela residential glial cells and blood - circulating cells that infil - tor is metal selectivity , typically a high selectivity being trate the diseased brain , probably starts as a time- and 65 required (as with , for example , the treatment of iron over site - specific defense mechanism that could later evolve into load associated with B - thalassaemia , where ligands with a a destructive and uncontrolled reaction . An acute neuroin - high selectivity for iron over copper and zinc are essential, US 9 ,890 , 195 B2 15 since chelation therapy is maintained for life ). Unfortu - burning, while the loss of sensation often is compared to the nately, the identity of the putative toxic metal is not always feeling of wearing a thin stocking or glove . In many cases, firmly established with many proposed treatments of neu - peripheral neuropathy symptoms , when caused by a treat rodegenerative diseases by chelation therapy . For example , able underlying condition , improve with time. Medications in Alzheimer ' s Disease , for instance , iron , copper and zinc 5 initially designed to treat other conditions, such as epilepsy all have been associated with the progression of the disease . and depression , often are used to reduce the painful symp Although there are clear guidelines for the design of iron toms of peripheral neuropathy. selective chelating agents (Liu & Hider , 2002 ) , no clear guidelines exist for the design of copper and zinc selective Autonomic Peripheral Neuropathy chelating agents . Furthermore, because of the need for ready 10 Autonomic neuropathy is a form of peripheral neuropathy permeation of the blood -brain barrier (BBB ), the size of that involves damage to the nerves that run through a part of useful chelators generally is limited to less than 300 Da , the PNS . It is a group of symptoms, not a specific disease , thereby excluding hexadentate ligands and seriously limit and has many causes. Symptoms occur when there is dam ing the potential for the design of selective copper( II ) and age to nerves that regulate vital functions, including heart zinc ( II ) chelators . Any agent that binds copper ( II) tightly 15 muscle , smooth muscles, those that regulate blood pressure , also will bind iron ( II ) , zinc ( II ), nickel ( II ), cobalt( II ) and heart rate , bowel and bladder emptying , digestion , and other manganese ( II ) , thereby causing a potential toxic insult to body functions . Autonomic neuropathy causes changes in most cell types (Liu & Hider, 2002 ). This limitation is a digestion , bowel and bladder function , sexual response , major issue for the design of chelators potentially useful for perspiration , can affect nerves in the lungs and eyes, and treating neurodegeneration . 20 may cause hypoglycemia unawareness , a condition in which Ion Channel Modulators patients no longer experience the warning symptoms of low Ion channels are pore - forming proteins that regulate the blood glucose levels. Damage to the autonomic nerves also cell potential across the plasma membrane of all living cells ; affects the function of areas connected to the problem nerve . ion channels allow a flow of ions down their electrochemical For example , damage to the nerves of the gastrointestinal gradient, i . e ., from high concentration to low concentration . 25 tract makes it harder to move food during digestion ( de Ion channels are prominent components of the nervous creased gastric motility ) . system since “ voltage - activated ” channels underlie the CNS Nerve Degeneration nerve impulse , and “ transmitter -activated ” channels mediate D amage to neurons of CNS may lead to progressive conduction across the synapses . There are numerous types of degenerative diseases . ion channels that can be classified by gating (meaning by 30 For example , Alzheimer ' s disease (AD ) , a progressive , what opens and closes the channel) including ( 1 ) voltage - degenerative brain disease that affects memory , thinking , gated ( ion channels that are reactive to membrane potential) ; and behavior , is characterized by loss of neurons and syn ( 2 ) ligand - gated ( ionotropic receptors that are reactive to apses in the cerebral cortex and certain subcortical regions, specific ligand molecules ); ( 3 ) ion gated ( those channels which results in gross atrophy of the affected regions, reactive to ions such as CI, K + , Na+ , Ca2 + ) and ( 4 ) other 35 including degeneration in the temporal lobe and parietal gating ( those reactive to , for example , second messengers ) . lobe, and parts of the frontal cortex and cingulate gyms. Several ion channel modulators with neuroprotective effects Both amyloid plaques and neurofibrillary tangles , which are include, but not limited to , arachidonic acid , dantrolene, aggregates of the microtubule - associated protein tau , which tetrodotoxin , polyamines , and estradiol. has become hyperphosphorylated and accumulates inside Nerve Damage and Neuropathies 40 the cells , are apparent. Although many older individuals Neuron injury may result in several types of neuropathy. develop some plaques and tangles as a consequence of Diabetic Neuropathies aging , the brains of AD patients have a greater number of Diabetic neuropathies are a family of nerve disorders them in specific brain regions , such as the temporal lobe . caused by diabetes. Patients with diabetes may, over time, Amyotrophic Lateral Sclerosis develop nerve damage throughout the body , while others 45 Amyotrophic lateral sclerosis ( ALS ) belongs to a class of may present no symptoms. Symptoms include pain , tingling, disorders known as motor neuron disorders in which the or numbness , in the hands, arms, feet , and legs. Nerve motor neurons located in the brain , brainstem and spinal problems can occur in every organ system , including the cord that serve as the controlling units and are vital for digestive tract, heart , and sex organs . Proximal neuropathy communication links between the nervous system and the results in pain in the thighs , hips , or buttocks and leads to 50 voluntary muscles of the body are affected . The loss of these weakness in the legs , and focal neuropathy results in the cells causes the muscles under their control to weaken and sudden weakness of one nerve or a group of nerves , causing waste away , leading to paralysis . It usually is fatal within muscle weakness or pain . five years of diagnosis . There is no cure for ALS , nor is there About 60 % - 70 % of patients with diabetes have some a proven therapy that will prevent or reverse its course . ALS form of neuropathy. The risk rises with age and longer 55 affects 30 , 000 U . S . residents with about 5 , 000 new cases duration of diabetes . The highest rates of neuropathy are occurring in the U . S . each year . In about 10 % of cases, ALS among patients who have had diabetes for at least 25 years . is caused by a genetic defect. In other cases , the cause of the Diabetic neuropathies also appear to be more common in nerve degeneration is unknown . patients who have problems controlling their blood glucose , Parkinson ' s Disease those with high levels of blood fat and blood pressure , and 60 Parkinson ' s disease is a progressive disorder of the brain those who are overweight . in which the nerve cells in the part of the brain that controls Peripheral Neuropathy muscle movement gradually are destroyed . Symptoms Peripheral neuropathy, the most common type of diabetic include tremor and difficulty with walking , movement , and neuropathy , also can result from traumatic injuries , infec - coordination . The exact reason that the cells of the brain tions, metabolic disorders and exposure to toxins . In its most 65 waste away is unknown . The disorder may affect one or both common form , it causes pain and numbness in a subject' s sides of the body , with varying degrees of loss of function . hands and feet. The pain typically is described as tingling or The disease affects approximately 2 of every 1 ,000 people , US 9 ,890 , 195 B2 17 18 both men and women , and most often develops after age 50 . W and F , or is an aliphatic amino acid ; X3 is selected from It may occur in younger adults , but is seen rarely in children . the group consisting of V , L , I , A , G , Q , N , S , T and C , or Spinal Cord Injury is an aliphatic amino acid ; X4 is selected from the group Spinal cord injury (SCI ) involves damage to the nerves consisting of Q , N , H , R and K ; X5 is selected from the within the spinal canal; most SCIs are caused by trauma to 5 group consisting of Q and N ; X6 is selected from the group the vertebral column , thereby affecting the spinal cord ' s consisting of C , A , G , L , V , I , M , Y , W and F or is an aliphatic ability to send and receive messages from the brain to the amino acid ; X7 is selected from the group consisting of S , body ' s systems that control sensory , motor and autonomic A , C , T and G or is an aliphatic amino acid ; X8 is selected function below the level of injury . Causes of paralysis from the group consisting of V , L , I and M ; X9 is absent or include stroke , post - polio syndrome, cerebral palsy , neuro - 10 is any amino acid ; X10 is absent or is any amino acid ; fibromatosis , traumatic brain injury , spinal cord injury , mul- wherein at least one of the following is true : ( a ) X3 is N and tiple sclerosis , and unspecified birth defect. Various types of X7 is not G ; ( b ) X7 is G and X3 is not N ; ( c ) X2 is not L ; accidents accounted for the great majority of SCI. ( d ) X4 is not R ; (e ) X5 is not Q ; (f ) X6 is not L ; (g ) X8 is The cost of living with spinal cord injury , which can be not V ; (h ) X10 is absent; ( i ) X9 and X10 are absent; wherein considerable , varies greatly depending on the severity of the 15 the composition enhances neurite outgrowth ; is neuropro injury . Average yearly expenses can range from $ 228 ,566 to tective , or enhances neuroregeneration following neural $ 775 , 567 in the first year. The estimated lifetime costs due injury. According to one embodiment, X2 , X3 , X6 and X7 to SCI can range from $ 691 , 843 to over $ 3 million for a 25 is any aliphatic amino acid . According to another embodi year old . Further , 87. 9 % of all SCI individuals are dis ment, X4 is R , X5 is Q and /or X8 is V . According to another charged from hospitals to private homes. 20 embodiment, X3 is selected from the group consisting of V , Generally , clinical treatments for nerve injury are lacking, L , I , A , G , Q and N . According to another embodiment, X6 with any nerve regeneration being modest at best . Nerve is selected from the group consisting of C , A , G , L , V , I , M , autografting (or autologous nerve grafting ) has been used to Y , W and F . According to another embodiment, X7 is treat large lesion gaps in the PNS . The procedure involves selected from the group consisting of S , A , C , T and G . transplanting nerve segments from a donor site within a 25 According to another embodiment, at least one of Z1 and Z2 subject to another ( injured ) site such that endoneurial tubes is a transduction domain . According to another embodiment, for axonal regeneration across the gap are provided . How the Z1 and Z2 are each independently selected from the ever , this treatment often provides only a limited functional group consisting of: ( R ) 4 - 9 SEQ ID NO : 1 ] ; GRKKRROR recovery . Additionally , partial deinnervation frequently is RRPPQ [ SEQ ID NO : 2 ] ; RQRRKKRG [SEQ ID NO : 3 ] ; experienced at the donor site and multiple surgeries are 30 GRKKRROR [SEQ ID NO : 4 ]; AYARAAARQARA [SEQ required to harvest the tissue and implant it . ID NO : 5 ] ; DAATATRGRSAASRPTERPRAPARSASR Several variations of nerve autografting have been PRRPVE ( SEQ ID NO : 61; GWTLNSAGYLLGLINLKA attempted . These include allografts ( utilizing tissue from a LAALAKKIL [ SEQ ID NO : 7 ) ; PLSSIFSRIGDP (SEQ ID donor that is implanted in the subject) and xenografts NO : 8 ] ; AAVALLPAVLLALLAP ( SEQ ID NO : 97; AAV (utilizing tissue from a different species ). Allografts and 35 LLPVLLAAP [SEQ ID NO : 10 ) ; VTVLALGALAGVGVG xenografts , in addition to having the disadvantages of [SEQ ID NO : 11 ; GALFLGWLGAAGSTMGAWSOP autografts , often require simultaneous immunosuppressive [SEQ ID NO : 12 ] ; GWTLNSAGYLLGLINLKALAALAK therapies to mediate the recipient subject' s immunological KIL (SEQ ID NO : 71; KLALKLALKALKAALKLA ( SEO acceptance of the foreign tissue . Further, disease transmis - ID NO : 13 ] ; KETWWETWWTEWSQPKKKRKV [ SEQ ID sion must be considered when introducing tissue from 40 NO : 14 ); KAFAKLAARLYRKA [ SEQ ID NO : 151; KAF another person or animal. AKLAARLYRAA [ SEQ ID NO : 16 ] ; AAFAKLAAAR Additional efforts to effect nerve regeneration include the LYRKA [SEQ ID NO : 17 ) ; KAFAALAARLYRKATSEQ ID fabrication and use of nerve guidance conduits to guide NO : 18 ] ; KAFAKLAARLYRKAGC [SEQ ID NO : 20 ) ; axonal regrowth (where the artificial nerve conduits are KAFAKLAARLYRAAGC [SEQ ID NO : 21 ) ; AAFAK introduced into the lesion ) and immunization . However , 45 LAARLYRKAGC [ SEQ ID NO : 22 ) ; KAFAALAAR these treatments also are lacking in effectiveness and may be LYRKAGC [ SEQ ID NO : 231; KAFAKLAAQLYRKAGC costly . SEQ ID NO : 247; AGGGGYGRKKRRORRR (SEQ ID While the efforts towards regenerating nerves of the PNS NO : 25 ]; YARAAARQARA SEQ ID NO : 26 ] ; YGRK have yielded sparse , if any , results , there are no effective KRRRRRR [SEQ ID NO : 27 ] ; WLRRIKAWLRRIKA [SEQ treatments for nerve injury or methods to facilitate nerve 50 ID NO : 28 ]; WLRRIKAWLRRIKAWLRRIKA [SEQ ID regeneration within the CNS . NO : 29 ] ; FAKLAARLYRKA [ SEQ ID NO : 30 ] ; KAF The described invention addresses this problem . It pro - AALAARLYRKA [ SEQ ID NO : 181; KAFAKLAAR vides and EPRO compositions comprising at least one LYRAA [ SEQ ID NO : 16 ] ; KAFAKLAARLYRA (SEQ ID peptide of formula I for improving or enhancing neurite NO : 19 ] ; FAKLAARLYRAA [SEQ ID NO : 31 ] ; and FAK outgrowth , neuroprotection , and nerve regeneration , and 55 LAARLYRA [ SEQ ID NO : 32 ] . According to another methods of use thereof. embodiment, at least one of Z1 and Z2 are selected from the group consisting of WLRRIKAWLRRIKA ( SEQ ID NO : SUMMARY 28 ]; WLRRIKAWLRRIKAWLRRIKA (SEQ ID NO : 291; YGRKKRRRRRR [SEQ ID NO : 27 ] ; YARAAARQARA According to one aspect , the described invention provides 60 [SEQ ID NO : 261; RORRKKRG [SEQ ID NO : 31; GRK an EPRO composition comprising a therapeutically effective KRROR [SEQ ID NO : 4 ) ; KAFAKLAARLYRKA [SEQ ID amount of a polypeptide having the amino acid sequence NO : 151; FAKLAARLYRKA SEQ ID NO : 301; KAF according to Formula I : Z1 - X1 -X2 -X3 -X4 - X5 - X6 -X7 -X8 - AALAARLYRKA [ SEQ ID NO : 181; KAFAKLAAR X9- X10 -Z2 , wherein Z1 and Z2 are independently absent or LYRAA [SEQ ID NO : 16 ]; KAFAKLAARLYRA [SEQ ID are transduction domains ; X1 is selected from the group 65 NO : 191; FAKLAARLYRAA [ SEQ ID NO : 31 ] ; and FAK consisting of A , KA , KKA , KKKA and RA , or is absent; X2 LAARLYRA [ SEQ ID NO : 32 ] . According to another is selected from the group consisting of G , L , A , V , I , M , Y , embodiment, the at least one polypeptide of formula I US 9 ,890 , 195 B2 20 comprises an amino acid sequence selected from the group X9 is absent or is any amino acid ; X10 is absent or is any consisting of YARAAARQARAKALARQLGVAA [SEQ amino acid ; wherein at least one of the following is true : ( a ) ID NO : 33 ]; YGRKKRRRRRRKALARQLGVAA ( SEQ ID X3 is N and X7 is not G ; (b ) X7 is G and X3 is not N ; (c ) NO : 341; RORRKKRGKALARQLGVAA [SEQ ID NO : X2 is not L ; ( d ) X4 is not R ; ( e ) X5 is not Q ; ( f ) X6 is not 351; GRKKRRORKALARQLGVAA SEQ ID NO : 361; 5 L ; ( g ) X8 is not V ; ( h ) X10 is absent ; (i ) X9 and X10 are WLRRIKAWLRRIKAKALARQLGVAA SEQ ID NO : absent; wherein the polypeptide when disposed on or in the 37 ] ; WLRRIKAWLRIKAWLRRIKAKALARQLGVAA device enhances neurite outgrowth ; is neuroprotective , or [ SEQ ID NO : 38 ] ; YARAAARQARAKKKALARQL enhances neuroregeneration following neural injury . GVAA [ SEQ ID NO : 39 ] ; YGRKKRRQRRRKKKALAR According to one embodiment, the biomedical device is QLGVAA [SEQ ID NO : 40 ] ;RQRRKKRGKKKALARQL - 10 selected from the group consisting of a stent, a graft , a shunt, GVAA [SEQ ID NO : 41 ] ; a stent graft, a fistula , an angioplasty device, a balloon GRKKRRQRKKKALARQLGVAA [ SEQ ID NO : 42 ] ; catheter, a venous catheter , an implantable drug delivery WLRRIKAWLRRIKAKKKALARQLGVAA SEQ ID NO : device , an adhesion barrier , a wound dressing , a hydrocol 43 ]; WLRRIKAWLRRIKAWLRRIKAKKKALARQL loid , a hydrogel , a foam , a hydrophilic foam , a hydrophobic GVAA (SEQ ID NO : 44 ] ; KAFAKLAARLYRKALARQL - 15 foam , a calcium alginate, a cellophane , a pluronic , a bio GVAA [SEQ ID NO : 45 ]; FAKLAARLYRKALARQL logical polymer, a microelectrode, a probe , and a tissue GVAA SEQ ID NO : 461; scaffold . According to another embodiment, X2 , X3 , X6 and KAFAKLAARLYRAALARQLGVAA ( SEQ ID NO : 471; X7 is any aliphatic amino acid . According to another KAFAKLAARLYRALARQLGVAA ( SEQ ID NO : 48 ] ; embodiment, X2 , X3, X6 and X7 can be any aliphatic amino KAFAALAARLYRAALAROLGVAA SEQ ID NO : 491; 20 acid . According to another embodiment, X4 is R , X5 is Q FAKLAARLYRAALARQLGVAA [SEQ ID NO : 50 ] ; and / or X8 is V . According to another embodiment, X3 is WLRRIKAWRRIKA - LNRQLGVAA ( SEQ ID NO : 561; selected from the group consisting of V , L , I , A , G , Q and N . YARAAARQARAKALNRQLGVA [SEQ ID NO : 51 ] ; According to another embodiment, X6 is selected from the KAFAKLAARLYRKALNROLAVAA ( SEQ ID NO : 52 ] ; group consisting of C , A , G , L , V, I, M , Y, W and F . FAKLAARLYRKALNROLAVAA ( SEQ ID NO : 531; KAF - 25 According to another embodiment, X7 is selected from the ALKAARLYRKA -LNRQLGVAA [SEQ ID NO : 57 ]; and group consisting of S , A , C , T and G . According to another FAKLAARLYRKA -LNROLGVAA ISEO ID NO : 58 ) . embodiment , at least one of Z1 and Z2 is a transduction According to another embodiment, the at least one polypep domain . According to another embodiment, the Z1 and Z2 tide of formula I of the EPRO composition is a peptide of are each independently selected from the group consisting amino sequence YARAAARQARAKALARQLGVAA 30 of: ( R ) 4 - 9 [ SEQ ID NO : 1 ] ; GRKKRRORRRPPO ISEO ID ( [SEQ ID NO : 33 ]) . According to another embodiment, the NO : 2 ] ; RQRRKKRG [ SEQ ID NO : 3 ] ; GRKKRROR [ SEQ at least one polypeptide of formula I of the EPRO compo - ID NO : 4 ]; AYARAAARQARA [SEQ ID NO : 5 ] ; sition is a peptide of amino acid sequence YARAAAR . DAATATRGRSAASRPTERPRAPARSASRPRRPVE QARAKALNRQLGVAA [SEQ ID NO : 51 ]. According to SEQ ID NO : 6 ); GWTLNSAGYLLGLINLKALAALAK another embodiment, the at least one polypeptide of formula 35 KIL [SEQ ID NO : 7 ] ; PLSSIFSRIGDP [ SEQ ID NO : 8 ] ; I of the EPRO composition is a peptide of amino acid AAVALLPAVLLALLAP [ SEQ ID NO : 9 ] ; AAVLLPVL sequence FAKLAARLYRKALALRQLGVAA SEQ ID LAAP SEQ ID NO : 10 ) ; VTVLALGALAGVGVG SEO NO : 46 ]. According to another embodiment, the composi - ID NO : 11; GALFLGWLGAAGSTMGAWSQP [ SEQ ID tion is a pharmaceutical composition . According to another NO : 127; GWTLNSAGYLLGLINLKALAALAKKIL ( SEQ embodiment, the composition further comprises at least one 40 ID NO : 7 ]; KLALKLALKALKAALKLA [ SEQ ID NO : additional active agent . According to another embodiment, 13 ] ; KETWWETWWTEWSQPKKKRKV [ SEQ ID NO : the composition inhibits production of at least one inflam - 14 ) ; KAFAKLAARLYRKA SEQ ID NO : 15 ) ; KAFAK matory cytokine following the nerve injury. According to LAARLYRAA [SEQ ID NO : 16 ]; AAFAKLAAARLYRKA another embodiment, the at least one inflammatory cytokine [SEQ ID NO : 17 ) ; KAFAALAARLYRKA (SEQ ID NO : is at least one of IL - 1 beta , IL - 6 , and TNF - alpha . According 45 18 ] ; KAFAKLAARLYRKAGC [SEQ ID NO : 20 ); KAF to another embodiment , the inflammatory cytokines are AKLAARLYRAAGC [SEQ ID NO : 21 ] ; AAFAKLAAR produced by activated microglia and astrocytes following LYRKAGC [SEQ ID NO : 221; KAFAALAARLYRKAGC nerve injury . According to another embodiment, the con - (SEQ ID NO : 231; KAFAKLAAQLYRKAGCSEQ ID NO : centration of MK2i in the therapeutic composition is from 24 ] ; AGGGGYGRKKRRRRRR [ SEQ ID NO : 251; 0 . 001 nM to less than 3 mM . 50 YARAAARQARA SEQ ID NO : 261; YGRKKRRRRRR According to another aspect, the described invention [SEQ ID NO : 27 ] ; WLRRIKAWLRRIKA [ SEQ ID NO : 28 ] ; provides a biomedical device comprising an EPRO compo - WLRRIKAWLRRIKAWLRRIKA [ SEQ ID NO : 29 ; FAK sition comprising at least one polypeptide having an amino LAARLYRKA [SEQ ID NO : 30 ]; KAFAALAARLYRKA acid sequence according to Formula I : Z1 - X1- X2- X3 -X4 - (SEQ ID NO : 181; KAFAKLAARLYRAA [ SEQ ID NO : X5 - X6 -X7 - X8 -X9 - X10 - Z2 , wherein Zi and Z2 are inde - 55 161; KAFAKLAARLYRA [SEQ ID NO : 191; FAKLAAR pendently absent or are transduction domains; X1 is selected LYRAA [ SEQ ID NO : 31 ] ; and FAKLAARLYRA [ SEQ ID from the group consisting of A , KA , KKA , KKKA and RA , NO : 32 ) . According to another embodiment, at least one of or is absent; X2 is selected from the group consisting of G , Z1 and Z2 are selected from the group consisting of WLR L , A , V , I , M , Y , W and F , or is an aliphatic amino acid ; X3 RIKAWLRRIKA SEQ ID NO : 281; WLRRIKAWLR is selected from the group consisting of V , L , I, A , G , Q , N , 60 RIKAWLRRIKA [SEQ ID NO : 291; YGRKKRRRRRR S , T and C , or is an aliphatic amino acid ; X4 is selected from [SEQ ID NO : 27 ]; YARAAARQARA [SEQ ID NO : 26 ]; the group consisting of Q , N , H , R and K ; X5 is selected RQRRKKRG [ SEQ ID NO : 3 ]; GRKKRROR [SEQ ID NO : from the group consisting of Q and N ; X6 is selected from 41; KAFAKLAARLYRKA ( SEO ID NO : 151; FAKLAAR the group consisting of C , A , G , L , V , I , M , Y , W and F or LYRKA [SEQ ID NO : 30 ] ;KAFAALAARLYRKA [SEQ ID is an aliphatic amino acid ; X7 is selected from the group 65 NO : 181; KAFAKLAARLYRAASEO ID NO : 161; KAF consisting of S , A , C , T and G or is an aliphatic amino acid ; AKLAARLYRA [SEQ ID NO : 19 ] ; FAKLAARLYRAA X8 is selected from the group consisting of V , L , I and M ; [SEQ ID NO : 31 ] ; and FAKLAARLYRA [ SEQ ID NO : 32 ]. US 9 ,890 , 195 B2 21 22 According to another embodiment, the at least one polypep According to another aspect , the described invention tide of formula I comprises an amino acid sequence selected provides a method for improving or enhancing neurite from the group consisting of YARAAARQARAKALAR outgrowth , the method comprising : (a ) providing a thera QLGVAA ( SEQ ID NO : 33 ]; YGRKKRRORRRKALAR peutically effective amount of an EPRO composition , the QLGVAA [SEQ ID NO : 34 ) ; RQRRKKRGKALARQL - 5 EPRO composition comprising : ( i) at least one polypeptide GVAA [ SEQ ID NO : 35 ] ; GRKKRRQRKALARQLGVAA having an amino acid sequence according to Formula I: [ SEQ ID NO : 36 ); WLRRIKAWLRRIKAKALARQL Z1- X1 -X2 - X3 - X4 - X5 - X6 -X7 - X8 -X9 - X10 - Z2 , wherein Z1 GVAA [SEQ ID NO : 37 ]; WLRRIKAWLRIKAWLR and Z2 are independently absent or are transduction RIKAKALARQLGVAA [ SEQ ID NO : 38 ]; YARAAAR domains; X1 is selected from the group consisting of A , KA , QARAKKKALARQLGVAA SEQ ID NO : 391; 10 KKA , KKKA and RA , or is absent; X2 is selected from the YGRKKRRRRRRKKKALARQLGVAA [SEQ ID NO : 40 ] ; group consisting of G , L , A , V , I , M , Y , W and F , or is an RORRKKRGKKKALARQLGVAA SEQ ID NO : 41 ] ; aliphatic amino acid ; X3 is selected from the group consist GRKKRRQRKKKALARQLGVAA [ SEQ ID NO : 42 ] ; ing of V , L , I, A , G , Q , N , S , T and C , or is an aliphatic amino WLRRIKAWLRRIKAKKKALARQLGVAA (SEQ ID NO : acid ; X4 is selected from the group consisting of Q , N , H , 43 ]; WLRRIKAWLRRIKAWLRRIKAKKKALARQL - 15 Rand K ; X5 is selected from the group consisting of Q and GVAA [ SEQ ID NO : 44 ]; KAFAKLAARLYRKALARQL N ; X6 is selected from the group consisting of C , A , G , L , GVAA [ SEQ ID NO : 451; FAKLAARLYRKALARQL - V , I , M , Y , W and F or is an aliphatic amino acid ; X7 is GVAA [SEQ ID NO : 46 ] ; selected from the group consisting of S , A , C , T and G or is KAFAKLAARLYRAALARQLGVAA [ SEQ ID NO : 47 ] ; an aliphatic amino acid ; X8 is selected from the group KAFAKLAARLYRALARQLGVAA ( SEQ ID NO : 48 ) ; 20 consisting of V , L , I and M ; X9 is absent or is any amino KAFAALAARLYRAALARQLGVAA [ SEQ ID NO : 49 ] ; acid ; X10 is absent or is any amino acid ; wherein at least one FAKLAARLYRAALARQLGVAA [ SEQ ID NO : 501; of the following is true : ( a ) X3 is N and X7 is not G ; ( b ) X7 WLRRIKAWRRIKALNRQLGVA [SEQ ID NO : 56 ]WLR is G and X3 is not N ; ( c ) X2 is not L ; ( d ) X4 is not R ; ( e ) RIKAWRRIKA - LNRQLGVAA ; YARAAARQARAKAL X5 is not Q ; ( f ) X6 is not L ; ( g ) X8 is not V ; ( h ) X10 is NRQLGVA [SEQ ID NO : 51 ] ; KAFAKLAARLYRKALN - 25 absent; ( i ) X9 and X10 are absent; wherein the polypeptide ROLAVAA [ SEQ ID NO : 52 ] ; enhances or improves outgrowth of at least one neurite FAKLAARLYRKALNRQLAVAA TSEQ ID NO : 53 ); KAF - process from a neuron cell body ; and ( ii ) a carrier; ( b ) ALKAARLYRKALNRQLGVA [SEQ ID NO : 57 ]KAFAL administering the EPRO composition to a subject in need KAARLYRKA -LNRQLGVAA ; and FAKLAARLYRKAL thereof; and ( c ) increasing neurite outgrowth relative to NROLGVA SEQ ID NO : 58 ]FAKLAARLYRKA - 30 neurite outgrowth of a neuron that has not been treated with LNRQLGVAA . According to another embodiment , the the EPRO composition . According to one embodiment, X2 , EPRO composition comprising at least one polypeptide X3, X6 and X7 is any aliphatic amino acid . According to having an amino acid sequence according to Formula I is another embodiment, X4 is R , X5 is Q and / or X8 is V . directly disposed onto the inner surface of the biomedical According to another embodiment, X3 is selected from the device . According to another embodiment , the EPRO com - 35 group consisting of V , L , I , A , G , Q and N . According to position comprising at least one polypeptide having an another embodiment, X6 is selected from the group consist amino acid sequence according to Formula I is directly ing of C , A , G , L , V , I , M , Y , W and F . According to another disposed onto the outer surface of the biomedical device . embodiment, X7 is selected from the group consisting of S , According to another embodiment , the EPRO composition A , C , T and G . According to another embodiment , at least comprising at least one polypeptide having an amino acid 40 one of Z1 and Z2 is a transduction domain . According to sequence according to Formula I is directly disposed into the another embodiment, the Z1 and Z2 are each independently biomedical device such that the at least one polypeptide is selected from the group consisting of: ( R ) 4 - 9 [SEQ ID NO : embedded into the inner surface of the biomedical device . 1 ]; GRKKRRRRRPPQ [SEQ ID NO : 2 ]; RQRRKKRG According to another embodiment, the EPRO composition [SEQ ID NO : 3 ] ; GRKKRROR SEQ ID NO : 41; comprising at least one polypeptide having an amino acid 45 AYARAAARQARA [ SEQ ID NO : 51; DAATATRGR sequence according to Formula I is directly disposed into the SAASRPTERPRAPARSASRPRRPVE [ SEQ ID NO : 6 ]; biomedical device such that the at least one polypeptide is GWTLNSAGYLLGLINLKALAALAKKIL [SEQ ID NO : embedded into the outer surface of the biomedical device . 7 ); PLSSIFSRIGDP [ SEQ ID NO : 8 ]; AAVALLPAVLLAL According to another embodiment, the EPRO composition LAP [SEQ ID NO : 9 ]; AAVLLPVLLAAP [SEQ ID NO : comprising the at least one polypeptide having an amino 50 10 ] ; VTVLALGALAGVGVG (SEQ ID NO : 11 ; GALFL acid sequence according to Formula I is disposed in a GWLGAAGSTMGAWSQP [SEQ ID NO : 12 ] ; GWTLN matrix . According to another embodiment , the EPRO com SAGYLLGLINLKALAALAKKIL [SEQ ID NO : 7 ); KLA position comprising at least one polypeptide having an LKLALKALKAALKLA [SEQ ID NO : 13 ]; amino acid sequence according to Formula I, is indirectly KETWWETWWTEWSQPKKKRKV [SEQ ID NO : 14 ]; dispersed onto or into the biomedical device , and enhances 55 KAFAKLAARLYRKA [SEQ ID NO : 15 ); KAFAKLAAR outgrowth of at least one neurite process from a neuron cell LYRAA [SEQ ID NO : 16 ] ; AAFAKLAAARLYRKA [ SEQ body . According to another embodiment , the at least one ID NO : 17 ) ; KAFAALAARLYRKA [ SEQ ID NO : 18 ] ; polypeptide having an amino acid sequence according to KAFAKLAARLYRKAGC [SEQ ID NO : 20 ]; KAFAK Formula I inhibits production of at least one inflammatory LAARLYRAAGC (SEQ ID NO : 21 ] ; AAFAKLAAR cytokine following the nerve injury . According to another 60 LYRKAGC [ SEQ ID NO : 22 ) ; KAFAALAARLYRKAGC embodiment, the at least one inflammatory cytokine is at [ SEQ ID NO : 23 ] ; KAFAKLAAQLYRKAGC [SEQ ID NO : least one of IL - 1 beta , IL - 6 , and TNF - alpha . According to 241; AGGGGYGRKKRRORRR SEQ ID NO : 251; another embodiment, the inflammatory cytokines are pro YARAAARQARA [SEQ ID NO : 26 ] ; YGRKKRRRRRR duced by activated microglia and astrocytes following nerve [SEQ ID NO : 27 ]; WLRRIKAWLRRIKA [SEQ ID NO : 28 ]; injury . According to another embodiment, the concentration 65 WLRRIKAWLRRIKAWLRRIKA [SEQ ID NO : 29 ] ; FAK of MK2i in the therapeutic composition is from 0 .001 nM to LAARLYRKA ( SEQ ID NO : 30 ] ; KAFAALAARLYRKA less than 3 mM . [ SEQ ID NO : 18 ]; KAFAKLAARLYRAA [SEQ ID NO : US 9 ,890 , 195 B2 23 24 161; KAFAKLAARLYRA SEQ ID NO : 191; FAKLAAR least one of IL - 1 beta , IL - 6 , and TNF - alpha . According to LYRAA [ SEQ ID NO : 31] ; and FAKLAARLYRA [SEQ ID another embodiment, the inflammatory cytokines are pro NO : 32 ] . According to another embodiment, at least one of duced by activated microglia and astrocytes following nerve Z1 and Z2 are selected from the group consisting of WLR - injury. According to another embodiment, the concentration RIKAWLRRIKA [SEQ ID NO : 28 ] ; WLRRIKAWLR - 5 of MK2i in the therapeutic composition is from 0 .001 nM to RIKAWLRRIKA [ SEQ ID NO : 29 ] ; YGRKKRRRRRR less than 3 mM . TSEQ ID NO : 271; YARAAARQARA ( SEQ ID NO : 261; According to another aspect, the described invention RORRKKRG SEQ ID NO : 31; GRKKRROR [SEQ ID NO : provides a method for improving or enhancing nerve regen 41; KAFAKLAARLYRKA [SEQ ID NO : 15 ] ; FAKLAAR - eration , the method comprising : ( a ) providing a therapeuti LYRKA ( SEO ID NO : 30 ) ; KAFAALAARLYRKATSEQ ID 10 cally effective amount of an EPRO composition , the com NO : 18 ]; KAFAKLAARLYRAA [ SEQ ID NO : 16 ]; KAF position comprising : ( i) at least one polypeptide having an AKLAARLYRA [ SEQ ID NO : 191; FAKLAARLYRAA amino acid sequence according to Formula I : Z1- X1 -X2 [SEQ ID NO : 31 ] ; and FAKLAARLYRA [ SEQ ID NO : 32 ]. X3 - X4 -X5 - X6 - X7- X8- X9 - X10 - Z2 , wherein Z1 and Z2 are According to another embodiment, the at least one polypep - independently absent or are transduction domains ; X1 is tide of formula I comprises an amino acid sequence selected 15 selected from the group consisting of A , KA , KKA , KKKA from the group consisting of YARAAARQARAKALAR - and RA , or is absent; X2 is selected from the group QLGVAA [SEQ ID NO : 33 ]; YGRKKRRQRRRKALAR - consisting of G , L , A , V , I , M , Y , W and F , or is an aliphatic QLGVAA [SEQ ID NO : 34 ); RQRRKKRGKALARQL - amino acid ; X3 is selected from the group consisting of V , GVAA (SEQ ID NO : 35 ] ; GRKKRRQRKALARQLGVAA L , I , A , G , Q , N , S , T and C , or is an aliphatic amino acid ; SEO ID NO : 36 ] ; WLRRIKAWLRRIKAKALARQL - 20 X4 is selected from the group consisting of Q , N , H , R and GVAA [SEQ ID NO : 371; WLRRIKAWLRIKAWLR K ; X5 is selected from the group consisting of Q and N ; X6 RIKAKALARQLGVAA [SEQ ID NO : 38 ]; YARAAAR - is selected from the group consisting of C , A , G , L , V , I, M , QARAKKKALARQLGVAA [SEQ ID NO : 39 ]; Y , W and F or is an aliphatic amino acid ; X7 is selected from YGRKKRRQRRRKKKALARQLGVAA [ SEQ ID NO : 40 ] ; the group consisting of S , A , C , T and G or is an aliphatic RORRKKRGKKKALARQLGVAA [SEQ ID NO : 41 ]; 25 amino acid ; X8 is selected from the group consisting of V , GRKKRRQRKKKALARQLGVAA [SEQ ID NO : 42 ]; L , I and M ; X9 is absent or is any amino acid ; X10 is absent WLRRIKAWLRRIKAKKKALARQLGVAA (SEQ ID NO : or is any amino acid ; wherein at least one of the following 43 ] ; WLRRIKAWLRRIKAWLRRIKAKKKALARQL is true : (a ) X3 is N and X7 is not G ; (b ) X7 is G and X3 is GVAA ( SEQ ID NO : 441; KAFAKLAARLYRKALARQL not N ; ( c ) X2 is not L ; ( d ) X4 is not R ; ( e ) X5 is not Q ; ( f ) GVAA SEQ ID NO : 451; FAKLAARLYRKALARQL - 30 X6 is not L ; ( g ) X8 is not V ; ( h ) X10 is absent; ( i ) X9 and GVAA SEQ ID NO : 461; X10 are absent; and ( ii ) a carrier ; ( b ) administering the KAFAKLAARLYRAALARQLGVAA [SEQ ID NO : 47 ] ; EPRO composition to a subject in need thereof; and (c ) KAFAKLAARLYRALARQLGVAA [SEQ ID NO : 48 ]; increasing neurite regrowth relative to regrowth of a neurite KAFAALAARLYRAALARQLGVAA [ SEQ ID NO : 49 ] ; process of a neuron that has not been treated with the EPRO FAKLAARLYRAALARQLGVAA [SEQ ID NO : 50 ]; 35 composition . According to one embodiment, X2, X3, X6 WLRRIKAWRRIKALNRQLGVA [SEQ ID NO : 56 ] WLR and X7 is an aliphatic amino acid . According to another RIKAWRRIKA -LNROLGVAA ; YARAAARQARAKAL - embodiment, X4 is R , X5 is Q and /or X8 is V . According to NRQLGVA [SEQ ID NO : 51 ]; KAFAKLAARLYRKALN another embodiment, X3 is selected from the group consist ROLAVAA SEQ ID NO : 52 ] ; ing of V , L , I , A , G , Q and N . According to another FAKLAARLYRKALNROLAVAA ( SEQ ID NO : 531; KAF - 40 embodiment, X6 is selected from the group consisting of C , ALKAARLYRKALNRQLGVA [SEQ ID NO : 57 ]KAFAL A , G , L , V , I , M , Y , W and F. According to another KAARLYRKA - LNROLGVAA ; and FAKLAARLYRKAL - embodiment , X7 is selected from the group consisting of S , NRQLGVA [SEQ ID NO : 58 ]FAKLAARLYRKA A , C , T and G . According to another embodiment, at least LNRQLGVAA . According to another embodiment, the one of Z1 and Z2 is a transduction domain . According to composition is a pharmaceutical composition . According to 45 another embodiment, the Z1 and Z2 are each independently another embodiment, the composition further comprises at selected from the group consisting of: ( R ) 4 - 9 [ SEQ ID NO : least one additional active agent. According to another 1 ] ; GRKKRRRRRRPPO [ SEQ ID NO : 21; RORRKKRG embodiment, the at least one polypeptide has an amino acid [SEQ ID NO : 3 ] ; GRKKRROR SEQ ID NO : 41; sequence of70 % substantial identity to a polypeptide having AYARAAARQARA [SEQ ID NO : 5 ]; DAATATRGR an amino acid sequence according to Formula I, wherein the 50 SAASRPTERPRAPARSASRPRRPVE [SEQ ID NO : 6 ] ; polypeptide having an amino acid sequence according to GWTLNSAGYLLGLINLKALAALAKKIL SEQ ID NO : Formula I enhances outgrowth of at least one neurite process 7 ]; PLSSIFSRIGDP [SEQ ID NO : 8 ] ; AAVALLPAVLLAL from a neuron cell body. According to another embodiment, LAP [SEQ ID NO : 9 ] ; AAVLLPVLLAAP [SEQ ID NO : the neurite process is an axon . According to another embodi - 10 ] ; VTVLALGALAGVGVG [SEQ ID NO : 11 ; GALFL ment, the neurite process is a dendrite . According to another 55 GWLGAAGSTMGAWSQP [SEQ ID NO : 12 ] ; GWTLN embodiment, outgrowth of the neurite process is increased at SAGYLLGLINLKALAALAKKIL [ SEQ ID NO : 71; KLA least 10 % in length relative to at least one dendrite of the LKLALKALKAALKLA SEQ ID NO : 13 ] ; neurite process that has not been treated with the EPRO KETWWETWWTEWSQPKKKRKV [ SEQ ID NO : 14 ] ; composition . According to another embodiment, the com - KAFAKLAARLYRKA [SEQ ID NO : 15 ); KAFAKLAAR position further comprises at least one additional active 60 LYRAA [ SEQ ID NO : 16 ] ; AAFAKLAAARLYRKA [SEQ agent. According to another embodiment, the carrier is a ID NO : 17 ); KAFAALAARLYRKA [ SEQ ID NO : 18 ]; pharmaceutically acceptable carrier. According to another KAFAKLAARLYRKAGC ( SEQ ID NO : 201; KAFAK embodiment, the EPRO composition comprising at least one LAARLYRAAGC [SEQ ID NO : 21 ] ; AAFAKLAAR polypeptide having an amino acid sequence according to LYRKAGC [ SEQ ID NO : 22 ) ; KAFAALAARLYRKAGC Formula I inhibits production of at least one inflammatory 65 [SEQ ID NO : 23 ]; KAFAKLAAQLYRKAGC [SEQ ID NO : cytokine following the nerve injury . According to another 24 ] ; AGGGGYGRKKRRRRRR [SEQ ID NO : 25] ; embodiment, the at least one inflammatory cytokine is at YARAAARQARA [SEQ ID NO : 26 ] ; YGRKKRRQRRR US 9 ,890 , 195 B2 25 26 [ SEQ ID NO : 271; WLRRIKAWLRRIKATSEQ ID NO : 28 ] ; According to another embodiment, the concentration of WLRRIKAWLRRIKAWLRRIKA [SEQ ID NO : 29 ] ; FAK - MK2i in the therapeutic composition is from 0 .001 nM to LAARLYRKA SEQ ID NO : 30 ] ; KAFAALAARLYRKA less than 3 mm . SEQ ID NO : 181; KAFAKLAARLYRAA [SEQ ID NO : According to another aspect, the described invention 161; KAFAKLAARLYRA (SEO ID NO : 191; FAKLAAR - 5 provides a method for protecting against progression of a LYRAA [ SEQ ID NO : 31 ] ; and FAKLAARLYRA [SEQ ID neuronal injury , the method comprising : (a ) providing a therapeutically effective amount of a EPRO composition , NO : 32 ]. According to another embodiment, at least one of the composition comprising : ( i ) at least one polypeptide Z1 and Z2 are selected from the group consisting of WLR having an amino acid sequence according to Formula I : RIKAWLRRIKA SEO ID NO : 281; WLRRIKAWLRD10 Z1- X1 - X2 -X3 -X4 - X5 - X6 - X7 -X8 -X9 - X10 - Z2 , wherein Zi RIKAWLRRIKA [SEQ ID NO : 29 ] ; YGRKKRRQRRR and Z2 are independently absent or are transduction SEQ ID NO : 271; YARAAARQARA ( SEQ ID NO : 261; domains ; X1 is selected from the group consisting of A , KA , RQRRKKRG [SEQ ID NO : 3 ] ; GRKKRROR [SEQ ID NO : KKA , KKKA and RA , or is absent; X2 is selected from the 4 ]; KAFAKLAARLYRKA [SEQ ID NO : 15 ]; FAKLAAR group consisting of G , L , A , V , I, M , Y , W and F , or is an LYRKA [ SEQ ID NO : 30 ]; KAFAALAARLYRKA [ SEQOD ID 15 aliphatic amino acid ; X3 is selected from the group consist NO : 18 ]; KAFAKLAARLYRAA [SEQ ID NO : 16 ]; KAF ing of V , L , I , A , G , Q , N , S , T and C , or is an aliphatic amino AKLAARLYRA [SEQ ID NO : 19 ] ; FAKLAARLYRAA acid ; X4 is selected from the group consisting of Q , N , H , [ SEQ ID NO : 31 ] ; and FAKLAARLYRA [SEQ ID NO : 32 ] . R and K ; X5 is selected from the group consisting of Q and According to another embodiment, the at least one polypep - N ; X6 is selected from the group consisting of C , A , G , L , tide of formula I comprises an amino acid sequence selected 20 V , I, M , Y, W and F or is an aliphatic amino acid ; X7 is from the group consisting of YARAAARQARAKALAR selected from the group consisting of S , A , C , T and G or is OLGVAA ( SEQ ID NO : 331; YGRKKRRRRRRKALAR - an aliphatic amino acid ; X8 is selected from the group QLGVAA (SEQ ID NO : 34 ); RORRKKRGKALARQL consisting of V , L , I and M ; X9 is absent or is any amino GVAA [SEQ ID NO : 35 ] ; GRKKRRQRKALARQLGVAA acid ; X10 is absent or is any amino acid ; wherein at least one TSEO ID NO : 361; WLRRIKAWLRRIKAKALAROL - 25 of the following is true : ( a ) X3 is N and X7 is not G ; ( b ) X7 GVAA SEO ID NO : 371; WLRRIKAWLRIKAWLR - is G and X3 is not N ; ( c ) X2 is not L ; ( d ) X4 is not R ; ( e ) RIKAKALAROLGVAA ( SEO ID NO : 387; YARAAAR - X5 is not Q ; ( f ) X6 is not L ; ( g ) X8 is not V ; ( h ) X10 is absent; (i ) X9 and X10 are absent; and (ii ) a carrier; (b ) QARAKKKALARQLGVAA SEQ ID NO : 39 ]; administering the composition to a subject in need thereof; YGRKKRRQRRRKKKALARQLGVAAISEO [ SEQO IDNO NO . : 41140 ] .; 30 and (c ) reducing or inhibiting at least one manifestation of RORRKKRGKKKALARQLGVAA [SEQ ID NO : 41 ]; progression of the neuronal injury in at least one neuronal GRKKRRORKKKALARQLGVAA [SEQ ID NO : 42 ] ; cell population affected by the neuronal injury ; and ( d ) WLRRIKAWLRRIKAKKKALARQLGVAA ( SEQ ID NO : increasing survival of the at least one neuronal cell popu 43 ]; WLRRIKAWLRRIKAWLRRIKAKKKALARQL lation affected by the neuronal injury. According to one GVAA [ SEQ ID NO : 44 ]; KAFAKLAARLYRKALARQL- 35 embodiment, the neuronal injury is a neurapraxia type GVAA [SEQ ID NO : 45 ); FAKLAARLYRKALARQL injury. According to another embodiment, the injury is a GVAA SEQ ID NO : 46 ] ; axonotmesis type injury . According to another embodiment, KAFAKLAARLYRAALARQLGVAA [ SEQ ID NO : 47 ) ; the injury is a neurtmesis type injury . According to another KAFAKLAARLYRALARQLGVAA [ SEQ ID NO : 48 ] ; embodiment, the injury results from an acute disorder . KAFAALAARLYRAALARQLGVAA [ SEQ ID NO : 49 ] ; 40 According to another embodiment, the acute disorder is a FAKLAARLYRAALARQLGVAA [SEQ ID NO : 50 ] ; stroke , a spinal cord injury, or a traumatic brain injury . WLRRIKAWRRIKALNRQLGVA [SEQ ID NO : 56 ] ; According to another embodiment, the injury results from a YARAAARQARAKALNRQLGVA [SEQ ID NO : 51 ] ; chronic neurodegenerative disease . According to another KAFAKLAARLYRKALNROLAVAA [SEQ ID NO : 52 ] ; embodiment, the chronic neurodegenerative disease is Par FAKLAARLYRKALNRQLAVAA [SEQ ID NO : 53 ) ; KAF - 45 kinson ' s disease , Alzheimer ' s disease , Multiple Sclerosis , ALKAARLYRKALNRQLGVA [ SEQ ID NO : 57 ) ; and Amyotrophic lateral sclerosis . or a neuropathy. According to FAKLAARLYRKALNROLGVA SEQ ID NO : 58 ) . another embodiment, the neuropathy is a diabetic neuropa According to another embodiment, the at least one polypep - thy. According to another embodiment, the at least one tide has an amino acid sequence of at least 70 % sequence manifestation of progression of the neuronal injury in at identity to an amino acid sequence according to Formula I , 50 least one neuronal cell population is apoptotic cell death . wherein the at least one polypeptide having an amino acid According to another embodiment, the at least one mani sequence according to Formula I enhances regrowth of at festation of progression of the neuronal injury in at least one least one neurite process from a neuron cell body . According neuronal cell population is microglial activation . According to another embodiment, the at least one polypeptide is a to another embodiment, the at least one manifestation of polypeptide having amino acid sequence YARAAAR - 55 progression of the neuronal injury in at least one neuronal QARAKALARQLGVAA [SEQ ID NO : 33 ]. According to cell population is inflammation . According to another another embodiment, the regrowth of the neurite process is embodiment, the at least one manifestation of progression of increased at least 10 % in length relative to at least one the neuronal injury in at least one neuronal cell population dendrite of the neurite process that has not been treated with is formation of a scar. According to another embodiment, the the EPRO composition . According to another embodiment, 60 neuronal cell population is a cortical cell population . the EPRO composition increases neurite regrowth by inhib - According to another embodiment, the neuronal cell popu iting expression of at least one inflammatory cytokine from lation is a mixed cortical cell population . According to activated microglia . According to another embodiment, the another embodiment, the mixed cortical cell population at least one inflammatory cytokine is at least one of IL - 1 comprises neurons, microglia , and astrocytes. According to beta , IL -6 , and TNF - alpha . According to another embodi - 65 another embodiment, X2, X3 , X6 and X7 is an aliphatic ment, the at least one inflammatory cytokine is produced by amino acid . According to another embodiment, X4 is R ; X5 activated microglia and astrocytes following nerve injury . is Q , and / or X8 is V . According to another embodiment, X3 US 9 ,890 , 195 B2 27 28 is selected from the group consisting of V , L , I , A , G , Q and YARAAARQARAKALNRQLGVA [SEQ ID NO : 51 ] ; N . According to another embodiment, X6 is selected from KAFAKLAARLYRKALNRQLAVAA [SEQ ID NO : 52 ] ; the group consisting of C , A , G , L , V , I, M , Y , W and F . FAKLAARLYRKALNROLAVAA SEQ ID NO : 531; KAF According to another embodiment, X7 is selected from the ALKAARLYRKALNRQLGVA [SEQ ID NO : 57 ] ; and group consisting of S , A , C , T and G . According to another 5 FAKLAARLYRKALNRQLGVA [SEQ ID NO : 58 ) . embodiment, at least one of Z1 and Z2 is a transduction According to another embodiment, the at least one polypep domain selected from the group consisting of: ( R ) 4 - 9 [ SEQ tide of formula I of the EPRO composition is a peptide of ID NO : 1 ] ; GRKKRRQRRRPPQ [ SEQ ID NO : 2 ] ; RQR - amino sequence YARAAARQARAKALARQLGVAA RKKRG (SEQ ID NO : 3 ] ; GRKKRROR [SEQ ID NO : 4 ] ; [ SEQ ID NO : 33 ) . According to another embodiment, the at AYARAAARQARA SEQ ID NO : 5 ] ; DAATATRGR - 10 least one polypeptide of formula I of the EPRO composition SAASRPTERPRAPARSASRPRRPVE [ SEQ ID NO : 6 ] ; is a peptide of amino acid sequence YARAAAR GWTLNSAGYLLGLINLKALAALAKKIL [ SEQ ID NO : QARAKALNRQLGVA [SEQ ID NO : 51] . According to 7 ]; PLSSIFSRIGDP [SEQ ID NO : 8 ]; AAVALLPAVLLAL - another embodiment , the at least one polypeptide of formula LAP (SEQ ID NO : 91 ; AAVLLPVLLAAP [ SEQ ID NO : I of the EPRO composition is a peptide of amino acid 101; VTVLALGALAGVGVG SEQ ID NO : 11 ; GALFL - 15 sequence FAKLAARLYRKALARQLGVAA [SEQ ID NO : GWLGAAGSTMGAWSOP [ SEQ ID NO : 12 ] ; GWTLN - 46 ). According to another embodiment, the at least one SAGYLLGLINLKALAALAKKIL (SEQ ID NO : 7 ) ; KLA polypeptide has at least about 70 % sequence identity to LKLALKALKAALKLA [SEQ ID NO : 13 ] ; amino acid sequence YARAAARQARAKALARQLGVAA KETWWETWWTEWSQPKKKRKV [ SEQ ID NO : 14 ] ; [ SEQ ID NO : 33 ) . According to another embodiment, the at KAFAKLAARLYRKA [SEQ ID NO : 15 ); KAFAKLAAR - 20 least one polypeptide has at least about 70 % sequence LYRAA (SEQ ID NO : 16 ] ; AAFAKLAAARLYRKA (SEQ identity to amino acid sequence YARAAARQARAKALN ID NO : 171; KAFAALAARLYRKA [SEQ ID NO : 18 ] ; ROLGVA ( SEQ ID NO : 51 ). According to another embodi KAFAKLAARLYRKAGC SEQ ID NO : 201; KAFAK ment , the at least one polypeptide has at least about 70 % LAARLYRAAGC [SER ID NO : 21 ] ; AAFAKLAAR sequence identity to amino acid sequence FAKLAAR LYRKAGC (SEQ ID NO : 221; KAFAALAARLYRKAGC 25 LYRKALARQLGVAA ( SEQ ID NO : 46 ) . According to [SEQ ID NO : 23 ]; KAFAKLAAQLYRKAGC [ SEQ ID NO : another embodiment, the EPRO composition protects at 24 ]; AGGGGYGRKKRRQRRR [ SEQ ID NO : 25 ] ; least one neuron from progression of a neuronal injury by YARAAARQARA [ SEQ ID NO : 26 ] ; YGRKKRRQRRR inhibiting expression of at least one inflammatory cytokine [ SEQ ID NO : 271; WLRRIKAWLRRIKA [ SEQ ID NO : 28 ] ; from activated microglia . According to another embodi WLRRIKAWLRRIKAWLRRIKA [ SEQ ID NO : 29 ] ; FAK - 30 ment, the at least one inflammatory cytokine is at least one LAARLYRKA ( SEQ ID NO : 30 ] ; KAFAALAARLYRKA of IL - 1 beta , IL - 6 , and TNF - alpha . [SEQ ID NO : 18 ] ; KAFAKLAARLYRAA [SEQ ID NO : 161; KAFAKLAARLYRA (SEQ ID NO : 191; FAKLAAR BRIEF DESCRIPTION OF THE DRAWINGS LYRAA SEQ ID NO : 31 ] ; and FAKLAARLYRA [SEQ ID NO : 32 ]. According to another embodiment, one or both of 35 FIG . 1 shows a graph of mean neurite length (um ) of Z1 and Z2 are selected from the group consisting of: control neurites ( cultured 24 hours then exposed for 5 hours WLRRIKAWLRRIKA [ SEQ ID NO : 28 ]; WLRRIKAWLWL . regular media ) and exposed neurites (cultured for 24 hours RRIKAWLRRIKA [SEQ ID NO : 291; YGRKKRRORRR then exposed to 100 mM MK2i) . [ SEQ ID NO : 271; YARAAARQARA [ SEQ ID NO : 26 ] ; FIGS . 2A and 2B shows micrographs of neurons , astro RQRRKKRG [ SEQ ID NO : 3 ] ;GRKKRROR [SEQ ID NO : 40 cytes, and microglia stained with antibodies against cell 4 ] ; KAFAKLAARLYRKA [ SEQ ID NO : 15 ] ; FAKLAAR type specific proteins corresponding to neuron (ß - 3 - tub ) , LYRKA [ SEQ ID NO : 307; KAFAALAARLYRKA [ SEQ ID microglia ( Ibal) , and GFAP( ) in the mixed cortical NO : 18 ] ; KAFAKLAARLYRAA [ SEQ ID NO : 16 ]; KAF culture . Cell nuclei and brightfield transmission light images AKLAARLYRA SEQ ID NO : 191; FAKLAARLYRAA ( Trans) also were taken , with nuclei labeled using the DNA [SEQ ID NO : 31 ] ; and FAKLAARLYRA [ SEQ ID NO : 32 ]. 45 dye Hoechst 33342. Cultures were imaged under laser According to another embodiment, the at least one polypep - confocal using a wide aperture (400 um ) . Scale bar 50 um tide of formula I comprises YARAAAROARAKALAROL - for FIG . 2A and 100 um for FIG . 2B . GVAA (SEQ ID NO : 33 ] ; YGRKKRRORRRKALAROL - FIG . 3 shows micrographs of neurons ( B - 3 - tub ) , astro GVAA ( SEQ ID NO : 347; RORRKKRGKALARQLGVAA cytes (GFAP ), and microglia (Ibal ), treated with 0 mm [ SEO ID NO : 351; GRKKRRORKALARQLGVAA ( SEQ 50 MK2i ( YARAAARQARAKALARQLGVAA ( SEQ ID NO : ID NO : 36 ] ; WLRRIKAWLRRIKAKALARQLGVAA 33 ] ) , 0 . 5 mM MK2i, 1 . 0 mM MK2i, and 3 mM MK2i. Scale [SEQ ID NO : 371; WLRRIKAWLRIKAWLRRIKAKA - bar is 100 um . LARQLGVAA [SEQ ID NO : 38 ] ; YARAAARQARAKK - FIG . 4 shows micrographs of neurons treated with MK2i KALARQLGVAA [SEQ ID NO : 39 ]; YGRKKRRQRRRK - (YARAAARQARAKALARQLGVAA [ SEQ ID NO : 33 ] ) KKALARQLGVAA [SEQ ID NO : 40 ] ; 55 and TNF - a . Row 1 shows neurons treated with O mM MK2i RORRKKRGKKKALARQLGVAA [ SEQ ID NO : 41 ]; and 0 ng/ ml TNF -a , 5 ng /ml TNF - a , and 10 ng /ml TNF - a , GRKKRRORKKKALARQLGVAA [SEQ ID NO : 42] ; respectively ; Row 2 shows neurons treated with 0 .5 mm WLRRIKAWLRRIKAKKKALARQLGVAA ( SEQ ID NO : MK2i and 0 ng /ml TNF - a , 5 ng /ml TNF - a , and 10 ng /ml 43 ] ; WLRRIKAWLRRIKAWLRRIKAKKKALARQL TNF - a , respectively ; Row 3 shows neurons treated with 1 GVAA [ SEQ ID NO : 44 ] ; KAFAKLAARLYRKALARQL - 60 mM MK2i and 0 ng /ml TNF - a , 5 ng/ ml TNF - a , and 10 GVAA [ SEQ ID NO : 45 ]; FAKLAARLYRKALARQL ng/ ml TNF - a , respectively ; and Row 4 shows neurons GVAA SEQ ID NO : 461; treated with 3 mM MK2i and 0 ng /ml TNF - a , 5 ng /ml KAFAKLAARLYRAALARQLGVAA [ SEQ ID NO : 47 ] ; TNF - a , and 10 ng /ml TNF - a , respectively . Scale bar is 100 KAFAKLAARLYRALARQLGVAA [SEQ ID NO : 48 ]; um . KAFAALAARLYRAALARQLGVAA [ SEQ ID NO : 49 ]; 65 FIG . 5 shows micrographs of microglia treated with FAKLAARLYRAALARQLGVAA [ SEQ ID NO : 50 ]; TNF - a and MK2i ( YARAAARQARAKALARQLGVAA WLRRIKAWRRIKALNRQLGVA SEQ ID NO : 56 ] ; [SEQ ID NO : 33 ] ) . Row 1 shows non -MK2i - treated micro US 9 ,890 , 195 B2 29 30 glia ( control) exposed to 0 ng /ml TNF - a and 10 ng /ml insufflation ( i . e . , through the mouth or through the nose ), or TNF- a ; Row 2 shows 1 mM MK2i- treated microglia rectally in dosage unit formulations containing the conven exposed to 0 ng/ ml TNF - a and 10 ng /ml TNF - a . Scale bar tional nontoxic pharmaceutically acceptable carriers , adju is 25 um . vants , and vehicles as desired , or may be locally adminis FIG . 6 shows micrographs of astrocytes treated with 5 tered by means such as , but not limited to , injection , TNF - a and MK2i ( YARAAARQARAKALARQLGVAA implantation , grafting, topical application , or parenterally . [ SEQ ID NO : 33 ] ) . Row 1 shows non -MK2i - treated astro The term " parenteral” as used herein refers to introduction cytes exposed to 0 ng /ml , 5 ng /ml and 10 ng /ml TNF - a , into the body by way of an injection (i . e . , administration by respectively ; Row 2 shows 0 . 5 mM MK2i - treated astrocytes injection ), including , for example , subcutaneously ( i . e . , an exposed to 0 ng /ml , 5 ng/ ml and 10 ng /ml TNF - a , respec - 10 injection beneath the skin ), intramuscularly ( i. e ., an injection tively ; Row 3 shows 1 mM MK2i- treated astrocytes exposed into a muscle ) , intravenously ( i. e . , an injection into a vein ) , to 0 ng/ ml , 5 ng /ml and 10 ng/ ml TNF - a , respectively ; and intrathecally (i . e . , an injection into the space around the Row 4 shows 3 mm MK2i- treated astrocytes exposed toO spinal cord or under the arachnoid membrane of the brain ) , ng/ ml , 5 ng /ml and 10 ng/ ml TNF - a , respectively. Scale bar intrasternal injection or infusion techniques. A parenterally is 100 um . 15 administered composition is delivered using a needle , e . g ., a FIG . 7 shows graphs ( A - F ) of mean concentrations of surgical needle . The term " surgical needle ” as used herein , IL - 6 and IL - 13 following 4 hour , 8 hour, and 24 hour refers to any needle adapted for delivery of fluid ( i . e . , treatments with TNF - a or TNF - a plus MK2i ( YARAAAR capable of flow ) compositions into a selected anatomical QARAKALARQLGVAA [ SEQ ID NO : 33 ]) . structure. Injectable preparations, such as sterile injectable FIG . 8 shows a graph of the net % dead cells versus 24 20 aqueous or oleaginous suspensions , may be formulated treatments of 1 ) 5 ng/ ml TNF - a plus 500 um MK2i according to the known art using suitable dispersing or ( YARAAARQARAKALARQLGVAA [ SEQ ID NO : 33 ] ) ; wetting agents and suspending agents . 2 ) 5 ng /ml TNF -a plus 1 mM MK2i; 3 ) 5 ng /ml TNF -a plus Additional administration may be performed , for 3 mM MK2i; 4 ) 10 nm /ml TNF -a plus 500 UM MK2i; 5 ) 10 example , intravenously , pericardially , orally , via implant, ng/ ml TNF - a plus 1 mM MK2i; and 6 ) 10 ng/ ml TNF -a plus 25 transmucosally , transdermally , intramuscularly , subcutane 3 mM MK2i. ously , intraperitoneally , intrathecally , intralymphatically, FIG . 9 shows a graph of normalized intensity of the intralesionally, or epidurally . Administering can be per expression level of the MK2 protein by cultured cortical formed , for example , once , a plurality of times , and / or over cells following 24 hour MK2i ( YARAAARQARAKALAR one or more extended periods. QLGVAA (SEQ ID NO : 33 ]) (500 uM ) treatment. The upper 30 The meanings for anatomical positions as used herein are right corner of the figure shows a western blot analysis of the as follows. When referring to animals that typically have one MK2 protein following MK2i (500 uM ) treatment. end with a head and mouth , with the opposite end often FIG . 10 shows a graph of myeloperoxidase enzyme having the anus and tail , the head end is referred to as the (MPO ) activity ( units /protein ) from 0 . 9 % NaC1, MK2i 500 " cranial end ," while the tail end is referred to as the “ caudal UM , MK2i 50 UM , MK2i 5 uM , and control. 35 end .” Within the head itself , “ rostral” refers to the direction toward the end of the nose , and " caudal” is used to refer to DETAILED DESCRIPTION the tail direction . The surface or side of an animal' s body that is normally oriented upwards, away from the pull of Glossary gravity , is the “ dorsal” side; the opposite side , typically the 40 one closest to the ground when walking on all legs , swim The abbreviations used herein for amino acids are those ming or flying , is the “ ventral” side . On the limbs or other abbreviations which are conventionally used : appendages, a point closer to the main body is " proximal” ; A = Ala - Alanine ; R = Arg = Arginine ; N = Asn = Asparagine ; a point farther away is “ distal .” Three basic reference planes D = Asp = Aspartic acid ; C = Cys = Cysteine ; are used in zoological anatomy: ( 1 ) a " sagittal " plane divides Q - Gln = Glutamine ; E = Glu = Gutamic acid ; G = Gly = Glycine; 45 the body into left and right portions, ( 2 ) the " midsagittal” H = His = Histidine ; 1 = Ile = Isoleucine; L = Leu = Leucine; plane is in the midline, i. e . it would pass through midline K = Lys= Lysine ; M = Met = Methionine ; F = Phe = Phenyalanine ; structures such as the spine, and all other sagittal planes are P = Pro = Proline ; S = Ser = Serine ; T = Thr = Threonine ; parallel to it , and (3 ) a " coronal” plane divides the body into W = Trp = Tryptophan ; Y = Tyr = Tyrosine ; V = Val = Valine . The dorsal and ventral portions . A “ transverse ” plane divides the amino acids may be L - or D - amino acids . An amino acid 50 body into cranial and caudal portions. may be replaced by a synthetic amino acid which is altered When referring to humans, the body and its parts are so as to increase the half- life of the peptide or to increase the always described using the assumption that the body is potency of the peptide , or to increase the bioavailability of standing upright. Portions of the body which are closer to the the peptide . head end are " superior” ( corresponding to cranial in ani The phrase " additional active agent” refers to an agent, 55 mals ) , while those farther away are “ inferior” (correspond other than a compound of the inventive composition , that ing to caudal in animals ) . Objects near the front of the body exerts a pharmacological, or any other beneficial activity . are referred to as " anterior" ( corresponding to ventral in Such additional active agents include , but are not limited to , animals ) ; those near the rear of the body are referred to as an antifungal agent, an antibiotic , an antiviral agent, an " posterior ” ( corresponding to dorsal in animals ). A trans antiprotozoal agent, an anesthetic agent, a chemotherapeutic 60 verse , axial, or horizontal plane is an X - Y plane, parallel to agent, a vitamin , a hormone and a steroid . the ground , which separates the superior/ head from the The terms “ administering ” or “ administration ” as used inferior/ feet . A coronal or frontal plane is an Y - Z plane , herein are used interchangeably to mean the giving or perpendicular to the ground , which separates the anterior applying of a substance and include in vivo administration , from the posterior. A sagittal plane is an X - Z plane, perpen as well as administration directly to tissue ex vivo . Gener - 65 dicular to the ground and to the coronal plane, which ally , compositions may be administered systemically either separates left from right. The midsagittal plane is the specific orally , buccally , parenterally , topically , by inhalation or sagittal plane that is exactly in the middle of the body. US 9 ,890 , 195 B2 31 32 Structures near the midline are called “ medial” and those tosine , Halethazole , Hexetidine , Loflucarban , Nifuratel, near the sides of animals are called “ lateral. ” Therefore , Potassium Iodide , Propionic Acid , Pyrithione , Salicy medial structures are closer to the midsagittal plane, lateral lanilide, Sodium Propionate , Sulbentine , Tenonitrozole , Tri structures are further from the midsagittal plane. Structures acetin , Ujothion , Undecylenic Acid , and Zinc Propionate . in the midline of the body are median . For example , the tip 5 The term “ anti -protozoal agent” as used herein means any of a human subject' s nose is in the median line . “ Ipsilateral” of a group of chemical substances having the capacity to means on the same side , " contralateral” means on the other inhibit the growth of or to destroy protozoans used chiefly in side and bilateral means on both sides. Structures that are close to the center of the body are proximal or central, while the treatment of protozoal diseases . Examples of antiproto ones more distant are distal or peripheral . For example , the 10 zoal agents , without limitation , include pyrimethamine hands are at the distal end of the arms, while the shoulders (Daraprim® ) sulfadiazine , and Leucovorin . are at the proximal ends . The term “ anti -viral agent" as used herein means any of The term “ anesthetic agents ” as used herein refers to a group of chemical substances having the capacity to inhibit agents that resulting in a reduction or loss of sensation . the replication of or to destroy viruses used chiefly in the Non - limiting examples of anesthetic drugs that are suitable 1515 treatreatment of viral diseases. Anti - viral agents include , but are for use in the context of the present invention include not limited to , Acyclovir , Cidofovir, Cytarabine , Dideoxy pharmaceutically acceptable salts of lidocaine , bupivacaine , adenosine , Didanosine , Edoxudine, Famciclovir , Floxuri chlorprocaine , dibucaine, etidocaine , mepivacaine , tetra dine , Ganciclovir , Idoxuridine , Inosine Pranobex , Lamivu caine , dyclonine , hexylcaine , procaine , cocaine , ketamine , dine , MADU , Penciclovir , Sorivudine , Stavudine , pramoxine and phenol. 20 Trifluridine , Valacyclovir, Vidarabine, Zalcitabine , Zidovu The term “ antibiotic agent" as used herein means any of dine , Acemannan , Acetylleucine, Amantadine , Amidinomy a group of chemical substances having the capacity to inhibit cin , Delavirdine , Foscamet, Indinavir , Interferons ( e . g ., IFN the growth of, or to destroy bacteria , and other microorgan - alpha ) , Kethoxal, Lysozyme, Methisazone , Moroxydine , isms, used chiefly in the treatment of infectious diseases . Nevirapine , Podophyllotoxin , Ribavirin , Rimantadine , Rito Examples of antibiotic agents include , but are not limited to , 25 navir2 , Saquinavir , Stailimycin , Statolon , Tromantadine , Penicillin G ; Methicillin ; Nafcillin ; Oxacillin ; Cloxacillin ; Zidovudine (AZT ) and Xenazoic Acid . Dicloxacillin ; Ampicillin ; Amoxicillin ; Ticarcillin ; Carbeni- The term “ associate ” or any of its grammatical forms as cillin ; Mezlocillin ; Azlocillin ; Piperacillin ; Imipenem ; used herein refers to joining , connecting , or combining to , Aztreonam ; Cephalothin ; Cefaclor ; Cefoxitin ; Cefuroxime; either directly , indirectly, actively , inactively, inertly , non Cefonicid ; Cefmetazole ; Cefotetan ; Cefprozil ; Loracarbef ; 30 inertly , completely or incompletely . Cefetamet; Cefoperazone ; Cefotaxime; Ceftizoxime; Ceftri- The term “ axon ” as used herein refers to the usually long axone; Ceftazidime; Cefepime; Cefixime; Cefpodoxime; process of a nerve fiber that generally conducts impulses Cefsulodin ; Fleroxacin ; Nalidixic acid ; Norfloxacin ; Cipro - away from the body of the nerve cell . floxacin ; Ofloxacin ; Enoxacin ; Lomefloxacin ; Cinoxacin ; The term “ biomedical device ” as used herein refers to an Doxycycline ; Minocycline ; Tetracycline ; Amikacin ; Gen - 35 instrumentality to be implanted into or onto a subject in tamicin ; Kanamycin ; Netilmicin ; Tobramycin ; Streptomy- order to bring about a desired result . Examples of biomedi cin ; Azithromycin ; Clarithromycin , Erythromycin ; Erythro cal devices, include , but are not limited to , stents , grafts , mycin estolate ; Erythromycin ethyl succinate ; Erythromycin shunts , stent grafts , fistulas, angioplasty devices , balloon glucoheptonate ; Erythromycin lactobionate ; Erythromycin catheters , venous catheters, implantable drug delivery stearate ; Vancomycin ; Teicoplanin ; Chloramphenicol; Clin - 40 devices , adhesion barriers , wound dressings, hydrocolloids, damycin , Trimethoprim ; Sulfamethoxazole ; Nitrofurantoin ; hydrogels , foams, hydrophilic foams, hydrophobic foams, Rifampin ; Mupirocin ; Metronidazole ; Cephalexin ; Rox - calcium alginates , cellophane, pluronics , biological poly ithromycin ; Co -amoxiclavuanate ; combinations of Pipera - mers , microelectrodes, probes , and tissue scaffolds . cillin and Tazobactam ; and their various salts , acids, bases, The terms “ carrier” and “ pharmaceutical carrier” as used and other derivatives . Anti - bacterial antibiotic agents 45 herein refer to a pharmaceutically acceptable inert agent or include , but are not limited to , penicillins , cephalosporins, vehicle for delivering one or more active agents to a mam carbacephems, cephamycins , carbapenems, monobactams, mal, and often is referred to as “ excipient . " aminoglycosides, glycopeptides , quinolones, tetracyclines, The term “ cell body ” as used herein refers to the meta macrolides, and fluoroquinolones . bolic center of a neuron . Three organelles are characteristic The term “ anti - fungal agent” as used herein means any of 50 of the cell body : the nucleus , the endoplasmic reticulum , and a group of chemical substances having the capacity to inhibit the Golgi apparatus . The cell body usually gives rise to the growth of or to destroy fungi. Anti - fungal agents include , several fine arborizing outgrowths or extensions called den but are not limited to , Amphotericin B , Candicidin , Dermo drites . The cell body also gives rise to the axon . statin , Filipin , Fungichromin , Hachimycin , Hamycin , The term “ chemotherapeutic agent” refers to chemicals Lucensomycin , Mepartricin , Natamycin , Nystatin , Pecilo - 55 useful in the treatment or control of a disease . Non - limiting cin , Perimycin , Azaserine , Griseofulvin , Oligomycins , Neo - examples of chemotherapeutic agents usable in context of mycin , Pyrrolnitrin , Siccanin , Tubercidin , Viridin , Buten the present invention include daunorubicin , doxorubicin , afine , Naftifine, Terbinafine , Bifonazole , Butoconazole , idarubicin , amrubicin , pirarubicin , epirubicin , mitoxantrone , Chlordantoin , Chlormidazole , Cloconazole , Clotrimazole , etoposide , teniposide , vinblastine , vincristine , mitomycin C , Econazole , Enilconazole , Fenticonazole , Flutrimazole , Iso - 60 5 - FU , paclitaxel, docetaxel, actinomycin D , colchicine, conazole , Ketoconazole , Lanoconazole , Miconazole, Omo - topotecan , irinotecan , gemcitabine cyclosporin , verapamil , conazole , Oxiconazole , Sertaconazole , Sulconazole , Tio - valspodor, probenecid , MK571, GF120918 , LY335979 , biri conazole , Tolciclate , Tolindate , Tolnaftate , Fluconawle , codar, terfenadine , quinidine , pervilleine A and XR9576 . Itraconazole , Saperconazole , Terconazole , Acrisorcin , Amo - The term " condition " as used herein refers to a variety of rolfine, Biphenamine, Bromosalicylchloranilide, Buclos - 65 health states and is meant to include disorders or diseases amide, Calcium Propionate , Chlorphenesin , Ciclopirox , caused by any underlying mechanism or disorder, injury , and Cloxyquin , Coparaffinate , Diamthazole, Exalamide, Flucy the promotion of healthy tissues and organs . US 9 ,890 , 195 B2 33 34 The term " contact ” as used herein refers to a state or The term " drug ” as used herein refers to a therapeutic condition of touching or of being in immediate or local agent or any substance , other than food , used in the preven proximity . The term " contacting” as used herein refersare toto tion , diagnosis , alleviation , treatment , or cure of disease . bringing or putting in contact, or to being in or coming into The term “ EPRO composition ” as used herein refers to a contact. Contacting a composition to a target destination , 5 composition of the described invention , which , when used in such as, but not limited to , an organ , tissue , cell, or tumor, a therapeutically effective amount, provides at least one of may occur by any means of administration known to the the following long term effects : enhanced neurite outgrowth ; skilled artisan . neuroprotection , or enhanced neural regeneration . For The term “ controlled release ” is intended to refer to any example , an EPRO composition can be a neurite outgrowth drug - containing formulation in which the manner and profile 10 enhancing composition , a neuroprotective composition , or a of drug release from the formulation are regulated . nerve regeneration enhancing composition . The phrase The term “ controllable regulatory element” as used herein “ nerve regeneration enhancing composition ” as used herein refers to nucleic acid sequences capable of effecting the refers to a composition that enhances nerve regeneration of expression of the nucleic acids, or the peptide or protein at least nerve process from a neuron cell body. The term product thereof. Controllable regulatory elements may be 15 " neurite outgrowth enhancing composition " as used herein operably linked to the nucleic acids , peptides , or proteins of refers to a composition that enhances outgrowth of at least the present invention . The controllable regulatory elements , one neurite process from a neuron cell body . The term such as , but not limited to , control sequences , need not be “ neuroprotective composition " as used herein refers to a contiguous with the nucleic acids, peptides, or proteins composition that protects at least one neuron from progres whose expression they control as long as they function to 20 sion of a neuronal injury . direct the expression thereof . Thus, for example , intervening The term " enhance ” as used herein refers to an increase or untranslated yet transcribed sequences may be present intensify in quality or quantity ; to make better or augment. between a promoter sequence and a nucleic acid of the The term “ graft” as used herein means a transplantation of present invention and the promoter sequence may still be a portion of living or artificial tissue from one part of a considered “ operably linked to the coding sequence . Other 25 subject to another , or from one subject to another, and refers such control sequences include , but are not limited to , to both natural and prosthetic grafts and implants . Grafts polyadenylation signals , termination signals , and ribosome include, but are not limited to , vascular grafts and stent binding sites. 8grafts . The term “ cytokine ” as used herein refers to small soluble The term " growth ” as used herein refers to a process of protein substances secreted by cells which have a variety of 30 becoming larger, longer or more numerous, or an increase in effects on other cells . Cytokines mediate many important size , number, or volume of cells in a cell population . physiological functions including growth , development. The term “ hormone ” as used herein refers to natural wound healing , and the immune response . They act by substances produced by organs of the body that travel by binding to their cell -specific receptors located in the cell blood to trigger activity in other locations or their synthetic membrane , which allows a distinct signal transduction cas - 35 analogs . Suitable hormones for use in the context of the cade to start in the cell , which eventually will lead to present invention include , but are not limited to , calciferol biochemical and phenotypic changes in target cells . Gener- (Vitamin D3 ) and its products , androgens, estrogens and ally, cytokines act locally. They include type I cytokines, progesterones . which encompass many of the interleukins, as well as The term " hybridization ” refers to the binding of two several hematopoietic growth factors ; type II cytokines , 40 single stranded nucleic acid molecules to each other through including the interferons and interleukin - 10 ; tumor necrosis base pairing . Nucleotides will bind to their complement factor (“ TNF” ) -related molecules, including TNFa and lym - under normal conditions, so two perfectly complementary photoxin ; immunoglobulin super- family members , includ - strands will bind (or “anneal ' ) to each other readily . How ing interleukin 1 (“ IL - 1 ” ) ; and the chemokines, a family of ever , due to the differentmolecular geometries of the nucleo molecules that play a critical role in a wide variety of 45 tides , a single inconsistency between the two strands will immune and inflammatory functions . The same cytokine can make binding between them more energetically unfavorable . have different effects on a cell depending on the state of the The effects of base incompatibility may be measured by cell. Cytokines often regulate the expression of, and trigger quantifying the rate at which two strands anneal; this may cascades of, other cytokines . provide information as to the similarity in base sequence The term " dendrite ” as used herein refers to a branched 50 between the two strands being annealed . protoplasmic outgrowth or extension of a nerve cell that The term “ hydrate ” as used herein refers to a compound conducts impulses from adjacent cells inward toward the formed by the addition of water or its elements to another cell body . A single nerve may possess many dendrites . molecule . The water usually is split off by heat, yielding the The term " delayed release ” is used herein in its conven - anhydrous compound . tional sense to refer to a drug formulation in which there is 55 The term " implant” refers to any device or material a time delay between administration of the formulation and inserted or placed , permanently or temporarily , into or onto the release of the drug there from . “ Delayed release " may or a subject and used for the administration or delivery of a may not involve gradual release of drug over an extended therapeutic agent( s ) or substance . period of time, and thus may or may not be “ sustained The term “ increase ” and its various grammatical forms as release . ” For example, delayed absorption of a parenterally 60 used herein refers to adding to , augmenting , making or administered drug form may be accomplished by dissolving becoming greater, as in number, size , strength , or quality . or suspending the drug in an oil vehicle . The term " inflammation ” as used herein refers to the The term “ disease ” or “ disorder ” as used herein refers to physiologic process by which vascularized tissues respond an impairment of health or a condition of abnormal func - to injury. See , e . g ., FUNDAMENTAL IMMUNOLOGY, 4th tioning . 65 Ed . , William E . Paul, ed . Lippincott -Raven Publishers , The term “ disposed ” as used herein means to place , set or Philadelphia ( 1999 ) at 1051- 1053 , incorporated herein by arrange in a particular order. reference . During the inflammatory process, cells involved US 9 ,890 , 195 B2 35 36 in detoxification and repair are mobilized to the compro - Zarling et al ., PCT/ US93 /03868 . Likewise , a naturally mised site by inflammatory mediators . Inflammation is often occurring nucleic acid ( for example , a promoter) becomes characterized by a strong infiltration of leukocytes at the site isolated if it is introduced by non -naturally occurring means of inflammation , particularly neutrophils (polymorphonu to a locus of the genome not native to that nucleic acid . clear cells ) . These cells promote tissue damage by releasing 5 Nucleic acids that are “ isolated ” as defined herein are toxic substances at the vascular wall or in uninjured tissue . inclusive of those termed " heterologous ” nucleic acids. Traditionally , inflammation has been divided into acute and The term “ long- term ” release , as used herein , means that chronic responses . an implant is constructed and arranged to deliver therapeutic The term “ acute inflammation " as used herein refers to the levels of the active ingredient for at least 7 days , or for about rapid , short- lived (minutes to days ) , relatively uniform 10 30 to about 60 days. response to acute injury characterized by accumulations of The term " macrophage ” as used herein refers to a mono fluid , plasma proteins , and neutrophilic leukocytes. nuclear , actively phagocytic cell arising from monocystic Examples of injurious agents that cause acute inflammation stem cells in the bone marrow . These cells are widely include , but are not limited to , pathogens ( e . g ., bacteria , distributed in the body and vary in morphology and motility . viruses , parasites ) , foreign bodies from exogenous ( e . g . 15 Phagocytic activity is typically mediated by serum recog asbestos ) or endogenous ( e . g ., urate crystals , immune com - nition factors, including certain immunoglobulins and com plexes ) , sources , and physical ( e . g ., burns ) or chemical ( e . g ., ponents of the complement system , but also may be non caustics ) agents. specific . Macrophages also are involved in both the The term “ chronic inflammation " as used herein refers to production of antibodies and in cell -mediated immune inflammation that is of longer duration and which has a 20 responses, particularly in presenting antigens to lympho vague and indefinite termination . Chronic inflammation cytes . They secrete a variety of immunoregulatory mol takes over when acute inflammation persists , either through ecules . incomplete clearance of the initial inflammatory agent or as The term " mammalian cell ” as used herein refers to a cell a result of multiple acute events occurring in the same derived from an animal of the class Mammalia . As used location . Chronic inflammation , which includes the influx of 25 herein , mammalian cells may include normal, abnormal and lymphocytes and macrophages and fibroblast growth , may transformed cells . Examples of mammalian cells utilized result in tissue scarring at sites of prolonged or repeated within the present invention , include , but are not limited to , inflammatory activity . neurons, epithelial cells , muscle cells , blood cells , immune The terms “ inhibiting” , “ inhibit ” or “ inhibition ” as used cells , stem cells , osteocytes, endothelial cells and blast cells . herein are used to refer to reducing the amount or rate of a 30 Cells may be utilized in vivo or in vitro . process, to stopping the process entirely , or to decreasing , The term “ manifestation " as used herein refers to a limiting , or blocking the action or function thereof. Inhibi perceivable or evident materialization of a disease , disorder, tion may include a reduction or decrease of the amount, rate , condition or injury . action function , or process by at least 5 % , at least 10 % , at The term “ microglia ” as used herein refers to the smallest least 15 % , at least 20 % , at least 25 % , at least 30 % , at least 35 of the glial cells that can act as phagocytic cells , cleaning up 40 % , at least 45 % , at least 50 % , at least 55 % , at least 60 % , CNS debris . They are considered to be a type of immune cell at least 65 % , at least 70 % , at least 75 % , at least 80 % , at least found in the brain . Microglia are close cousins of other 85 % , at least 90 % , at least 95 % , at least 98 % , or at least 99 % phagocytic cells including macrophages and dendritic cells . when compared to a reference substance , wherein the ref Like macrophages, microglia are derived from myeloid erence substance is a substance that is not inhibited . 40 progenitor cells from the bone marrow . During embryonic The term “ injury ” as used herein refers to damage or harm development, these cells migrate to the CNS where they to a structure or function of the body caused by an outside differentiate into microglia . agent or force , which may be physical or chemical. The term " modulate ” as used herein means to regulate , The term “ isolated ” refers to a material, such as a nucleic alter, adapt , or adjust to a certain measure or proportion . acid , a peptide , or a protein , which is : ( 1 ) substantially or 45 The term “ neurite ” as used herein refers to any projection essentially free from components that normally accompany or process from the cell body of a neuron . or interact with it as found in its naturally occurring envi- The term “ neuron " as used herein refers to a specialized , ronment. The terms “ substantially or essentially free ” are impulse - conducting cell that is the functional unit of the used to refer to a material, which is at least 80 % free from nervous system , comprising the cell body and its processes , components that normally accompany or interact with it as 50 the axon and dendrites . found in its naturally occurring environment. The isolated The term “ neuropathy ” as used herein refers to a diseased material optionally comprises material not found with the condition of the nervous system . material in its natural environment ; or ( 2 ) if the material is The term “ non - steroidal anti - inflammatory agents ” refers in its natural environment, the material has been syntheti - to a large group of agents that are aspirin - like in their action , cally ( non -naturally ) altered by deliberate human interven - 55 including, but not limited to , ibuprofen , naproxen sodium , tion to a composition and/ or placed at a location in the cell and acetaminophen . Additional examples of non - steroidal ( e . g . , genome or subcellular organelle ) not native to a anti - inflammatory agents that are usable in the contextof the material found in that environment. The alteration to yield present invention include , without limitation , oxicams, such the synthetic material may be performed on the material as piroxicam , isoxicam , tenoxicam , sudoxicam , and CP - 14 , within , or removed , from its natural state . For example , a 60 304 ; disalcid , benorylate , trilisate, safapryn , solprin , difluni naturally occurring nucleic acid becomes an isolated nucleic sal , and fendosal ; acetic acid derivatives, such as diclofenac , acid if it is altered , or if it is transcribed from DNA that has fenclofenac , indomethacin , sulindac , tolmetin , isoxepac , been altered , by means of human intervention performed furofenac , tiopinac , zidometacin , acematacin , fentiazac , within the cell from which it originates . See , for example , zomepirac , clindanac , oxepinac , felbinac , and ketorolac ; Compounds and Methods for Site Directed Mutagenesis in 65 fenamates , such as mefenamic , meclofenamic , flufenamic , Eukaryotic Cells , Kmiec , U . S . Pat. No. 5 , 565 , 350 ; In Vivo niflumic , and tolfenamic acids ; propionic acid derivatives , Homologous Sequence Targeting in Eukaryotic Cells ; such as ibuprofen , naproxen , benoxaprofen , flurbiprofen , US 9 ,890 , 195 B2 37 38 ketoprofen , fenoprofen , fenbufen , indopropfen , pirprofen , by human manipulation which do not occur naturally . Cir carprofen , oxaprozin , pranoprofen , miroprofen , tioxaprofen , cular, branched and branched circular polypeptides may be suprofen , alminoprofen , and tiaprofenic ; pyrazoles, such as synthesized by non - translation natural process and by phenylbutazone , oxyphenbutazone , feprazone , azapropa entirely synthetic methods, as well . zone , and trimethazone . Mixtures of these non -steroidal 5 The term " peptidomimetic ” as used herein refers to a anti - inflammatory agents may also be employed , as well as small protein - like chain designed to mimic a peptide . A the dermatologically acceptable salts and esters of these peptidomimetic typically arises from modification of an agents . existing peptide in order to alter the molecule ' s properties . The term “ nucleic acid ” as used herein refers to a deoxy - The term “ pharmaceutical composition ” as used herein ribonucleotide or ribonucleotide polymer in either single - or 10 refers to a composition that is employed to prevent, reduce double -stranded form , and unless otherwise limited , encom - in intensity , cure or otherwise treat a target condition , passes known analogues having the essential nature of syndrome, disorder or disease . natural nucleotides in that they hybridize to single - stranded The term “ pharmaceutically acceptable carrier” as used nucleic acids in a manner similar to naturally occurring herein refers to one or more compatible solid or liquid filler , nucleotides ( e . g . , peptide nucleic acids ) . 15 diluents or encapsulating substances which are suitable for The term “ nucleotide ” as used herein refers to a chemical administration to a human or other vertebrate animal. compound that consists of a heterocyclic base , a sugar, and The term " pharmaceutically acceptable salt ” as used one or more phosphate groups . In the most common nucleo herein refers to those salts which are , within the scope of tides the base is a derivative of purine or pyrimidine , and the sound medical judgment, suitable for use in contact with the sugar is the pentose deoxyribose or ribose . Nucleotides are 20 tissues of humans and lower animals without undue toxicity , the monomers of nucleic acids , with three or more bonding irritation , allergic response and the like and are commensu together in order to form a nucleic acid . Nucleotides are the rate with a reasonable benefit /risk ratio . structural units of RNA , DNA , and several cofactors , includ - The term “ polynucleotide ” refers to a deoxyribopoly ing , but not limited to , CoA , FAD , DMN , NAD , and NADP. nucleotide , ribopolynucleotide , or analogs thereof that have The purines include adenine ( A ) , and guanine ( G ) ; the 25 the essential nature of a natural ribonucleotide in that they pyrimidines include cytosine ( C ) , thymine ( T ) , and uracil hybridize, under stringent hybridization conditions , to sub ( U ) . stantially the same nucleotide sequence as naturally occur The term " operably linked ” as used herein refers to a ring nucleotides and /or allow translation into the same functional linkage between a promoter and a second amino acid ( s ) as the naturally occurring nucleotide( s ). A sequence , wherein the promoter sequence initiates and 30 polynucleotide may be full- length or a subsequence of a mediates transcription of the DNA sequence corresponding native or heterologous structural or regulatory gene . Unless to the second sequence . Generally , operably linked means otherwise indicated , the term includes reference to the that the nucleic acid sequences being linked are contiguous specified sequence as well as the complementary sequence and , where necessary to join two protein coding regions, are thereof. Thus , DNAs or RNAs with backbones modified for contiguous and in the same reading frame. 35 stability or for other reasons are " polynucleotides” as that The term " outgrowth ” as used herein refers to an exten - term is intended herein . Moreover, DNAs or RNAs com sion or projection from a neuron cell body . prising unusual bases , such as inosine , or modified bases , The term “ particles” as used herein refers to nanoparticles such as tritylated bases, to name just two examples , are or microparticles ( or in some instances larger) that may polynucleotides as the term is used herein . It will be appre contain in whole or in part the EPRO composition . 40 ciated that a great variety of modifications have been made The term “ peptide ” as used herein refers to a polymer to DNA and RNA that serve many useful purposes known to formed from the linking together, in a defined order, of those of skill in the art . The term polynucleotide as it is amino acids. The link between one amino acid residue and employed herein embraces such chemically , enzymatically the next is known as an amide or peptide bond . By some or metabolically modified forms of polynucleotides, as well conventions, for example , a peptide is a short polymer , of at 45 as the chemical forms of DNA and RNA characteristic of least 2 amino acids, a " polypeptide” is a single chain of viruses and cells , including among other things, simple and amino acids, and a " protein " contains one or more polypep - complex cells . tides . The term peptide as used herein is inclusive of a The term " process ” as used herein refers to a prolongation polypeptide, a protein or a peptidomimetic . These terms or projection from a nerve ' s cell body , and includes axons apply to amino acid polymers in which one or more amino 50 and dendrites . acid residue is an artificial chemical analogue of a corre The term “ progression " as used herein refers to moving sponding naturally occurring amino acid , as well as to forward or increasing in severity, intensity , or growth . naturally occurring amino acid polymers . The essential The term " reduce ” or “ reducing ” as used herein refers to nature of such analogues of naturally occurring amino acids a decrease in size ; a slowing of the growth or proliferative is that, when incorporated into a protein that protein is 55 rate ; a lowering in degree , or intensity ; or to limiting the specifically reactive to antibodies elicited to the same pro - occurrence of a disorder in individuals at risk of developing tein but consisting entirely of naturally occurring amino the disorder. acids . The terms polypeptide , peptide and protein also are The term “ regenerate ” or “ regeneration ” means regrowth inclusive of modifications including , but not limited to , of a lost or damaged part so that the original function is glycosylation , lipid attachment, sulfation , gamma - carboxy - 60 restored . lation of glutamic acid residues , hydroxylation and ADP - The term “ regulatory sequence ” ( also referred to as a ribosylation . It will be appreciated , as is well known and as " regulatory region ” or “ regulatory element" ) refers to a noted above, that polypeptides may not be entirely linear. promoter, enhancer or other segment of DNA where regu For instance , polypeptides may be branched as a result of latory proteins , such as transcription factors, bind preferen ubiquitination , and they may be circular , with or without 65 tially to control gene expression and thus protein expression . branching , generally as a result of posttranslational events , The following terms are used herein to describe the including natural processing event and events brought about sequence relationships between two or more nucleic acids or US 9 ,890 , 195 B2 39 40 polynucleotides : ( a ) “ reference sequence ” , (b ) " comparison neighborhood word score threshold ( Altschul et al. , supra ) . window ” , ( c ) “ sequence identity ” , ( d ) “ percentage of These initial neighborhood word hits act as seeds for initi sequence identity ” , and ( e ) “ substantial identity ” . ating searches to find longer HSPs containing them . The The term “ reference sequence” refers to a sequence used word hits then are extended in both directions along each as a basis for sequence comparison . A reference sequence 5 sequence for as far as the cumulative alignment score can be may be a subset or the entirety of a specified sequence ; for increased . Cumulative scores are calculated using , for example , as a segment of a full - length cDNA or gene nucleotide sequences, the parameters M ( reward score for a sequence, or the complete cDNA or gene sequence . pair of matching residues ; always > 0 ) and N (penalty score The term " comparison window ” refers to a contiguous for mismatching residues ; always < 0 ) . For amino acid and specified segment of a polynucleotide sequence , 10 sequences , a scoring matrix is used to calculate the cumu wherein the polynucleotide sequence may be compared to a lative score . Extension of the word hits in each direction are reference sequence and wherein the portion of the poly halted when : the cumulative alignment score falls off by the nucleotide sequence in the comparison window may com - quantity X from its maximum achieved value ; the cumula prise additions or deletions ( i. e ., gaps ) compared to the tive score goes to zero or below , due to the accumulation of reference sequence (which does not comprise additions or 15 one or more negative - scoring residue alignments , or the end deletions ) for optimal alignment of the two sequences of either sequence is reached . The BLAST algorithm param Generally , the comparison window is at least 20 contiguous eters W , T , and X determine the sensitivity and speed of the nucleotides in length , and optionally can be at least 30 alignment. The BLASTN program ( for nucleotide contiguous nucleotides in length , at least 40 contiguous sequences ) uses as defaults a word length ( W ) of 11, an nucleotides in length , at least 50 contiguous nucleotides in 20 expectation ( E ) of 10 , a cutoff of 100 , M = 5 , N = - 4 , and a length , at least 100 contiguous nucleotides in length , or comparison of both strands. For amino acid sequences , the longer. Those of skill in the art understand that to avoid a BLASTP program uses as defaults a word length ( W ) of 3 , high similarity to a reference sequence due to inclusion of an expectation ( E ) of 10 , and the BLOSUM62 scoring gaps in the polynucleotide sequence, a gap penalty typically matrix ( see Henikoff & Henikoff ( 1989) Proc. Natl . Acad . is introduced and is subtracted from the number of matches . 25 Sci. USA 89 : 10915 ) . Methods of alignment of sequences for comparison are In addition to calculating percent sequence identity , the well -known in the art . Optimal alignment of sequences for BLAST algorithm also performs a statistical analysis of the comparison may be conducted by the local homology algo similarity between two sequences (see , e . g ., Karlin & Alts rithm of Smith and Waterman , Adv. Appl. Math . 2 :482 chul, Proc . Natl . Acad . Sci. USA 90 :5873 - 5787 ( 1993 )) . One ( 1981 ) ; by the homology alignment algorithm of Needleman 30 measure of similarity provided by the BLAST algorithm is and Wunsch , J . Mol. Biol. 48 : 443 ( 1970 ) ; by the search for the smallest sum probability ( P ( N ) ) , which provides an similarity method of Pearson and Lipman , Proc . Natl. Acad . indication of the probability by which a match between two Sci . 85 : 2444 ( 1988 ) ; by computerized implementations of nucleotide or amino acid sequences would occur by chance . these algorithms, including, but not limited to : CLUSTAL in BLAST searches assume that proteins may be modeled as the PC /Gene program by Intelligenetics , Mountain View , 35 random sequences. However, many real proteins comprise Calif. ; GAP , BESTFIT , BLAST, FASTA , and TFASTA in the regions of nonrandom sequences, which may be homopoly Wisconsin Genetics Software Package , Genetics Computer meric tracts , short -period repeats, or regions enriched in one Group (GCG ) , 575 Science Dr. , Madison , Wis . , USA ; the or more amino acids . Such low - complexity regions may be CLUSTAL program is well described by Higgins and Sharp , aligned between unrelated proteins even though other Gene 73 : 237 - 244 ( 1988 ) ; Higgins and Sharp , CABIOS 40 regions of the protein are entirely dissimilar. A number of 5 : 151- 153 ( 1989 ) ; Corpet , et al. , Nucleic Acids Research low - complexity filter programs may be employed to reduce 16 : 10881- 90 ( 1988 ); Huang , et al. , Computer Applications such low - complexity alignments . For example , the SEG in the Biosciences 8 : 155 -65 ( 1992 ) , and Pearson , et al. , (Wooten and Federhen , Comput. Chem . , 17 : 149- 163 ( 1993 ) ) Methods in Molecular Biology 24 :307 - 331 ( 1994 ) . The and XNU ( Claverie and States , Comput. Chem . , 17 : 191 - 201 BLAST family of programs, which can be used for database 45 ( 1993 ) low - complexity filters may be employed alone or in similarity searches , includes : BLASTN for nucleotide query combination . sequences against nucleotide database sequences; BLASTX As used herein , “ sequence identity ” or “ identity ” in the for nucleotide query sequences against protein database context of two nucleic acid or polypeptide sequences refers sequences ; BLASTP for protein query sequences against to the residues in the two sequences which are the same protein database sequences ; TBLASTN for protein query 50 when aligned for maximum correspondence over a specified sequences against nucleotide database sequences ; and comparison window . When percentage of sequence identity TBLASTX for nucleotide query sequences against nucleo is used in reference to proteins it is recognized that residue tide database sequences . See, Current Protocols in Molecu - positions that are not identical often differ by conservative lar Biology, Chapter 19 , Ausubel , et al ., Eds. , Greene amino acid substitutions , i . e . , where amino acid residues are Publishing and Wiley - Interscience , New York ( 1995 ) . 55 substituted for other amino acid residues with similar chemi Unless otherwise stated , sequence identity / similarity val- cal properties ( e . g . charge or hydrophobicity ) and therefore ues provided herein refer to the value obtained using the do not change the functional properties of the molecule . BLAST 2 . 0 suite of programs using default parameters . Where sequences differ in conservative substitutions, the Altschul et al ., Nucleic Acids Res . 25 : 3389 - 3402 ( 1997 ) . percent sequence identity may be adjusted upwards to Software for performing BLAST analyses is publicly avail - 60 correct for the conservative nature of the substitution . able , e . g . , through the National Center for Biotechnology - Sequences that differ by such conservative substitutions are Information (http :/ / www .hcbi . nlm .nih . gov /) . This algorithm said to have “ sequence similarity ” or “ similarity ” .Means for involves first identifying high scoring sequence pairs (HSPs ) making this adjustment are well -known to those of skill in by identifying short words of length W in the query the art. Typically this involves scoring a conservative sub sequence , which either match or satisfy some positive - 65 stitution as a partial rather than a full mismatch , thereby valued threshold score T when aligned with a word of the increasing the percentage sequence identity . Thus , for same length in a database sequence . T is referred to as the example , where an identical amino acid is given a score of US 9 ,890 , 195 B2 42 1 and a non -conservative substitution is given a score of tative examples of steroidal anti - inflammatory drugs zero , a conservative substitution is given a score between include , without limitation , corticosteroids such as hydro zero and 1 . The scoring of conservative substitutions is cortisone , hydroxyltriamcinolone , alpha -methyl dexametha calculated , e . g ., according to the algorithm of Meyers and sone , dexamethasone -phosphate , beclomethasone dipropi Miller , Computer Applic . Biol. Sci. , 4 : 11 - 17 ( 1988 ) e . g . , as 5 onates , clobetasol valerate , desonide, desoxymethasone , implemented in the program PC /GENE ( Intelligenetics , desoxycorticosterone acetate , dexamethasone , dichlorisone , Mountain View , Calif . , USA ) . diflorasone diacetate , diflucortolone valerate , fluadrenolone , As used herein , " percentage of sequence identity ” means fluclorolone acetonide, fludrocortisone , flumethasone piva the value determined by comparing two optimally aligned late , fluosinolone acetonide, fluocinonide, flucortine buty sequences over a comparison window , wherein the portion 10 lesters, fluocortolone , fluprednidene ( fluprednylidene ) of the polynucleotide sequence in the comparison window acetate , flurandrenolone , halcinonide , hydrocortisone may comprise additions or deletions ( i . e . , gaps ) relative to acetate , hydrocortisone butyrate ,methylprednisolone , triam the reference sequence (which does not comprise additions cinolone acetonide , cortisone , cortodoxone , flucetonide , or deletions) for optimal alignment of the two sequences . fludrocortisone , difluorosone diacetate , fluradrenolone , The percentage is calculated by determining the number of 15 fludrocortisone, difluorosone diacetate , fluradrenolone positions at which the identical nucleic acid base or amino acetonide, medrysone , amcinafel , amcinafide, betametha acid residue occurs in both sequences to yield the number of sone and the balance of its esters, chloroprednisone, chlo matched positions, dividing the number of matched posi - rprednisone acetate , clocortelone, clescinolone, dichlor tions by the total number of positions in the window of isone , diflurprednate , flucloronide, flunisolide , comparison , and multiplying the result by 100 to yield the 20 fluoromethalone, fluperolone, fluprednisolone , hydrocorti percentage of sequence identity . sone valerate , hydrocortisone cyclopentylpropionate , hydro The term “ substantial identity ” of polynucleotide cortamate , meprednisone , paramethasone , prednisolone , sequences means that a polynucleotide comprises a prednisone, beclomethasone dipropionate , triamcinolone, sequence that has at least 70 % sequence identity, at least and mixtures thereof. 80 % sequence identity , at least 90 % sequence identity and at 25 The term " solvate” as used herein refers to a complex least 95 % sequence identity , compared to a reference formed by the attachment of solvent molecules to that of a sequence using one of the alignment programs described solute . using standard parameters . One of skill will recognize that The term " solvent” refers to a substance capable of these values may be adjusted appropriately to determine dissolving another substance ( termed a “ solute " ) to form a corresponding identity of proteins encoded by two nucleo - 30 uniformly dispersed mixture ( solution ) . tide sequences by taking into account codon degeneracy, The term “ specifically hybridizes” as used herein refers to amino acid similarity , reading frame positioning and the the process whereby a nucleic acid distinctively or defini like. Substantial identity of amino acid sequences for these tively forms base pairs with complementary regions of at purposes normally means sequence identity of at least 60 % , least one strand ofDNA that was not originally paired to the or at least 70 % , at least 80 % , at least 90 % , or at least 95 % . 35 nucleic acid . A nucleic acid that selectively hybridizes Another indication that nucleotide sequences are substan - undergoes hybridization , under strigent hybridization con tially identical is if two molecules hybridize to each other ditions, of the nucleic acid sequence to a specified nucleic under stringent conditions . However , nucleic acids that do acid target sequence to a detectably greater degree ( e . g . , at not hybridize to each other under stringent conditions are least 2 - fold over background ) than its hybridization to still substantially identical if the polypeptides that they 40 non - target nucleic acid sequences and to the substantial encode are substantially identical . This may occur , e . g . , exclusion of non -target nucleic acids. Selectively hybridiz when a copy of a nucleic acid is created using the maximum ing sequences typically have about at least 80 % sequence codon degeneracy permitted by the genetic code . One indi- identity , at least 85 % sequence identity , at least 90 % cation that two nucleic acid sequences are substantially sequence identity , at least 95 % sequence identity , or at least identical is that the polypeptide that the first nucleic acid 45 100 % sequence identity ( i . e . , complementary ) with each encodes is immunologically cross reactive with the poly - other. peptide encoded by the second nucleic acid . The term “ stent” as used herein refers to a slender thread , The terms “ substantial identity ” in the context of a peptide rod or catheter inserted into a tubular structure to provide indicates that a peptide comprises a sequence with at least support . Stents may be used to provide support to a blood 70 % sequence identity to a reference sequence , at least 80 % , 50 vessel , or to immobilize or hold in place a surgical graft . at least 85 % , at least 90 % or 95 % sequence identity to the The term “ subject" or " individual” or “ patient” are used reference sequence over a specified comparison window . interchangeably to refer to a member of an animal species of Optionally , optimal alignment is conducted using the homol- mammalian origin , including but not limited to , a mouse , a ogy alignment algorithm of Needleman and Wunsch , J. Mol . rat, a cat , a goat, sheep , horse , hamster , ferret, pig , a dog , a Biol. 48 :443 ( 1970 ) . An indication that two peptide 55 guinea pig , a platypus , a rabbit and a primate , such as, for sequences are substantially identical is that one peptide is example , a monkey , ape, or human . immunologically reactive with antibodies raised against the The term " survival” as used herein refers to a state of second peptide . Thus , a peptide is substantially identical to remaining alive and biologically functional in spite of some a second peptide, for example , where the two peptides differ threat, hardship , adversity or occurrence . only by a conservative substitution . Peptides which are 60 The term " sustained release” (also referred to as " substantially similar ” share sequences as noted above " extended release ” ) is used herein in its conventional sense except that residue positions that are not identical may differ to refer to a drug formulation that provides for gradual by conservative amino acid changes. release of a drug over an extended period of time, and that The term " steroidal anti - inflammatory agent” , as used preferably , although not necessarily , results in substantially herein , refers to any one ofnumerous compounds containing 65 constantblood levels of a drug over an extended time period . a 17 -carbon 4 - ring system and includes the sterols , various The term " syndrome” as used herein refers to a pattern of hormones ( as anabolic steroids ), and glycosides . Represen symptoms indicative of some disease or condition . US 9 ,890 , 195 B2 43 44 The terms “ topical administration ” and “ topically apply the severity of a disorder ; ( b ) limiting the development of ing” as used herein are used interchangeably to refer to symptoms characteristic of a disorder being treated ; (c ) delivering a peptide , a nucleic acid , or a vector comprising limiting the worsening of symptoms characteristic of a the peptide or the nucleic acid onto one or more surfaces of disorder being treated ; ( d ) limiting the recurrence of a a tissue or cell, including epithelial surfaces . Although 5 disorder in patients that previously had the disorder ; and ( e ) topical administration , in contrast to transdermal adminis lirlimiting recurrence of symptoms in patients that were pre tration , generally provides a local rather than a systemic viously symptomatic for the disorder . The term “ treat ” or effect , the terms “ topical administration ” and “ transdermal " treating ” also includes abrogating , substantially inhibiting , administration " as used herein , unless otherwise stated or implied , are used interchangeably . slowing or reversing the progression of a disease , condition The term “ therapeutic agent” as used herein refers to a or disorder , substantially ameliorating clinical or esthetical drug , molecule, nucleic acid , protein , composition or other symptoms of a condition , substantially preventing the substance that provides a therapeutic effect . The term appearance of clinical or esthetical symptoms of a disease , " active " as used herein refers to the ingredient, component condition , or disorder, and protecting from harmful or or constituent of the compositions of the present inventionon 15 amannoying symptoms. responsible for the intended therapeutic effect. The terms The term “ vitamin ” as used herein , refers to any of “ therapeutic agent" and " active agent" are used interchange various organic substances essential in minute quantities to ably herein . An active agent includes , but is not limited to , the nutrition of most animals act especially as coenzymes a nerve regeneration enhancing composition , neurite out and precursors of coenzymes in the regulation of metabolic growth enhancing composition , or a neuroprotective com - 20 processesP . Non -limiting examples of vitamins usable in position . context of the present invention include vitamin A and its The term “ therapeutic component” as used herein refers to analogs and derivatives: retinol, retinal, retinyl palmitate , a therapeutically effective dosage (i . e . , dose and frequency retinoic acid , tretinoin , iso - tretinoin (known collectively as of administration ) that eliminates , reduces , or prevents the retinoids ) , vitamin E ( tocopherol and its derivatives ) , vita progression of a particular disease manifestation in a per - 25smin C ( L - ascorbic acid and its esters and other derivatives ) , centage of a population . An example of a commonly used vitamin B , ( niacinamide and its derivatives) , alpha hydroxy therapeutic component is the ED50 which describes the dose acids ( such as glycolic acid , lactic acid , tartaric acid , malic in a particular dosage that is therapeutically effective for a acid , citric acid , etc . ) and beta hydroxy acids ( such as particular disease manifestation in 50 % of a population . salicylic acid and the like ) . The term “ therapeutic effect” as used herein refers to a 30 1 . Peptides consequence of treatment, the results of which are judged to The described invention provides EPRO compositions. be desirable and beneficial. A therapeutic effectmay include , According to one aspect , an EPRO composition comprises directly or indirectly, the arrest, reduction , or elimination of a therapeutically effective amount of a polypeptide having a disease manifestation . A therapeutic effect also may an amino acid sequence according to Formula I: include , directly or indirectly , the arrest reduction or elimi- 35 nation of the progression of a disease manifestation . 21- 11- 12- 13- 14- 15- 16- 17- 18- 19- 110- 22 The term " therapeutically effective amount" or an w herein Zi and Z2 are independently absent or are " amount effective ” of one or more of the active agents of the transduction domains ; X1 is selected from the group con present invention is an amount that is sufficient to provide a sisting of A , KA , KKA , KKKA and RA , or is absent; therapeutic effect . Generally , an effective amount of the 40 X2 is selected from the group consisting of G , L , A , V , I, active agents that can be employed ranges from about M , Y , W and F , or is an aliphatic amino acid ; 0 .000001 mg/ kg body weight to about 100 mg/ kg body X 3 is selected from the group consisting of V , L , I , A , G , weight. However , dosage levels are based on a variety of Q , N , S , T and C , or is an aliphatic amino acid ; factors , including the type of injury , the age , weight, sex , X4 is selected from the group consisting of Q , N , H , R and medical condition of the patient, the severity of the condi- 45 K ; tion , the route of administration , and the particular active X 5 is selected from the group consisting of Q and N ; agent employed . Thus the dosage regimen may vary widely , X6 is selected from the group consisting of C , A , G , L , V , but can be determined routinely by a physician using stan - I, M , Y, W and F or is an aliphatic amino acid ; dard methods. X7 is selected from the group consisting of S , A , C , T and The terms “ transduction , ” or “ transduce ” as used herein 50 G or is an aliphatic amino acid ; are used interchangeably to refer to the process of crossing X8 is selected from the group consisting of V , L , I and M ; biological membranes. The crossing of biological mem X9 is absent or is any amino acid ; branes may be from one cell to another , from the extracel X10 is absent or is any amino acid ; lular environment to the intracellular environment, or across wherein at least one of the following is true : a cell membrane or nuclear membrane . Materials that may 55 (a ) X3 is N and X7 is not G ; undergo transduction include , but are not limited to , pro (b ) X7 is G and X3 is not N ; teins, fusion proteins, peptides, polypeptides , amino acids, ( c ) X2 is not L ; viral DNA , and bacterial DNA . ( d ) X4 is not R ; As used herein , the term " transduction domain ” means ( e ) X5 is not Q ; one ormore polypeptide or any other molecule that can carry 60 ( f ) X6 is not L ; the active domain across cell membranes . These domains ( g ) X8 is not V ; can be linked to other polypeptides to direct movement of (h ) X10 is absent; the linked polypeptide across cell membranes . In some cases ( i ) X9 and X10 are absent; the transducing molecules do not need to be covalently wherein the polypeptide provides a long term beneficial linked to the active polypeptide . 65 neuronal effect. The term “ treat” or “ treating ” as used herein refers to According to one embodiment, the long term beneficial accomplishing one or more of the following: (a ) reducing neuronal effect is improved or enhanced neurite outgrowth . US 9 ,890 , 195 B2 45 46 According to another embodiment, the long term benefi - continued cial neuronal effect is neuroprotection . According to another embodiment , the long term benefi KAFAALAARLYRKAGC ; [ SEQ ID NO : 23] cial neuronal effect is improved or enhanced neural regen KAFAKLAAQLYRKAGC ; [SEQ ID NO : 24 ] eration . According to another embodiment , in addition to the AGGGGYGRKKRRQRRR ; [SEQ ID NO : 25 ] recited amino acids, X2, X3 , X6 and X7 can be any aliphatic amino acid (whether naturally occurring or not) , including , YARAAARQARA ; [SEQ ID NO : 26 ] but not limited to , beta -alanine and 2 - aminocyclohexane - 1 YGRKKRRORRR ; [SEQ ID NO : 27 ] carboxylic acid . 10 According to another embodiment, X4 is R ; X5 is Q , WLRRIKAWLRRIKA ; [ SEQ ID NO : 28 ] and / or X8 is V . According to another embodiment, X3 is WLRRIKAWLRRIKAWLRRIKA ; [SEQ ID NO : 29] selected from the group consisting of V , L , I, A , G , Q and N . According to another embodiment , X6 is selected from the FAKLAARLYRKA ; [SEQ ID NO : 30 ] group consisting of C , A , G , L , V , I, M , Y, W and F . KAFAALAARLYRKA ; [SEQ ID NO : 18 ] According to another embodiment, X7 is selected from the group consisting of S , A , C , T and G . KAFAKLAARLYRAA ; [SEQ ID NO : 16 ] According to another embodiment, at least one of Z1 and KAFAKLAARLYRA ; [SEQ ID NO : 19 ] Z2 is a transduction domain . According to another embodiment, the transduction FAKLAARLYRAA ; [ SEQ ID NO : 31 ] domain is linked to the rest of the polypeptide via peptide and bonding . (See , for example , Cell 55 : 1179 - 1188 , 1988 ; Cell FAKLAARLYRA . [ SEQ ID NO : 32 ] 55 : 1189 - 1193 , 1988 ; Proc Natl Acad Sci USA 91: 664 -668 , 1994 ; Science 285 : 1569 - 1572 , 1999 ; J Biol Chem 276 : Further exemplary polypeptides according to the inven 3254 -3261 , 2001; and Cancer Res 61: 474 - 477, 2001, each| 25 tion include, but are not limited to any of those listed above , of which is incorporated in their entirety herein by refer wherein one or both of Z1 and Z2 are selected from the ence ) . group consisting of: According to another embodiment, the transduction domain ( s) is / are selected from the group consisting of: 30 WLRRIKAWLRRIKA ; [ SEQ ID NO : 28 ] WLRRIKAWLRRIKAWLRRIKA ; [ SEQ ID NO : 29 ]

( R ) 4 - 9 ; [SEQ .ID NO : 1 ] YGRKKRRRRRR ; [ SEQ ID NO : 27 ] GRKKRRORRRPPQ ; [SEQ ID NO : 2 ] 35 YARAAARQARA ; [ SEQ ID NO : 26 ] RORRKKRG ; [ SEQ ID NO : 3 ] 3 RORRKKRG ; [SEQ ID NO : 3 ] GRKKRROR ; [SEQ ID jääNO : 4 ] 45 GRKKRROR ; [SEQ ID NO : 4 ] AYARAAARQARA ; [ SEQ ID NO : 5 ] 40 KAFAKLAARLYRKA ; [SEQ ID NO : 15 ] DAATATRGRSAASRPTERPRAPARSASRPRRPVE ; [ SEQ ID NO : 6 ] 70 FAKLAARLYRKA ; [SEQ ID NO : 30 ] GWTLNSAGYLLGLINLKALAALAKKIL : [ SEQ ID NO : 7 ] KAFAALAARLYRKA ; [ SEQ ID NO : 18 ] PLSSIFSRIGDP ; [SEQ ID NO : 8 ] KAFAKLAARLYRAA ; [ SEQ ID NO : 16 ] AAVALLPAVLLALLAP ; [ SEQ ID NO : 97 45 KAFAKLAARLYRA ; [SEQ ID NO : 19 ] AAVLLPVLLAAP ; [ SEQ ID NO : 10 ] FAKLAARLYRAA ; [SEQ ID NO : 31 ] VTVLALGALAGVGVG ; [ SEQ ID NO : 11 and GALFLGWLGAAGSTMGAWSQP ; [ SEQ ID NO : 12 ] 50 FAKLAARLYRA . [ SEQ ID NO : 32 ] GWTLNSAGYLLGLINLKALAALAKKIL ; [ SEQ ID NO : 7 ] Further exemplary polypeptides according to the inven tion include , but are not limited to , those comprising or KLALKLALKALKAALKLA ; [ SEQ ID NO : 13 ] consisting of: KETWWETWWTEWSQPKKKRKV ; [SEQ ID NO : 14 ] 55 KAFAKLAARLYRKA ; [ SEQ ID NO : 15 ] YARAAARQARAKALARQLGVAA ; [SEQ ID NO : 33 ] KAFAKLAARLYRAA ; [ SEQ ID NO : 16 ] YGRKKRRQRRRKALARQLGVAA ; [SEQ ID NO : 34 ] AAFAKLAAARLYRKA ; ID NO : 117 ] 30 RORRKKRGKALARQLGVAA ; [SEQ ID NO : 35 ] KAFAALAARLYRKA ; [ SEQ ID NO : 18 ] GRKKRRQRKALARQLGVAA ; [ SEQ ID NO : 36 ] KAFAKLAARLYRKAGC ; NO : 20 ] WLRRIKAWLRRIKAKALARQLGVAA ; [SEQ ID NO : 37 ] KAFAKLAARLYRAAGC ; WLRRIKAWLRIKAWLRRIKAKALARQLGVAA ; [SEQ ID NO : 21 ] 65 [SEQ ID NO : 38 ] AAFAKLAARLYRKAGC ; [SEQ ID NO : 22 ] YARAAARQARAKKKALAROLGVAA ; [ SEQ ID NO : 39 ] US 9 ,890 , 195 B2 47 48 - continued combination of D - and L - amino acids, and various " designer ” amino acids ( e . g ., B -methyl amino acids , C . al YGRKKRRORRRKKKALARQLGVAA ; [SEQ ID NO : 40 ] pha .- methyl amino acids, and Na- methyl amino acids, etc . ) RORRKKRGKKKALARQLGVAA ; [SEQ ID NO : 41] to convey special properties. Synthetic amino acids include ornithine for lysine , and norleucine for leucine or isoleucine. GRKKRRORKKKALARQLGVAA ; In addition , the polypeptides can have peptidomimetic bonds , such as ester bonds , to prepare peptides with novel WLRRIKAWLRRIKAKKKALARQLGVAA ; [SEQ ID NO : 43 ] properties. For example , a peptide may be generated that WLRRIKAWLRRI KAWLRRIKAKKKALAROLGVAA ; ID NO : 44 | incorporates a reduced peptide bond , i . e . , R , — CH , — NH 10 Ry, where R , and R , are amino acid residues or sequences . KAFAKLAARLYRKALARQLGVAA ; [ SEQ ID NO : 45 ] A reduced peptide bond may be introduced as a dipeptide FAKLAARLYRKALARQLGVAA ; [SEQ ID NO : 46 ] subunit. Such a polypeptide would be resistant to protease activity , and would possess an extended half- life in vivo . KAFAKLAARLYRAALARQLGVAA ; [ SEQ ID NO : 47 ] According to another embodiment, the EPRO composi 15 tion is a pharmaceutical composition . KAFAKLAARLYRALARQLGVAA ; [ SEQ ID NO : 48 ] According to another embodiment, the EPRO composi KAFAALAARLYRAALARQLGVAA ; [ SEQ ID NO : 49] tion further comprises at least one additional active agent. According to another embodiment, the additional active FAKLAARLYRAALARQLGVAA ; [ SEQ ID NO : 50 ] agent is an antifungal agent. According to another embodi 20 ment, the additional active agent is an antiviral agent . WLRRIKAWRRIKA - LNRQLGVAA ; According to another embodiment, the additional active YARAAARQARAKALNRQLGVA ; [SEQ ID NO : 51 ] agent is an antiprotozoal agent. According to another embodiment , the additional active agent is an anesthetic KAFAKLAARLYRKALNROLAVAA ; [SEQ ID NO : 52 ] agent . According to another embodiment, the additional FAKLAARLYRKALNROLAVAA ; [ SEQ ID NO : 53 ] 25 active agent is a chemotherapeutic agent. According to another embodiment, the additional active agent is a vita KAFALKAARLYRKA - LNROLGVAA ; min . According to another embodiment, the additional active and agent is a hormone. According to another embodiment, the FAKLAARLYRKA - LNRQLGVAA . additional active agent is a steroid . 30 The pharmaceutical compositions described herein con Further exemplary peptides include WLRRIKAWRmmmmmmmmmmmmmm tain a therapeutically effective amount of an EPRO compo RIKALNRQLGVA SEQ ID NO : 56 ] , KAFALKAAR - sition and optionally at least one other therapeutic agent LYRKALNRQLGVA ( SEQ ID NO : 57 ] , and FAKLAAR - included in a pharmaceutically - acceptable carrier. LYRKALNRQLGVA [SEQ ID NO : 58 ] . According to another embodiment, the EPRO composi Further exemplary peptides include YARAAAR - 35 tion may be formulated for parenteral administration by QARAKALNRQLGVAA [ SEQ ID NO : 59 ] . injection , for example , by bolus injection or continuous Further exemplary polypeptides according to the inven - infusion . Formulations for injection may be presented in unit tion include , but are not limited to , those comprising or dosage form , e . g ., in ampoules or in multi - dose containers , consisting of: KALNRQLGVA [ SEQ ID NO : 54 ] , and with an added preservative . The compositions may take such KALNRQLGVA [ SEQ DNOID NO .: 55 ) . 40 forms as suspensions , solutions or emulsions in oily or The polypeptides of the described invention may be aqueous vehicles , and may contain formulatory agents such chemically synthesized . Synthetic polypeptides, prepared as suspending , stabilizing and /or dispersing agents . Pharma using the well known techniques of solid phase , liquid ceutical formulations for parenteral administration include phase , or peptide condensation techniques , or any combi - aqueous solutions of the active compounds in water - soluble nation thereof, can include natural and unnatural amino 45 form . Additionally , suspensions of the active compounds acids. Amino acids used for peptide synthesis may be may be prepared as appropriate oily suspensions. Suitable standard Boc (Ne - amino protected Na- t -butyloxycarbonyl ) lipophilic solvents or vehicles include fatty oils such as amino acid resin with the standard deprotecting , neutraliza - sesame oil , or synthetic fatty acid esters, such as ethyl oleate tion , coupling and wash protocols of the original solid phase or triglycerides, or liposomes. Aqueous injection suspen procedure of Merrifield ( 1963 , J . Am . Chem . Soc . 85 :2149 - 50 sions may contain substances which increase the viscosity of 2154 ), or the base - labile N - amino protected 9 - fluorenyl- the suspension , such as sodium carboxymethyl cellulose , methoxycarbonyl (Fmoc ) amino acids first described by sorbitol, or dextran . Optionally , the suspension also may Carpino and Han ( 1972 , J . Org . Chem . 37 :3403 - 3409 ) . Both contain suitable stabilizers or agents which increase the Fmoc and Boc Na - amino protected amino acids can be solubility of the compounds to allow for the preparation of obtained from Sigma, Cambridge Research Biochemical, or 55 highly concentrated solutions. Alternatively , the active com other chemical companies familiar to those skilled in the art. pounds may be in powder form for constitution with a In addition , the polypeptides can be synthesized with other suitable vehicle , for example , sterile pyrogen - free water, Na- protecting groups that are familiar to those skilled in this before use . art . The EPRO compositions also may comprise suitable solid Solid phase peptide synthesis may be accomplished by 60 or gel phase carriers or excipients . The (pharmaceutical ) techniques familiar to those in the art and provided , for carrier must be of sufficiently high purity and of sufficiently example , in Stewart and Young , 1984 , Solid Phase Synthe - low toxicity to render it suitable for administration to the sis , Second Edition , Pierce Chemical Co ., Rockford , ill .; mammalbeing treated . The (pharmaceutical ) carrier further Fields and Noble , 1990 , Int. J . Pept. Protein Res. 35 : 161 should maintain the stability and bioavailability of an active 214 , or using automated synthesizers . The polypeptides of 65 agent. The (pharmaceutical ) carrier can be liquid or solid the invention may comprise D - amino acids (which are and is selected , with the planned manner of administration resistant to L -amino acid -specific proteases in vivo ), a in mind , to provide for the desired bulk , consistency, etc ., US 9 ,890 , 195 B2 49 50 when combined with an active agent and other components ited to , acetate , adipate , alginate , citrate , aspartate , benzoate , of a given composition . The (pharmaceutical ) carrier can be , benzenesulfonate , bisulfate , butyrate , camphorate , camphor without limitation , a binding agent ( e . g ., pregelatinised sulfonate , digluconate , glycerophosphate , hemisulfate , hep maize starch , polyvinylpyrrolidone or hydroxypropyl meth tanoate , hexanoate , fumarate , hydrochloride, hydrobromide , ylcellulose , etc . ) , a filler ( e . g . , lactose and other sugars, 5 hydroiodide , 2 - hydroxyethansulfonate ( isethionate ) , lactate , microcrystalline cellulose , pectin , gelatin , calcium sulfate , maleate , methanesulfonate , nicotinate , 2 - naphthalenesul ethyl cellulose , polyacrylates, calcium hydrogen phosphate , fonate, oxalate , pamoate , pectinate , persulfate , 3 -phenylpro etc .) , a lubricant ( e . g . , magnesium stearate , talc , silica , pionate , picrate , pivalate , propionate, succinate , tartrate , colloidal silicon dioxide, stearic acid , metallic stearates , thiocyanate , phosphate , glutamate , bicarbonate , p - toluene hydrogenated vegetable oils , corn starch , polyethylene gly - 10 sulfonate and undecanoate . Also , the basic nitrogen - contain cols , sodium benzoate , sodium acetate , etc . ) , a disintegrant ing groups may be quaternized with such agents as lower ( e . g ., starch , sodium starch glycolate , etc . ) , or a wetting alkyl halides such as methyl, ethyl, propyl , and butyl chlo agent ( e . g ., sodium lauryl sulphate , etc . ). Other suitable rides , bromides and iodides ; dialkyl sulfates like dimethyl, (pharmaceutical ) carriers for the compositions of the diethyl, dibutyl and diamyl sulfates ; long chain halides such described invention include , but are not limited to , water , 15 as decyl , lauryl, myristyl and stearyl chlorides , bromides and salt solutions, alcohols , polyethylene glycols , gelatins, amy iodides; arylalkyl halides like benzyl and phenethyl bro loses , magnesium stearates , talcs , silicic acids, viscous par mides and others . Water or oil -soluble or dispersible prod affins, hydroxymethylcelluloses, polyvinylpyrrolidones and ucts are thereby obtained . Examples of acids which may be the like . Compositions of the described invention that are for employed to form pharmaceutically acceptable acid addition cutaneous administration , such as topical ( i . e . , local) , can 20 salts include such inorganic acids as hydrochloric acid , include (pharmaceutical ) carriers such as sterile and non - hydrobromic acid , sulphuric acid and phosphoric acid and sterile aqueous solutions , non - aqueous solutions in common such organic acids as oxalic acid , maleic acid , succinic acid solvents such as alcohols , or solutions in liquid or solid oil and citric acid . Basic addition salts may be prepared in situ bases . Such ( pharmaceutical) carrier solutions also can con during the final isolation and purification of compounds tain buffers , diluents and other suitable additives. Compo - 25 described within the invention by reacting a carboxylic sitions of the described invention that are for parenteral acid - containing moiety with a suitable base such as the administration , such as intramuscular or subcutaneously , can hydroxide , carbonate or bicarbonate of a pharmaceutically include ( pharmaceutical) carriers such as sterile aqueous acceptable metal cation or with ammonia or an organic solutions , non - aqueous solutions in common solvents such primary , secondary or tertiary amine . Pharmaceutically as alcohols , or solutions in a liquid oil base . Examples of 30 acceptable salts include , but are not limited to , cations based such carriers or excipients include , but are not limited to , on alkali metals or alkaline earth metals such as lithium , calcium carbonate , calcium phosphate , various sugars , sodium , potassium , calcium , magnesium and aluminum salts starches , cellulose derivatives , gelatin , and polymers such as and the like and nontoxic quaternary ammonia and amine polyethylene glycols . cations including ammonium , tetramethylammonium , tetra Suitable liquid or solid pharmaceutical preparation forms 35 ethylammonium , methylamine , dimethylamine , trimethyl are , for example , microencapsulated , and if appropriate , amine , triethylamine, diethylamine, ethylamine and the like . with one or more excipients , encochleated , coated onto Other representative organic amines useful for the formation microscopic gold particles , contained in liposomes , pellets of base addition salts include ethylenediamine , etha for implantation into the tissue , or dried onto an object to be nolamine, diethanolamine, piperidine , piperazine and the rubbed into the tissue. Such pharmaceutical compositions 40 like. Pharmaceutically acceptable salts also may be obtained also may be in the form of granules, beads, powders , tablets , using standard procedures well known in the art , for coated tablets, (micro capsules, suppositories , syrups , emul- example , by reacting a sufficiently basic compound such as sions , suspensions , creams, drops or preparations with pro - an amine with a suitable acid affording a physiologically tracted release of active compounds, in whose preparation acceptable anion . Alkali metal ( for example, sodium , potas excipients and additives and / or auxiliaries such as disinte - 45 sium or lithium ) or alkaline earth metal (for example cal grants , binders , coating agents, swelling agents , lubricants , cium or magnesium ) salts of carboxylic acids also may be or solubilizers are customarily used as described above . The made . pharmaceutical compositions are suitable for use in a variety The formulations may be presented conveniently in unit of drug delivery systems. For a brief review of methods for dosage form and may be prepared by any of the methods drug delivery , see Langer 1990 Science 249, 1527 - 1533 , 50 well known in the art of pharmacy . All methods include the which is incorporated herein by reference . step of bringing into association an EPRO composition , or The EPRO composition , and optionally at least one other a pharmaceutically acceptable salt or solvate thereof (“ active therapeutic , may be administered per se (neat ) or in the form compound " ) , with the carrier , which constitutes one or more of a pharmaceutically acceptable salt , solvate or hydrate accessory agents . In general, the formulations are prepared thereof. When used in medicine , the salts should be phar - 55 by uniformly and intimately bringing into association the maceutically acceptable , but non - pharmaceutically accept- active agent with liquid carriers or finely divided solid able salts may conveniently be used to prepare pharmaceu - carriers or both , and then , if necessary , shaping the product tically acceptable salts thereof. into the desired formulation . Pharmaceutically acceptable salts are well -known in the The pharmaceutical agent or a pharmaceutically accept art . For example , P . H . Stahl, et al . describe pharmaceuti - 60 able ester, salt, solvate or prodrug thereofmay bemixed with cally acceptable salts in detail in “Handbook of Pharmaceu other active materials that do not impair the desired action , tical Salts : Properties, Selection , and Use ” (Wiley VCH , or with materials that supplement the desired action . Solu Zurich , Switzerland : 2002 ) . The salts may be prepared in tions or suspensions used for parenteral , intradermal , sub situ during the final isolation and purification of the com - cutaneous, intrathecal, or topical application may include , pounds described within the present invention or separately 65 but are not limited to , for example , the following compo by reacting a free base function with a suitable organic acid . nents : a sterile diluent such as water for injection , saline Representative acid addition salts include , but are not lim solution , fixed oils , polyethylene glycols , glycerine , propyl US 9 ,890 , 195 B2 51 52 ene glycol or other synthetic solvents ; antibacterial agents employed or as a solvent or suspending medium . For this such as benzyl alcohol or methyl parabens ; antioxidants purpose any bland fixed oil may be employed including such as ascorbic acid or sodium bisulfite ; chelating agents synthetic mono - or diglycerides. In addition , fatty acids such such as ethylenediaminetetraacetic acid ; buffers such as as oleic acid are used in the preparation of injectables . acetates , citrates or phosphates and agents for the adjustment 5 Formulations for parenteral ( including but not limited to , of tonicity such as sodium chloride or dextrose . The parental subcutaneous , intradermal, intramuscular, intravenous , preparation may be enclosed in ampoules, disposable intrathecal and intraarticular) administration include aque syringes or multiple dose vials made of glass or plastic . ous and non -aqueous sterile injection solutions that may Administered intravenously , particular carriers are physi contain anti - oxidants , buffers, bacteriostats and solutes , ological saline or phosphate buffered saline ( PBS ) . 10 which render the formulation isotonic with the blood of the Pharmaceutical compositions for parenteral injection intended recipient ; and aqueous and non - aqueous sterile comprise pharmaceutically acceptable sterile aqueous or suspensions , which may include suspending agents and nonaqueous solutions , dispersions , suspensions or emul - thickening agents . The formulations may be presented in sions and sterile powders for reconstitution into sterile unit - dose or multi- dose containers , for example sealed injectable solutions or dispersions . Examples of suitable 15 ampules and vials , and may be stored in a freeze - dried aqueous and nonaqueous carriers, diluents , solvents or (lyophilized ) condition requiring only the addition of the vehicles include water, ethanol, polyols (propylene glycol, sterile liquid carrier , for example , saline, water - for - injection , polyethylene glycol, glycerol, and the like ) , suitable mix - immediately prior to use . Extemporaneous injection solu tures thereof, vegetable oils ( such as olive oil) and injectable tions and suspensions may be prepared from sterile powders, organic esters such as ethyl oleate . Proper fluidity may be 20 granules and tablets of the kind previously described . maintained , for example , by the use of a coating such as Another method of formulation of the compositions lecithin , by the maintenance of the required particle size in described herein involves conjugating the compounds the case of dispersions, and by the use of surfactants . described herein to a polymer that enhances aqueous solu These compositions also may contain adjuvants including bility . Examples of suitable polymers include but are not preservative agents , wetting agents , emulsifying agents , and 25 limited to polyethylene glycol, poly - ( d - glutamic acid ) , poly dispersing agents . Prevention of the action of microorgan - ( 1 - glutamic acid ), poly - ( 1 - glutamic acid ) , poly - ( d -aspartic isms may be ensured by various antibacterial and antifungal acid ) , poly - ( 1 - aspartic acid ), poly - ( 1 - aspartic acid ) and agents , for example , parabens, chlorobutanol, phenol, sorbic copolymers thereof. Polyglutamic acids having molecular acid , and the like . It also may be desirable to include isotonic weights between about 5 ,000 to about 100 ,000 , with agents , for example , sugars , sodium chloride and the like. 30 molecular weights between about 20 , 000 and about 80 , 000 Prolonged absorption of the injectable pharmaceutical form may be used and with molecular weights between about may be brought about by the use of agents delaying absorp - 30 , 000 and about 60 , 000 also may be used . The polymer is tion , for example , aluminum monostearate and gelatin . conjugated via an ester linkage to one or more hydroxyls of Suspensions , in addition to the active compounds, may an inventive peptide . contain suspending agents, as, for example , ethoxylated 35 Suitable buffering agents include : acetic acid and a salt isostearyl alcohols , polyoxyethylene sorbitol and sorbitan (1 - 2 % w / v ) ; citric acid and a salt ( 1 - 3 % w /v ) ; boric acid and esters, microcrystalline cellulose, aluminum metahydroxide, a salt ( 0 . 5 - 2 . 5 % w / v ) ; and phosphoric acid and a salt bentonite , agar- agar, tragacanth , and mixtures thereof. ( 0 . 8 - 2 % w / v ) . Suitable preservatives include benzalkonium Injectable depot forms are made by forming microencap - chloride ( 0 . 003 - 0 . 03 % w / v ) ; chlorobutanol ( 0 . 3 - 0 . 9 % w / v ) ; sulated matrices of the drug in biodegradable polymers , such 40 parabens ( 0 .01 - 0 . 25 % w / v ) and thimerosal (0 . 004 - 0 . 02 % as polylactide- polyglycolide . Depending upon the ratio of w / v ) . drug to polymer and the nature of the particular polymer The therapeutic agent( s ) , including the EPRO composi employed , the rate of drug release may be controlled . Such tion , may be provided in particles . The particles may contain long acting formulations may be formulated with suitable the therapeutic agent( s ) in a core surrounded by a coating . polymeric or hydrophobic materials ( for example as an 45 The therapeutic agent ( s ) also may be dispersed throughout emulsion in an acceptable oil ) or ion exchange resins, or as the particles. The therapeutic agent( s ) also may be adsorbed sparingly soluble derivatives, for example , as a sparingly o n at least one surface of the particles . The particles may be soluble salt. Examples of other biodegradable polymers of any order release kinetics , including zero order release , include poly ( orthoesters ) and poly ( anhydrides ) . Depot first order release , second order release , delayed release , injectable formulations are also prepared by entrapping the 50 sustained release , immediate release , etc . , and any combi drug in liposomes or microemulsions which are compatible nation thereof. The particle may include , in addition to the with body tissues . therapeutic agent (s ), any of those materials routinely used in Injectable formulationsmay be sterilized , for example , by the art of pharmacy and medicine, including , but not limited filtration through a bacterial- retaining filter or by incorpo - to , erodible , nonerodible , biodegradable , or nonbiodegrad rating sterilizing agents in the form of sterile solid compo - 55 able material or combinations thereof. The particles may be sitions that may be dissolved or dispersed in sterile water or microcapsules that contain the EPRO composition in a other sterile injectable medium just prior to use . Injectable solution or in a semi - solid state . The particles may be of preparations , for example , sterile injectable aqueous or virtually any shape . oleaginous suspensions ,may be formulated according to the Both non - biodegradable and biodegradable polymeric known art using suitable dispersing or wetting agents and 60 materials may be used in the manufacture of particles for suspending agents . The sterile injectable preparation also delivering the therapeutic agent ( s ). Such polymers may be may be a sterile injectable solution , suspension or emulsion natural or synthetic polymers . The polymer is selected based in a nontoxic , parenterally acceptable diluent or solvent such on the period of time over which release is desired . Bioad as a solution in 1 , 3 -butanediol . Among the acceptable hesive polymers of particular interest include bioerodible vehicles and solvents that may be employed are water, 65 hydrogels as described by Sawhney et al in Macromolecules Ringer ' s solution , U . S . P . and isotonic sodium chloride solu - ( 1993 ) 26 , 581 - 587 , the contents of which are incorporated tion . In addition , sterile , fixed oils conventionally are herein by reference . These include polyhyaluronic acids, US 9 ,890 , 195 B2 53 54 casein , gelatin , glutin , polyanhydrides , polyacrylic acid , polypeptide enhances outgrowth of at least one neurite alginate , chitosan , poly (methyl methacrylates) , poly ( ethyl process from a neuron cell body . According to another methacrylates ), poly (butylmethacrylate ), polyisobutyl embodiment, the described invention provides an isolated methacrylate ) , poly (hexylmethacrylate ) , poly ( isodecyl nucleic acid that encodes a polypeptide having at least 85 % methacrylate ) , poly ( laurylmethacrylate ), poly ( phenyl meth - 5 amino acid sequence identity to a peptide having an amino acrylate ), poly (methyl acrylate ), poly (isopropyl acrylate ), acid sequence YARAAARQARAKALARQLGVAA [SEQ poly (isobutyl acrylate ) , and poly (octadecyl acrylate ). ID NO : 33 ], wherein the polypeptide enhances outgrowth of The therapeutic agent( s ) may be contained in controlled at least one neurite process from a neuron cell body. release systems. In order to prolong the effect of a drug , it Methods of extraction of RNA are well -known in the art often is desirable to slow the absorption of the drug from 10 and are described , for example , in J . Sambrook et al . , subcutaneous, intrathecal, or intramuscular injection . This “ Molecular Cloning: A Laboratory Manual” ( Cold Spring may be accomplished by the use of a liquid suspension of Harbor Laboratory Press , Cold Spring Harbor, N . Y . , 1989 ) , crystalline or amorphous material with poor water solubility. vol. 1 , ch . 7 , “ Extraction , Purification , and Analysis of The rate of absorption of the drug then depends upon its rate Messenger RNA from Eukaryotic Cells , " incorporated of dissolution which , in turn , may depend upon crystal size 15 herein by this reference . Other isolation and extraction and crystalline form . This refers to controlled release, imme- methods also are well -known , for example in F . Ausubel et diate as well as non -immediate release formulations , with al. , “ Current Protocols in Molecular Biology ” , John Wiley & non - immediate release formulations including, but not lim - Sons , 2007 ) . Typically, isolation is performed in the pres ited to , sustained release and delayed release formulations. ence of chaotropic agents , such as guanidinium chloride or Use of a long - term sustained release implant may be 20 guanidinium thiocyanate , although other detergents and particularly suitable for treatment of chronic conditions. extraction agents alternatively may be used . Typically, the Long -term sustained release implants are well - known to mRNA is isolated from the total extracted RNA by chroma those of ordinary skill in the art and include some of the tography over oligo (dT ) - cellulose or other chromatographic release systems described above . media that have the capacity to bind the polyadenylated 2 . Isolated Nucleic Acids 25 3 '- portion of mRNA molecules . Alternatively , but less pref According to another aspect, the described invention erably , total RNA can be used . However, it generally is provides an isolated nucleic acid that encodes a polypeptide preferred to isolate poly ( A ) + RNA from mammalian sources . having at least 85 % amino acid sequence identity to a According to another embodiment , the described inven peptide having an amino acid sequence according to For - tion provides an antibody or an antibody fragment that mula I , wherein the polypeptide enhances outgrowth of at 30 specifically binds to an amino acid sequence of a peptide least one neurite process from a neuron cell body . In some having an amino acid sequence according to Formula I , embodiments , the isolated nucleic acid encodes a polypep - wherein the polypeptide enhances outgrowth of at least one tide with 90 % amino acid sequence identity to a peptide neurite process from a neuron cell body . In some such having an amino acid sequence according to Formula I , embodiments , the antibody is used in purification of such wherein the polypeptide enhances outgrowth of at least one 35 peptides . In some such embodiments , the antibody is used in neurite process from a neuron cell body. In some embodi- inhibition of such peptides . In some such embodiments , the ments , the isolated nucleic acid encodes a polypeptide with antibody is used in diagnostic detection of such peptides . 95 % amino acid sequence identity to a peptide having an According to another embodiment, the described inven amino acid sequence according to Formula I , wherein the tion provides an antibody or an antibody fragment that polypeptide enhances outgrowth of at least one neurite 40 specifically binds to an amino acid sequence of a peptide of process from a neuron cell body. In some embodiments , the amino acid sequence YARAAARQARAKALARQLGVAA isolated nucleic acid encodes a polypeptide with 100 % [ SEQ ID NO : 33 ]. According to another embodiment, the amino acid sequence identity to a peptide having an amino described invention provides an antibody or an antibody acid sequence according to Formula I , wherein the polypep - fragment that specifically binds to an amino acid sequence tide enhances outgrowth of at least one neurite process from 45 of a peptide of amino acid sequence YARAAAR a neuron cell body . In some embodiments , the isolated QARAKALNRQLGVA [ SEQ ID NO : 51] . According to nucleic acid is operably linked to a controllable regulatory another embodiment, the described invention provides an element. antibody or an antibody fragment that specifically binds to According to another embodiment, the described inven - an amino acid sequence of a peptide of amino acid sequence tion provides an isolated nucleic acid that encodes a poly - 50 FAKLAARLYRKALARQLGVAA [ SEQ ID NO : 46 ] . peptide having at least 85 % amino acid sequence identity to According to another embodiment, the isolated nucleic a peptide having an amino acid sequence YARAAAR - acids encoding a peptide having an amino acid sequence QARAKALARQLGVAA [ SEQ ID NO : 33 ], wherein the according to Formula I, wherein the polypeptide enhances polypeptide enhances outgrowth of at least one neurite outgrowth of at least one neurite process from a neuron cell process from a neuron cell body. 55 body , are incorporated into an expression vector. According According to another embodiment, the described inven - to some such embodiments , the expression vector is for an tion provides an isolated nucleic acid that specifically eukaryotic cell. According to some such embodiments , the hybridizes to mRNA encoding a peptide comprising an eukaryotic cell is a CHO cell . According to some such amino acid sequence according to Formula I . For example , embodiments , the eukaryotic cell is a BHK cell . According a nucleic acid that may bind or hybridize to at least a portion 60 to some such embodiments , the eukaryotic cell is an NIH of an mRNA of a cell encoding a peptide comprising an 3T3 cell. According to some such embodiments , the eukary amino acid sequence according to Formula I may be con - otic cell is a Cos - 7 cell . According to another embodiment, sidered a nucleic acid that specifically hybridizes. the isolated nucleic acid is an isolated nucleic acid encoding According to another embodiment, the described inven - a polypeptide of amino acid sequence YARAAAR tion provides an isolated nucleic acid that specifically 65 QARAKALARQLGVAA [ SEQ ID NO : 33 ] . According to hybridizes to mRNA encoding a peptide comprising an another embodiment, the isolated nucleic acid is an isolated amino acid sequence according to Formula I , wherein the nucleic acid encoding a polypeptide of amino acid sequence US 9 ,890 , 195 B2 55 56 YARANARQARAKALNRQLGVA (SEQ ID NO : 51 ). ID NO : 5 ] ; DAATATRGRSAASRPTERPRAPARSASR According to another embodiment, the isolated nucleic acid PRRPVE ( SEQ ID NO : 61; GWTLNSAGYLLGLINLKA is an isolated nucleic acid encoding a polypeptide of amino LAALAKKIL ( SEQ ID NO : 71; PLSSIFSRIGDP ( SEQ ID acid sequence FAKLAARLYRKALARQLGVAA [ SEQ ID NO : 8 ] ; AAVALLPAVLLALLAP ( SEQ ID NO : 91; AAV NO : 46 ] . 5 LLPVLLAAP SEQ ID NO : 10 ); VTVLALGALAGVGVG 3 . Biomedical Devices SEQ ID NO : 11 ; GALFLGWLGAAGSTMGAWSOP According to another aspect, the described invention TSEO ID NO : 12 ] ; GWTLNSAGYLLGLINLKALAALAK provides a biomedical device comprising an EPRO compo - KIL (SEQ ID NO : 71; KLALKLALKALKAALKLA (SEQ sition comprising at least one polypeptide of an amino acid ID NO : 13 ] ; KETWWETWWTEWSQPKKKRKV SEQ ID sequence according to Formula 1: 10 NO : 14 ] ; KAFAKLAARLYRKA (SEQ ID NO : 15 ) ; KAF AKLAARLYRAA [ SEQ ID NO : 16 ]; AAFAKLAAAR Z1 - X1 - 02- 33- 34 - 35 - 06- 17- 18- 19- 210- 22 LYRKA SEQ ID NO : 17 ) ; KAFAALAARLYRKATSEQ ID wherein Z1 and Z2 are independently absent or are NO : 18 ]; KAFAKLAARLYRKAGC [SEQ ID NO : 20 ] ; transduction domains; X1 is selected from the group con - KAFAKLAARLYRAAGC [SEQ ID NO : 21 ] ; AAFAK sisting of A , KA , KKA , KKKA and RA , or is absent; X2 is 15 LAARLYRKAGC [SEQ ID NO : 22 ]; KAFAALAAR selected from the group consisting of G , L , A , V , I, M , Y , W LYRKAGC [ SEQ ID NO : 231; KAFAKLAAQLYRKAGC and F , or is an aliphatic amino acid ; X3 is selected from the SEQ ID NO : 24 ] ; AGGGGYGRKKRRRRRR [SEQ ID group consisting of V , L , I, A , G , Q , N , S , T and C , or is an NO : 25 ]; YARAAARQARA [ SEQ ID NO : 26 ] ; YGRK aliphatic amino acid ; X4 is selected from the group consist - KRRQRRR [SEQ ID NO : 27 ] ;WLRRIKAWLRRIKA [SEQ ing of Q , N , H , R and K ; X5 is selected from the group 20 ID NO : 28 ]; WLRRIKAWLRRIKAWLRRIKA (SEQ ID consisting of Q and N ; X6 is selected from the group NO : 29 ] ; FAKLAARLYRKA [ SEQ ID NO : 30 ] ; KAF consisting of C , A , G , L , V , I , M , Y , W and F or is an aliphatic AALAARLYRKA [SEQ ID NO : 18 ]; KAFAKLAAR amino acid ; X7 is selected from the group consisting of S , LYRAA [SEQ ID NO : 16 ] ; KAFAKLAARLYRA [ SEQ ID A , C , T and G or is an aliphatic amino acid ; X8 is selected NO : 191; FAKLAARLYRAA [SEQ ID NO : 31 ) ; and FAK from the group consisting of V , L , I and M ; X9 is absent or 25 LAARLYRA [SEQ ID NO : 32 ] . is any amino acid ; X10 is absent or is any amino acid ; According to another embodiment, polypeptides accord wherein at least one of the following is true: ( a ) X3 is N and ing to the invention include , but are not limited to any of X7 is not G ; ( b ) X7 is G and X3 is not N ; ( c ) X2 is not L ; those listed above, wherein one or both of Z1 and Z2 are ( d ) X4 is not R ; ( e ) X5 is not Q ; ( f ) X6 is not L ; ( g ) X8 is selected from the group consisting of : WLRRIKAWLR not V ; ( h ) X10 is absent; ( i ) X9 and X10 are absent; wherein 30 RIKA [ SEQ ID NO : 281; WLRRIKAWLRRIKAWLRRIKA the composition enhances outgrowth of at least one neurite [ SEQ ID NO : 29 ] ; YGRKKRRRRRR [SEQ ID NO : 27 ] ; process from a neuron cell body ; is neuroprotective, or YARAAARQARA [ SEQ ID NO : 26 ]; RQRRKKRG [SEQ enhances neuroregeneration following neural injury, when ID NO : 3 ] ; GRKKRROR [ SEQ ID NO : 4 ] ; KAFAKLAAR disposed on or in the device. LYRKA (SEO ID NO : 15 ) ; FAKLAARLYRKA ( SEO ID According to another embodiment, in addition to the 35 NO : 30 ) ; KAFAALAARLYRKA SEO ID NO : 18 ) ; KAF recited amino acids, X2, X3 , X6 and X7 can be any aliphatic AKLAARLYRAA [SEQ ID NO : 16 ] ; KAFAKLAARLYRA amino acid (whether naturally occurring or not) , including , [ SEQ ID NO : 191; FAKLAARLYRAA ( SEQ ID NO : 31 ] ; but not limited to , beta -alanine and 2 -aminocyclohexane - 1 - and FAKLAARLYRA [ SEQ ID NO : 32 ]. carboxylic acid . According to another embodiment, the at least one poly According to another embodiment, X4 is R ; X5 is Q , 40 peptide of formula I comprises YARAAARQARAKALAR and /or X8 is V . According to another embodiment, X3 is QLGVAA [SEQ ID NO : 33 ] ; YGRKKRRQRRRKALAR selected from the group consisting of V , L , I, A , G , Q and N . QLGVAA [SEQ ID NO : 34 ]; According to another embodiment, X6 is selected from the RQRRKKRGKALARQLGVAA [SEQ ID NO : 35 ]; GRK group consisting of C , A , G , L , V , I , M , Y , W and F . KRRORKALARQLGVAA [ SEQ ID NO : 361; WLR According to another embodiment, X7 is selected from the 45 RIKAWLRRIKAKALARQLGVAA [ SEQ ID NO : 37 ] ; group consisting of S , A , C , T and G . WLRRIKAWLRIKAWLRRIKAKALARQLGVAA SEQ According to another embodiment, the at least one poly . ID NO : 38 ] ; YARAAARQARAKKKALARQLGVAA SEQ peptide of formula I is a peptide of amino sequence ID NO : 391; YGRKKRRORRRKKKALARQLGVAA SEQ YARAAARQARAKALARQLGVAA ( SEQ ID NO : 33 ) . ID NO : 401; RORRKKRGKKKALARQLGVAA ( SEQ ID According to another embodiment, the at least one polypep - 50 NO : 41 ] ; GRKKRRORKKKALAROLGVAASEO ID NO : tide of formula I is a peptide of amino acid sequence 42 ] ; WLRRIKAWLRRIKAKKKALARQLGVAA [ SEQ ID YARAAARQARAKALNRQLGVA [ SEQ ID NO : 51 ]. NO : 431; WLRRIKAWLRRIKAWLRRIKAKKKALAR According to another embodiment, the at least one polypep - QLGVAA [SEQ ID NO : 44 ) ; KAFAKLAARLYRKALAR tide of formula I is a peptide of amino acid sequence QLGVAA ( SEQ ID NO : 45 ] ; FAKLAARLYRKALARQL FAKLAARLYRKALARQLGVAA [ SEQ ID NO : 46 ] . 55 GVAA [ SEQ ID NO : 46 ]; According to another embodiment, the at least one poly - KAFAKLAARLYRAALARQLGVAA [SEQ ID NO : 47 ] ; peptide of formula I is a peptide of amino acid sequence KAFAKLAARLYRALARQLGVAA [SEQ ID NO : 48 ]; YARAAARQARAKALNRQLGVAA [SEQ ID NO : 59 ] . KAFAALAARLYRAALARQLGVAA ( SEQ ID NO : 491; According to another embodiment , the at least one polypep - FAKLAARLYRAALARQLGVAA [ SEQ ID NO : 50 ] ; tide of formula I is a peptide of amino acid sequence 60 WLRRIKAWRRIKA -LNRQLGVAA ; YARAAAR FAKLAARLYRKLALRQLGVAA [SEQ ID NO : 60 ]. QARAKALNRQLGVA [SEQ ID NO : 51] ; KAFAKLAAR According to another embodiment, at least one of Z1 and LYRKALNRQLAVAA [ SEQ ID NO : 521; FAKLAAR Z2 is a transduction domain . According to another embodi LYRKALNRQLAVAA [SEQ ID NO : 53 ] ; ment, the transduction domain ( s ) is / are selected from the KAFALKAARLYRKA -LNRQLGVAA ; and FAKLAAR group consisting of: ( R . SEQ ID NO : 1 ] ; GRKKRROR - 65 LYRKA - LNRQLGVAA . RRPPQ [ SEQ ID NO : 2 ] ; RQRRKKRG [SEQ ID NO : 3 ]; Further exemplary peptides include WLRRIKAWR GRKKRROR [ SEQ ID NO : 4 ] ; AYARAAARQARA [SE R IKALNRQLGVA [ SEQ ID NO : 56 ] , KAFALKAAR US 9 , 890 , 195 B2 57 58 LYRKALNRQLGVA [SEQ ID NO : 57 ], and FAKLAAR another embodiment, the biomedical device is a suture . LYRKALNRQLGVA [SEQ ID NO : 58 ] . According to another embodiment, the biomedical device is Further exemplary polypeptides according to the inven a tissue scaffold . tion include , but are not limited to , those comprising or In some embodiments, the EPRO composition comprising consisting of : KALNROLGVA ( SEO ID NO : 541, and 5 at least one polypeptide having an amino acid sequence according to Formula I, wherein the polypeptide enhances KALNRQLGVA [SEQ ID NO : 55 ] . nerve regeneration , is directly disposed onto or into a According to another embodiment, the EPRO composi biomedical device . According to some such embodiments , tion is a pharmaceutical composition . the EPRO composition comprising at least one polypeptide According to another embodiment, the EPRO composi 10 is directly disposed onto the outer surface of the biomedical tion further comprises at least one additional active agent. device . According to some such embodiments, the EPRO According to another embodiment, at least one axon composition comprising at least one polypeptide is directly regenerates through an EPRO composition treated tissue disposed onto the inner surface of the biomedical device . more effectively than through untreated tissues. According According to some such embodiments , the EPRO compo to some such embodiments , the at least one axon regenerated 15 sition comprising at least one polypeptide is directly dis extend at least twice as far through the EPRO composition posed into the biomedical device such that the at least one treated tissue as do axons regenerating through untreated polypeptide is embedded into the outer surface of the tissues . biomedical device . According to some such embodiments , According to another embodiment, at least one axon EPRO composition comprising the at least one polypeptide treated with the EPRO composition regenerates more effec - 20 is directly disposed into the biomedical device such that the tively than an untreated axon . According to some such at least one polypeptide is embedded into the inner surface embodiments , the at least one axon treated with the EPRO of the biomedical device . composition extends at least twice as far as an untreated Direct disposition of the EPRO composition comprising axon . at least one polypeptide having an amino acid sequence According to another embodiment, at least one dendrite 25 according to Formula I , wherein the polypeptide enhances regenerates through EPRO composition treated tissue more outgrowth of at least one neurite process from a neuron cell effectively than through untreated tissues . According to body , includes , but is not limited to , a biomedical device in some such embodiments , the at least one dendrite regener a solution containing the EPRO composition comprising at ated extends at least twice as far through EPRO composition least one polypeptide , spin coating or spraying a solution treated tissue than at least one dendrite regenerating throughrouch 30 containing the EPRO composition comprising at least one untreated tissues. polypeptide onto the device , implanting any device that According to another embodiment, the at least one den would deliver the at least one polypeptide, and administer drite treated with the EPRO composition regenerates more ing the EPRO composition comprising at least one polypep effectively than at least one untreated dendrite . According to tide through a catheter directly onto a surface or into any some such embodiments , the at least one dendrite treated In some embodiments , the EPRO composition comprising with EPRO composition extends at least twice as far as at at least one polypeptide having an amino acid sequence least one untreated dendrite. according to Formula I , wherein the polypeptide enhances According to another embodiment , the biomedical device outgrowth of at least one neurite process from a neuron cell is a stent. According to another embodiment, the biomedical 40 body , is indirectly dispersed onto or into the biomedical device is a graft. According to another embodiment, the device . Indirect disposition results in the EPRO composition biomedical device is a shunt. According to another embodi comprising at least one polypeptide being not directly in ment, the biomedical device is a stent graft. According to contact with the biomedical device . another embodiment, the biomedical device is a fistula . According to another embodiment, the EPRO composi According to another embodiment, the biomedical device is 45 tion comprising at least one polypeptide is disposed in a an angioplasty device . According to another embodiment, matrix . According to some such embodiments , the matrix is the biomedical device is a balloon catheter . According to a gelmatrix or a viscous fluid . According to another embodi another embodiment, the biomedical device is a venous ment, the gelmatrix is disposed onto the biomedical device . catheter. According to another embodiment, the biomedical According some such embodiments , the gel matrix is a device is an implantable drug delivery device . According to 50 heparin coating. As used herein “ heparin coating ” includes another embodiment, the biomedical device is an adhesion heparin adsorbed to a surface , heparin bonded to a surface , barrier . According to another embodiment, the biomedical and heparin embedded in a PTFE polymer surface . Heparin device is a wound dressing . According to another embodi- coatings may be in a gel form , such as a hydrogel, or a ment, the biomedical device is a hydrocolloid . According to non - gel form . According to some embodiments , the matrix another embodiment, the biomedical device is a hydrogel. 55 is a thin - film , silica sol- gel coating . According to another embodiment, the biomedical device is Such matrices may be prepared to modify the binding and a foam . According to another embodiment, the biomedical release properties of the at least one polypeptide as required . device is a hydrophilic foam . According to another embodi- According to another embodiment, the at least one polypep ment, the biomedical device is a hydrophobic foam . Accord tide is layered between heparin coatings onto a biomedical ing to another embodiment, the biomedical device is a 60 device . In a non - limiting example , the release of the at least calcium alginate . According to another embodiment, the one polypeptide from interstitial surfaces of a biomedical biomedical device is a cellophane . According to another device , such as, for example , a poly ( tetrafluoroethylene ) embodiment, the biomedical device is a pluronic . According (PTFE ) vascular device or sheet , may be controlled by first to another embodiment, the biomedical device is a biologi- adsorbing or bonding heparin to the surface and / or inter cal polymer . According to another embodiment, the bio - 65 stices of the device followed by adsorption of the at least one medical device is a microelectrode . According to another polypeptide . Alternating layers of heparin and the at least embodiment, the biomedical device is a probe .According to one polypeptide may be used to increase the at least one US 9 ,890 , 195 B2 59 polypeptide dose and / or time of release . Under physiologi - least one polypeptide has at least about 80 % sequence cal conditions within the body, the kinetics of the association identity to amino acid sequence YARAAARQARAKALN and dissociation of the polypeptides disclosed herein to and RQLGVAA [SEQ ID NO : 59 ]. According to some embodi from heparin will lead to a delayed release profile relative to ments , the at least one polypeptide has at least about 85 % release of the polypeptide from a bare device . In addition , 5 sequence identity to amino acid sequence YARAAAR the release profile may be further altered through changes in OARAKALNROLGVAA ISEO ID NO : 59 ). local temperature , pH or ionic strength . According to some embodiments, the at least one poly According to another embodiment , the at least one poly peptide has at least about 70 % sequence identity to amino peptide is a peptide having an amino acid sequence YARAAARQARAKALARQLGVAA [SEQ ID NO : 33] . 10 acid sequence FAKLAARLYRKALARQLGVAA ( SEQ ID According to another embodiment, the at least one polypep NO : 46 ] . According to some embodiments , the at least one tide is a peptide having an amino acid sequence YARAAAR polypeptide has at least about 75 % sequence identity to QARAKALNRQLGVA [ SEQ ID NO : 51 ]. According to amino acid sequence FAKLAARLYRKALARQLGVAA another embodiment, the at least one polypeptide is a (SEQ ID NO : 46 ) . According to some embodiments , the at peptide having an amino acid sequence FAKLAARLYRKA - 15 least! one polypeptide has at least about 80 % sequence LARQLGVAA [ SEQ ID NO : 46 ]. According to some identity to amino acid sequence FAKLAARLYRKALAR embodiments , the at least one polypeptide has at least about QLGVAA (SEQ ID NO : 46 ). According to some embodi 70 % sequence identity to a polypeptide having an amino ments , the at least one polypeptide has at least about 85 % acid sequence according to Formula I . According to some sequence identity to amino acid sequence FAKLAAR embodiments , the at least one polypeptide has at least about 20 LYRKALARQLGVAA [ SEQ ID NO : 46 ] . 75 % sequence identity to a polypeptide having an amino According to some embodiments , the at least one poly acid sequence according to Formula I . According to some peptide has at least about 70 % sequence identity to amino embodiments , the at least one polypeptide has at least about acid sequence FAKLAARLYRKLALRQLGVAA (SEQ ID 80 % sequence identity to a polypeptide having an amino NO : 60 ) . According to some embodiments , the at least one acid sequence according to Formula I . According to some 25 polypeptide has at least about 75 % sequence identity to embodiments , the at least one polypeptide has at least about amino acid sequence FAKLAARLYRKLALRQLGVAA 85 % sequence identity to a polypeptide having an amino [SEQ ID NO : 60 ]. According to some embodiments , the at acid sequence according to Formula I. least one polypeptide has at least about 80 % sequence According to another embodiment, the at least one polyJu identity to amino acid sequence FAKLAARLYRKLAL peptide is a peptide having an amino acid sequence 30 RQLGVAA [ SEQ ID NO : 60 ]. According to some embodi YARAAARQARAKALNRQLGVAA [SEQ ID NO : 59 ) . ments , the at least one polypeptide has at least about 85 % According to another embodiment, the at least one polypep sequence identity to amino acid sequence FAKLAAR tide is a peptide having an amino acid sequence FAKLAAR LYRKLALRQLGVAA [SEQ ID NO : 60 ] . LYRKLALRQLGVAA ( SEQ ID NO : 60 ) . As will be understood by those of skill in the art, any According to some embodiments, the at least one poly - 35 sulfated polysaccharide or negatively charged polymer can peptide has at least about 70 % sequence identity to amino be used in like manner to heparin to provide desired release acid sequence YARAAARQARAKALARQLGVAA [ SEQ characteristics. ID NO : 33 ] . According to some embodiments , the at least 4 . Methods for Improving or Enhancing Neurite Outgrowth one polypeptide has at least about 75 % sequence identity to According to another aspect , the described invention amino acid sequence YARAAAROARAKALAROLGVAA 40 provides a method for improving or enhancing neurite [ SEQ ID NO : 33 ] . According to some embodiments , the at outgrowth , the method comprising: ( a ) providing a thera least one polypeptide has at least about 80 % sequence peutically effective amount of an EPRO composition , the identity to amino acid sequence YARAAARQARAKA EPRO composition comprising : (i ) at least one polypeptide LARQLGVAA [ SEQ ID NO : 33 ]. According to some having an amino acid sequence according to Formula I: embodiments , the at least one polypeptide has at least about 45 85 % sequence identity to amino acid sequence YARAAAR Z1- X1- 02- 33- 34- 35- 16- 17- 18- 19- X10- 22 QARAKALARQLGVAA [ SEQ ID NO : 33 ] . wherein Zi and Z2 are independently absent or are According to some embodiments, the at least one poly - transduction domains ; X1 is selected from the group con peptide has at least about 70 % sequence identity to amino sisting of A , KA , KKA , KKKA and RA , or is absent; X2 is acid sequence YARAAARQARAKALNRQLGVA ( SEQ ID 50 selected from the group consisting of G , L , A , V , I , M , Y , W NO : 51 ) . According to some embodiments, the at least one and F , or is an aliphatic amino acid ; X3 is selected from the polypeptide has at least about 75 % sequence identity to group consisting of V , L , I , A , G , Q , N , S , T and C , or is an amino acid sequence YARAAARQARAKALNRQLGVA aliphatic amino acid ; X4 is selected from the group consist [ SEQ ID NO : 51] . According to some embodiments , the at ing of Q , N , H , R and K ; X5 is selected from the group least one polypeptide has at least about 80 % sequence 55 consisting of Q and N ; X6 is selected from the group identity to amino acid sequence YARAAARQARAKALN consisting of C , A , G , L , V , I, M , Y , W and F or is an aliphatic RQLGVA [SEQ ID NO : 51 ]. According to some embodi amino acid ; X7 is selected from the group consisting of S , ments , the at least one polypeptide has at least about 85 % A , C , T and G or is an aliphatic amino acid ; X8 is selected sequence identity to amino acid sequence YARAAAR - from the group consisting of V , L , I and M ; X9 is absent or QARAKALNRQLGVA [ SEQ ID NO : 51] . 60 is any amino acid ; X10 is absent or is any amino acid ; According to some embodiments , the at least one poly - wherein at least one of the following is true : ( a ) X3 is N and peptide has at least about 70 % sequence identity to amino X7 is not G ; ( b ) X7 is G and X3 is not N ; ( c ) X2 is not L ; acid sequence YARAAARQARAKALNRQLGVAA [SEQ (d ) X4 is not R ; ( e) X5 is not Q ; (f ) X6 is not L ; ( g ) X8 is ID NO : 59 ) . According to some embodiments , the at least not V ; ( h ) X10 is absent; ( i ) X9 and X10 are absent; wherein one polypeptide has at least about 75 % sequence identity to 65 the polypeptide enhances or improves outgrowth of at least amino acid sequence YARAAARQARAKALNRQLGVAA one neurite process from a neuron cell body ; and ( ii ) a [ SEQ ID NO : 59 ). According to some embodiments , the at carrier ; (b ) administering the EPRO composition to a subject US 9 ,890 , 195 B2 62 in need thereof; and (c ) increasing neurite outgrowth relative ID NO : 387; YARAAARQARAKKKALARQLGVAA SEQ to neurite outgrowth of a neuron that has not been treated ID NO : 391; YGRKKRRRRRRKKKALARQLGVAA SEQ with the EPRO composition . ID NO : 40 ] ; RORRKKRGKKKALARQLGVAA ( SEQ ID According to another embodiment, in addition to the NO : 41 ] ; GRKKRRORKKKALARQLGVAA ( SEQ ID NO : recited amino acids, X2 , X3, X6 and X7 can be any aliphatic 5 42 ]; WLRRIKAWLRRIKAKKKALARQLGVAA [SEQ ID amino acid (whether naturally occurring or not) , including , NO : 43 ] ; WLRRIKAWLRRIKAWLRRIKAKKKALAR but not limited to , beta - alanine and 2 - aminocyclohexane - 1 QLGVAA [ SEQ ID NO : 441; KAFAKLAARLYRKALAR carboxylic acid . QLGVAA [SEQ ID NO : 45 ]; FAKLAARLYRKALARQL According to another embodiment, X4 is R ; X5 is , GVAA SEQ ID NO : 461; and /or X8 is V . According to another embodiment , X3 is 10 KAFAKLAARLYRAALARQLGVAA [ SEQ ID NO : 47 ]; selected from the group consisting of V , L , I, A , G , Q and N . KAFAKLAARLYRALARQLGVAA [SEQ ID NO : 48 ] ; According to another embodiment , X6 is selected from the KAFAALAARLYRAALARQLGVAA [SEQ ID NO : 49 ]; group consisting of C , A , G , L , V , I , M , Y , W and F . FAKLAARLYRAALARQLGVAA [SEQ ID NO : 50 ] ; According to another embodiment , X7 is selected from the WLRRIKAWRRIKA - LNRQLGVAA ; YARAAAR group consisting of S , A , C , T and G . 15 QARAKALNRQLGVA [SEQ ID NO : 51 ]; KAFAKLAAR According to another embodiment, at least one of Z1 and LYRKALNRQLAVAA [SEQ ID NO : 52 ]; FAKLAAR Z2 is a transduction domain . According to another embodi - LYRKALNROLAVAA SEQ ID NO : 53 ] ; ment, the transduction domain (s ) is /are selected from the KAFALKAARLYRKA -LNRQLGVAA ; and FAKLAAR group consisting of: ( R ) . SEO ID NO : 1 ] ; GRKKRROR - LYRKA -LNROLGVAA . RRPPQ SEQ ID NO : 2 ] ; RORRKKRG ( SEQ ID NO : 31; 20 Further exemplary peptides include WLRRIKAWR GRKKRROR [SEQ ID NO : 4 ] ; AYARAAARQARA [ SEQRIKALNRQLGVA [SER ID NO : 56 ] , KAFALKAAR ID NO : 51; DAATATRGRSAASRPTERPRAPARSASR - LYRKALNROLGVA (SEO ID NO : 57 ) , and FAKLAAR PRRPVE [ SEQ ID NO : 6 ]; GWTLNSAGYLLGLINLKA - LYRKALNRQLGVA [ SEQ ID NO : 58 ]. LAALAKKIL [SEQ ID NO : 7 ]; PLSSIFSRIGDP [SEQ ID Further exemplary polypeptides according to the inven NO : 8 ] ; AAVALLPAVLLALLAP (SEQ ID NO : 97; AAV - 25 tion include , but are not limited to , those comprising or LLPVLLAAP [SEQ ID NO : 10 ]; VTVLALGALAGVGVG consisting of: KALNRQLGVA [SEQ ID NO : 54 ], and [ SEQ ID NO : 11; GALFLGWLGAAGSTMGAWSOP KALNRQLGVA [SEQ ID NO : 55 ) . SEQ ID NO : 12 ] ; GWTLNSAGYLLGLINLKALAALAK - According to one embodiment, the at least one polypep KIL ( SEQ ID NO : 7 ) ; KLALKLALKALKAALKLA [SEQ tide has an amino acid sequence of at least 70 % sequence ID NO : 13 ] ; KETWWETWWTEWSQPKKKRKV [SEQ ID 30 identity to an amino acid sequence according to Formula I, NO : 14 ] ; KAFAKLAARLYRKA [ SEQ ID NO : 15 ); KAF - wherein the polypeptide having an amino acid sequence AKLAARLYRAA [SEQ ID NO : 16 ] ; AAFAKLAAAR according to Formula I enhances outgrowth of at least one LYRKA (SEQ ID NO : 171; KAFAALAARLYRKA [ SEQ ID neurite process from a neuron cell body . According to one NO : 181; KAFAKLAARLYRKAGC ( SEQ ID NO : 2013 embodiment, the at least one polypeptide has an amino acid KAFAKLAARLYRAAGC [ SEQ ID NO : 21 ]; AAFAK - 35 sequence of at least 75 % sequence identity to an amino acid LAARLYRKAGC [ SEQ ID NO : 22 ) ; KAFAALAAR sequence according to Formula I, wherein the polypeptide LYRKAGC SEQ ID NO : 231; KAFAKLAAQLYRKAGC having an amino acid sequence according to Formula I [ SEQ ID NO : 241; AGGGGYGRKKRRRRRR [ SEQ ID enhances outgrowth of at least one neurite process from a NO : 251; YARAAARQARA SEQ ID NO : 26 ] ; YGRK neuron cell body . According to one embodiment, the at least KRRORRR [ SEQ ID NO : 271; WLRRIKAWLRRIKA SEQ 40 one polypeptide has an amino acid sequence of at least 80 % ID NO : 28 ]; WLRRIKAWLRRIKAWLRRIKA [ SEQ ID sequence identity to an amino acid sequence according to NO : 29 ] ; FAKLAARLYRKA [SEQ ID NO : 30 ]; KAF - Formula I, wherein the polypeptide having an amino acid AALAARLYRKA SEQ ID NO : 18 ] ; KAFAKLAAR sequence according to Formula I enhances outgrowth of at LYRAA [ SEQ ID NO : 161; KAFAKLAARLYRA [SEQ ID least one neurite process from a neuron cell body . According NO : 19 ] ; FAKLAARLYRAA [ SEQ ID NO : 31 ]; and FAK - 45 to one embodiment, the at least one polypeptide has an LAARLYRA [ SEQ ID NO : 32 ] . amino acid sequence of at least 85 % sequence identity to an According to another embodiment, the at least one poly - amino acid sequence according to Formula 1 , wherein the peptide of Formula I includes, but are not limited to any of polypeptide having an amino acid sequence according to those listed above, wherein one or both of Z1 and 22 are Formula I enhances outgrowth of at least one neurite process selected from the group consisting of: WLRRIKAWLR - 50 from a neuron cell body . According to some embodiments , RIKA [SEQ ID NO : 28 ]; WLRRIKAWLRRIKAWLRRIKA the at least one polypeptide has at least about 70 % sequence TSEQ ID NO : 291; YGRKKRRORRR (SEQ ID NO : 271; identity to amino acid sequence YARAAARQARAKA YARAAARQARA [ SEQ ID NO : 26 ]; RQRRKKRG [SEQ LARQLGVAA [SEQ ID NO : 33 ]. According to some ID NO : 3 ] ; GRKKRROR SEQ ID NO : 41; KAFAKLAAR embodiments, the at least one polypeptide has at least about LYRKA [ SEQ ID NO : 15 ] ; FAKLAARLYRKA [SEQ ID 55 75 % sequence identity to amino acid sequence YARAAAR NO : 30 ] ; KAFAALAARLYRKA [SEQ ID NO : 18 ]; KAF - QARAKALARQLGVAA [SEQ ID NO : 33 ]. According to AKLAARLYRAA [ SEQ ID NO : 161; KAFAKLAARLYRA some embodiments , the at least one polypeptide has at least SEQ ID NO : 191; FAKLAARLYRAA [ SEQ ID NO : 31 ] ; about 80 % sequence identity to amino acid sequence and FAKLAARLYRA [SEQ ID NO : 32 ] . YARAAARQARAKALARQLGVAA [SEQ ID NO : 33 ] . According to another embodiment, the at least one poly - 60 According to some embodiments , the at least one polypep peptide of Formula I comprises YARAAARQARAKALAR tide has at least about 85 % sequence identity to amino acid QLGVAA [SEQ ID NO : 33 ]; YGRKKRRQRRRKALAR - sequence YARANARQARAKALARQLGVAA [ SEQ ID QLGVAA [ SEQ ID NO : 34 ] ; NO : 33 ] . RQRRKKRGKALARQLGVAA [SEQ ID NO : 35 ] ; GRK - According to some embodiments , the at least one poly KRRQRKALARQLGVAA [ SEQ ID NO : 36 ] ; WLR - 65 peptide has at least about 70 % sequence identity to amino RIKAWLRRIKAKALARQLGVAA [SEQ ID NO : 37 ]; acid sequence YARAAARQARAKALNRQLGVA [SEQ ID WLRRIKAWLRIKAWLRRIKAKALARQLGVAA [ SEQ NO : 51 ] . According to some embodiments , the at least one US 9 ,890 , 195 B2 63 64 polypeptide has at least about 75 % sequence identity to been treated with the EPRO composition . According to amino acid sequence YARAAARQARAKALNRQLGVA some embodiments , the extension of the neurite process is [ SEQ ID NO : 51 ] . According to some embodiments, the at increased at least 60 % in length relative to the extension of least one polypeptide has at least about 80 % sequence the neurite process of a neuron that has not been treated with identity to amino acid sequence YARAAARQARAKALN - 5 the EPRO composition . According to some embodiments , RQLGVA [SEQ ID NO : 51 ] . According to some embodi- the extension of the neurite process is increased at least 70 % ments, the at least one polypeptide has at least about 85 % in length relative to the extension of the neurite process of sequence identity to amino acid sequence YARAAAR - a neuron that has not been treated with the EPRO compo QARAKALNRQLGVA [SEQ ID NO : 51] . sition . According to some embodiments , the extension of the According to some embodiments , the at least one poly - 10 neurite process is increased at least 80 % in length relative to peptide has at least about 70 % sequence identity to amino the extension of the neurite process of a neuron that has not acid sequence YARAAARQARAKALNRQLGVAA [SEQ been treated with the EPRO composition . According to ID NO : 59 ). According to some embodiments , the at least some embodiments , the extension of the neurite process is one polypeptide has at least about 75 % sequence identity to increased at least 90 % in length relative to the outgrowth of amino acid sequence YARAAARQARAKALNRQLGVAA 15 the neurite process of a neuron that has not been treated with [SEQ ID NO : 59 ) . According to some embodiments , the at the EPRO composition . least one polypeptide has at least about 80 % sequence According to another embodiment, the EPRO composi identity to amino acid sequence YARAAARQARAKALN tion enhances neurite outgrowth by inhibiting expression of RQLGVAA (SEQ ID NO : 59 ) . According to some embodi- at least one inflammatory cytokine from activated microglia . ments, the at least one polypeptide has at least about 85 % 20 According to another embodiment, the at least one inflam sequence identity to amino acid sequence YARAAAR - matory cytokine is at least one of IL - 1 beta , IL - 6 , and QARAKALNRQLGVAA ( SEQ ID NO : 59 ) . TNF - alpha . According to some embodiments , the at least one poly - According to another embodiment, at least one axon peptide has at least about 70 % sequence identity to amino regenerates through a EPRO composition treated tissue acid sequence FAKLAARLYRKALARQLGVAA (SEQ ID 25 more effectively than through at least one untreated tissue . NO : 46 ] . According to some embodiments , the at least one According to some such embodiments , the at least one axon polypeptide has at least about 75 % sequence identity to regenerated extends at least twice as far through a EPRO amino acid sequence FAKLAARLYRKALARQLGVAA composition treated tissue as do those axons regenerating [ SEQ ID NO : 46 ] . According to some embodiments , the at through untreated tissues. least one polypeptide has at least about 80 % sequence 30 According to another embodiment, the at least one poly identity to amino acid sequence FAKLAARLYRKALAR - peptide of formula I regenerates at least one axon treated QLGVAA [ SEQ ID NO : 46 ] . According to some embodi - with the at least one polypeptide of formula I more effec ments, the at least one polypeptide has at least about 85 % tively than an untreated axon . According to some such sequence identity to amino acid sequence FAKLAAR - embodiments , the at least one axon treated with the at least LYRKALARQLGVAA [SEQ ID NO : 46 ] . 35 one polypeptide of formula I extends at least twice as far as According to some embodiments , the at least one poly - an untreated axon . peptide has at least about 70 % sequence identity to amino According to another embodiment, the neurite process is acid sequence FAKLAARLYRKLALRQLGVAA [ SEQ ID at least one dendrite . According to some such embodiments , NO : 60 ]. According to some embodiments , the at least one the outgrowth of the neurite process is increased at least 10 % polypeptide has at least about 75 % sequence identity to 40 in length relative to at least one dendrite of the neurite amino acid sequence FAKLAARLYRKLALRQLGVAA process that has not been treated with the EPRO composi [SEQ ID NO : 60 ] . According to some embodiments , the at tion . According to some such embodiments , the outgrowth least one polypeptide has at least about 80 % sequence of the neurite process is increased at least 20 % in length identity to amino acid sequence FAKLAARLYRKLAL - relative to at least one dendrite of the neurite process that has RQLGVAA (SEQ ID NO : 60 ) . According to some embodi- 45 not been treated with the EPRO composition . According to ments, the at least one polypeptide has at least about 85 % some such embodiments , the outgrowth of the neurite pro sequence identity to amino acid sequence FAKLAAR - cess is increased at least 30 % in length relative to at least one LYRKLALRQLGVAA [ SEQ ID NO : 60 ] . dendrite of the neurite process that has not been treated with According to another embodiment, the neurite process is the EPRO composition . According to some such embodi an axon . According to some embodiments , the extension of 50 ments , the outgrowth of the neurite process is increased at the neurite process is increased at least 10 % in length least 40 in length relative to at least one dendrite of the relative to the extension of the neurite process of a neuron neurite process that has not been treated with the EPRO that has not been treated with the EPRO composition . composition . According to some such embodiments , the According to some embodiments , the extension of the outgrowth of the neurite process is increased at least 50 % in neurite process is increased at least 20 % in length relative to 55 length relative to at least one dendrite of the neurite process the extension of the neurite process of a neuron that has not that has not been treated with the EPRO composition . been treated with the EPRO composition . According to According to some such embodiments , the outgrowth of the some embodiments , the extension of the neurite process is neurite process is increased at least 60 % in length relative to increased at least 30 % in length relative to the extension of at least one dendrite of the neurite process that has not been the neurite process of a neuron that has not been treated with 60 treated with the EPRO composition . According to some such the EPRO composition . According to some embodiments , embodiments , the outgrowth of the neurite process is the extension of the neurite process is increased at least 40 % increased at least 70 % in length relative to at least one in length relative to the extension of the neurite process of dendrite of the neurite process that has not been treated with a neuron that has not been treated with the EPRO compo - the EPRO composition . According to some such embodi sition . According to some embodiments , the extension of the 65 ments , the outgrowth of the neurite process is increased at neurite process is increased at least 50 % in length relative to least 80 % in length relative to at least one dendrite of the the extension of the neurite process of a neuron that has not neurite process that has not been treated with the EPRO US 9 ,890 , 195 B2 65 66 composition . According to some such embodiments , the According to another embodiment, X7 is selected from the outgrowth of the neurite process is increased at least 90 % in group consisting of S , A , C , T and G . length relative to at least one dendrite of the neurite process According to another embodiment, at least one of Z1 and that has not been treated with the EPRO composition . Z2 is a transduction domain . According to another embodi According to another embodiment , at least one dendrite 5 ment, the transduction domain ( s ) is /are selected from the regenerates through an EPRO composition treated tissue group consisting of: ( R ) 4 - 9 ( SEQ ID NO : 1 ] ; GRKKRRQR more effectively than through untreated tissues . According RRPPO [SEQ ID NO : 2 ]; RORRKKRG ( SEQ ID NO : 3 ] ; GRKKRROR [ SEQ ID NO : 41; AYARAAARQARA ( SEQ to some such embodiments , the at least one dendrite regen ID NO : 5 ] ; DAATATRGRSAASRPTERPRAPARSASR erated extends at least twice as far through an EPRO 10 PRRPVE ( SEQ ID NO : 6 ) ; GWTLNSAGYLLGLINLKA composition treated tissue as at least one dendrite regener LAALAKKIL [SEQ ID NO : 7 ] ; PLSSIFSRIGDP [SEQ ID ating through untreated tissues . NO : 8 ) ; AAVALLPAVLLALLAP (SEQ ID NO : 91; AAV According to another embodiment, the at least one poly LLPVLLAAP [ SEQ ID NO : 10 ] ; VTVLALGALAGVGVG peptide of formula I regenerates at least one dendrite treated [SEQ ID NO : 11; GALFLGWLGAAGSTMGAWSQP with the at least one polypeptide of formula I more effec 15 [SEQ ID NO : 12 ]; GWTLNSAGYLLGLINLKALAALAK tively than at least one untreated dendrite . According to KIL ( SEO ID NO : 71; KLALKLALKALKAALKLA (SEQ some such embodiments , the at least one dendrite treated ID NO : 13 ) ; KETWWETWWTEWSOPKKKRKV ( SEQ ID with the at least one polypeptide of formula I extends at least NO : 141; KAFAKLAARLYRKA (SEQ ID NO : 151; KAF twice as far as at least one untreated dendrite . AKLAARLYRAA (SEQ ID NO : 161; AAFAKLAAAR According to another embodiment, the EPRO composiompost - 2030 TYLYRKA SEQ ID NO : 17 ) ; KAFAALAARLYRKA SEQ ID tion is a pharmaceutical composition . NO : 18 ]; KAFAKLAARLYRKAGC [ SEQ ID NO : 20 ]; According to another embodiment, the composition fur KAFAKLAARLYRAAGC SEQ ID NO : 21 ]; AAFAK ther comprises at least one additional active agent. LAARLYRKAGC SEQ ID NO : 221; KAFAALAAR 5 .Methods for Improving or Enhancing Nerve Regeneration LYRKAGC [ SEQ ID NO : 23 ] ; KAFAKLAAQLYRKAGC According to another aspect, the described inventionntion ,25 [SEQ ID NO : 24 ]; AGGGGYGRKKRRQRRR [SEQ ID provides a method for improving or enhancing nerve regen NO : 25 ] ; YARAAARQARA [SEQ ID NO : 26 ] ; YGRK eration , the method comprising: ( a ) providing a therapeutic KRRORRR (SEQ ID NO : 271; WLRRIKAWLRRIKA SEQ cally effective amount of an EPRO composition , the com ID NO : 281; WLRRIKAWLRRIKAWLRRIKA ( SEQ ID position comprising : ( i) at least one polypeptide having an NO : 29 ] ; FAKLAARLYRKA [ SEQ ID NO : 30 ] ; KAF amino acid sequence according to Formula I : 30 AALAARLYRKA SEQ ID NO : 181; KAFAKLAAR LYRAA [SEQ ID NO : 16 ] ; KAFAKLAARLYRA [SEQ ID 21 - 11- 12- 13- 14- 15 - 16- 17- 18 - 19 - 210- Z2 NO : 19 ] ; FAKLAARLYRAA [ SEQ ID NO : 31 ) ; and FAK wherein Z1 and Z2 are independently absent or are LAARLYRA [ SEQ ID NO : 32 ]. transduction domains ; X1 is selected from the group con - According to another embodiment, exemplary polypep sisting of A , KA , KKA , KKKA and RA , or is absent; X2 is 35 tides according to the invention include, but are not limited selected from the group consisting of G , L , A , V , I, M , Y , W to any of those listed above , wherein one or both of Z1 and and F , or is an aliphatic amino acid ; X3 is selected from the Z2 are selected from the group consisting of: WLR group consisting of V , L , I, A , G , Q , N , S , T and C , or is an RIKAWLRRIKA [SEQ ID NO : 28 ] ; WLRRIKAWLR aliphatic amino acid ; X4 is selected from the group consist - RIKAWLRRIKA [SEQ ID NO : 291; YGRKKRRORRR ing of Q , N , H , R and K ; X5 is selected from the group 40 [SEQ ID NO : 27 ] ; YARAAARQARA [SEQ ID NO : 26 ] ; consisting of Q and N ; X6 is selected from the group RQRRKKRG [ SEQ ID NO : 3 ] ; GRKKRROR [SEQ ID NO : consisting of C , A , G , L , V , I , M , Y , W and F or is an aliphatic 41; KAFAKLAARLYRKA [SEQ ID NO : 151; FAKLAAR amino acid ; X7 is selected from the group consisting of S , LYRKA [ SEQ ID NO : 30 ]; KAFAALAARLYRKA [SEQ ID A , C , T and G or is an aliphatic amino acid ; X8 is selected NO : 18 ]; KAFAKLAARLYRAA (SEQ ID NO : 161; KAF from the group consisting of V , L , I and M ; X9 is absent or 45 AKLAARLYRA SEQ ID NO : 191; FAKLAARLYRAA is any amino acid ; X10 is absent or is any amino acid ; [ SEQ ID NO : 31 ]; and FAKLAARLYRA [SEQ ID NO : 32 ]. wherein at least one of the following is true: ( a ) X3 is N and According to another embodiment, the at least one poly X7 is not G ; (b ) X7 is G and X3 is not N ; ( c ) X2 is not L ; peptide of formula I comprises YARAAARQARAKALAR ( d ) X4 is not R ; ( e ) X5 is not Q ; (f ) X6 is not L ; (g ) X8 is QLGVAA [ SEQ ID NO : 33 ] ; YGRKKRRRRRRKALAR not V ; ( h ) X10 is absent; ( i) X9 and X10 are absent; and ( ii ) 50 QLGVAA SEQ ID NO : 34 ) ; a carrier ; ( b ) administering the composition to a subject in RORRKKRGKALARQLGVAA [SEQ ID NO : 35 ] ; GRK need thereof; and (c ) increasing neurite regrowth relative to KRRQRKALARQLGVAA [ SEQ ID NO : 36 ]; WLR the regrowth of a neurite process of a neuron that has not RIKAWLRRIKAKALARQLGVAA SEQ ID NO : 371; been treated with the EPRO composition . WLRRIKAWLRIKAWLRRIKAKALARQLGVAA SEQ According to another embodiment, the method further 55 ID NO : 38 ]; YARAMARQARAKKKALARQLGVAA [SEQ comprises step ( d ) effecting nerve regeneration by increas ID NO : 397; YGRKKRRORRRKKKALARQLGVAA (SEQ ing the number of neurite projections. ID NO : 407; RORRKKRGKKKALARQLGVAA (SEQ ID According to another embodiment, in addition to the NO : 41 ] ; GRKKRRORKKKALARQLGVAA ( SEQ ID NO : recited amino acids , X2, X3, X6 and X7 can be any aliphatic 42 ] ; WLRRIKAWLRRIKAKKKALARQLGVAA ( SEQ ID amino acid (whether naturally occurring or not) , including, 60 NO : 43 ] ; WLRRIKAWLRRIKAWLRRIKAKKKALAR but not limited to , beta - alanine and 2 - aminocyclohexane - 1 - QLGVAA [SEQ ID NO : 44 ]; KAFAKLAARLYRKALAR carboxylic acid . QLGVAA ( SEQ ID NO : 451; FAKLAARLYRKALARQL According to another embodiment, X4 is R ; X5 is Q , GVAA SEQ ID NO : 46 ] ; and /or X8 is V . According to another embodiment, X3 is KAFAKLAARLYRAALARQLGVAA (SEQ ID NO : 471; selected from the group consisting of V , L , I , A , G , Q and N . 65 KAFAKLAARLYRALARQLGVAA [SEQ ID NO : 48 ]; According to another embodiment , X6 is selected from the KAFAALAARLYRAALARQLGVAA ( SEQ ID NO : 491; group consisting of C , A , G , L , V , I, M , Y, W and F. FAKLAARLYRAALARQLGVAA [SEQ ID NO : 50 ] ; US 9 ,890 , 195 B2 67 68 WLRRIKAWRRIKA -LNRQLGVAA ; YARAAAR - 85 % sequence identity to amino acid sequence YARAAAR QARAKALNRQLGVA [SEQ ID NO : 51 ]; KAFAKLAAR QARAKALARQLGVAA [ SEQ ID NO : 33 ] . LYRKALNROLAVAA [SEQ ID NO : 52 ] ; FAKLAAR According to some embodiments , the at least one poly LYRKALNROLAVAA SEO ID NO : 53 ) ; peptide has at least about 70 % sequence identity to amino KAFALKAARLYRKA - LNROLGVAA ; and FAKLAAR - 5 acid sequence YARAAARQARAKALNRQLGVA SEQ ID LYRKA -LNRQLGVAA . NO : 51 ]. According to some embodiments , the at least one Further exemplary peptides include WLRRIKAWR - polypeptide has at least about 75 % sequence identity to amino acid sequence YARAAARQARAKALNRQLGVA RIKALNRQLGVA [SEQ ID NO : 56 ], KAFALKAAR SEQ ID NO : 51 ] . According to some embodiments , the at LYRKALNRQLGVA [SEQ ID NO : 57 ], and FAKLAAR 10 least one polypeptide has at least about 80 % sequence LYRKALNRQLGVA [SEQ ID NO : 58 ] . identity to amino acid sequence YARAAARQARAKALN Further exemplary polypeptides according to the inven RQLGVA [SEQ ID NO : 51 ]. According to some embodi tion include , but are not limited to , those comprising or ments , the at least one polypeptide has at least about 85 % consisting of: KALNRQLGVA [ SEQ ID NO : 54 ), and sequence identity to amino acid sequence YARAAAR KALNRQLGVA [SEQ ID NO : 55 ] . 15 QARAKALNROLGVA ( SEQ ID NO : 51 ) . According to another embodiment, the at least one poly According to some embodiments , the at least one poly peptide of formula I of the EPRO composition is a peptide peptide has at least about 70 % sequence identity to amino of amino sequence YARAAARQARAKALARQLGVAA acid sequence YARAAARQARAKALNRQLGVAA [ SEQ ( SEO ID NO : 33 ) . According to another embodiment, the at ID NO : 59 ) . According to some embodiments , the at least least one polypeptide of formula I of the EPRO composition 20 one polypeptide has at least about 75 % sequence identity to is a peptide of amino acid sequence YARAAAR amino acid sequence YARAAARQARAKALNRQLGVAA QARAKALNRQLGVA [SEQ ID NO : 51 ]. According to [ SEQ ID NO : 59 ]. According to some embodiments , the at another embodiment, the at least one polypeptide of formula least one polypeptide has at least about 80 % sequence I of the EPRO composition is a peptide of amino acid identity to amino acid sequence YARAAARQARAKALN sequence FAKLAARLYRKALARQLGVAA [SEQ ID NO : 25 RQLGVAA [SEQ ID NO : 59 ). According to some embodi 46 ] . ments , the at least one polypeptide has at least about 85 % According to another embodiment, the at least one poly - sequence identity to amino acid sequence YARAAAR peptide of formula I of the EPRO composition is a peptide QARAKALNRQLGVAA [ SEQ ID NO : 59 ] . of amino acid sequence YARAAARQARAKALNRQL - According to some embodiments, the at least one poly GVAA [ SEQ ID NO : 59 ] . According to another embodi - 30 peptide has at least about 70 % sequence identity to amino ment, the at least one polypeptide of formula I of the EPRO acid sequence FAKLAARLYRKALARQLGVAA [SEQ ID composition is a peptide of amino acid sequence FAK NO : 46 ]. According to some embodiments , the at least one LAARLYRKLALRQLGVAA [SEQ ID NO : 60 ]. polypeptide has at least about 75 % sequence identity to According to one embodiment, the at least one polypep - amino acid sequence FAKLAARLYRKALARQLGVAA tide has an amino acid sequence of at least 70 % sequence 35 [SEQ ID NO : 46 ] . According to some embodiments , the at identity to an amino acid sequence according to Formula 1, least one polypeptide has at least about 80 % sequence wherein the polypeptide having an amino acid sequence identity to amino acid sequence FAKLAARLYRKALAR according to Formula I enhances regrowth of at least one QLGVAA [SEQ ID NO : 46 ]. According to some embodi neurite process from a neuron cell body . According to one m ents , the at least one polypeptide has at least about 85 % embodiment, the at least one polypeptide has an amino acid 40 sequence identity to amino acid sequence FAKLAAR sequence of at least 75 % sequence identity to an amino acid LYRKALARQLGVAA [SEQ ID NO : 46 ) . sequence according to Formula I, wherein the polypeptide According to some embodiments , the at least one poly having an amino acid sequence according to Formula I peptide has at least about 70 % sequence identity to amino enhances regrowth of at least one neurite process from a acid sequence FAKLAARLYRKLALRQLGVAA [ SEQ ID neuron cell body . According to one embodiment, the at least 45 NO : 60 ) . According to some embodiments, the at least one one polypeptide has an amino acid sequence of at least 80 % polypeptide has at least about 75 % sequence identity to sequence identity to an amino acid sequence according to amino acid sequence FAKLAARLYRKLALRQLGVAA Formula I , wherein the polypeptide having an amino acid [SEQ ID NO : 60 ) . According to some embodiments , the at sequence according to Formula 1 enhances regrowth of at least one polypeptide has at least about 80 % sequence least one neurite process from a neuron cell body . According 50 identity to amino acid sequence FAKLAARLYRKLAL to one embodiment, the at least one polypeptide has an RQLGVAA ( SEQ ID NO : 60 ) . According to some embodi amino acid sequence of at least 85 % sequence identity to an ments , the at least one polypeptide has at least about 85 % amino acid sequence according to Formula I , wherein the sequence identity to amino acid sequence FAKLAAR polypeptide having an amino acid sequence according to LYRKLALRQLGVAA [ SEQ ID NO : 60 ) . Formula I enhances regrowth of at least one neurite process 55 According to another embodiment, the neurite process is from a neuron cell body . an axon . According to some embodiments , the regrowth of According to some embodiments , the at least one poly - the neurite process is increased at least 10 % in length peptide has at least about 70 % sequence identity to amino relative to the regrowth of a neurite process of a neuron that acid sequence YARAAARQARAKALARQLGVAA (SEQ has not been treated with the EPRO composition . According ID NO : 33 ). According to some embodiments , the at least 60 to some embodiments , the regrowth of the neurite process is one polypeptide has at least about 75 % sequence identity to increased at least 20 % in length relative to the regrowth of amino acid sequence YARAAARQARAKALARQLGVAA a neurite process of a neuron that has not been treated with [ SEQ ID NO : 33 ]. According to some embodiments , the at the EPRO composition . According to some embodiments , least one polypeptide has at least about 80 % sequence the regrowth of the neurite process is increased at least 30 % identity to amino acid sequence YARAAARQARAKA - 65 in length relative to the regrowth of a neurite process of a LARQLGVAA [ SEQ ID NO : 33 ]. According to some neuron that has not been treated with the EPRO composi embodiments , the at least one polypeptide has at least about tion . According to some embodiments , the regrowth of the US 9 ,890 , 195 B2 69 70 neurite process is increased at least 40 % in length relative to dendrite of the neurite process that has not been treated with the regrowth of a neurite process of a neuron that has not the EPRO composition . According to some such embodi been treated with the EPRO composition . According to ments , the regrowth of the neurite process is increased at some embodiments , the regrowth of the neurite process is least 80 % in length relative to at least one dendrite of the increased at least 50 % in length relative to the regrowth of 5 neurite process that has not been treated with the EPRO a neurite process of a neuron that has not been treated with composition . According to some such embodiments , the the EPRO composition . According to some embodiments , regrowth of the neurite process is increased at least 90 % in the regrowth of the neurite process is increased at least 60 % length relative to at least one dendrite of the neurite process in length relative to the regrowth of a neurite process of a that has not been treated with the EPRO composition . neuron that has not been treated with the EPRO composi- 10 According to another embodiment , at least one dendrite tion . According to some embodiments , the regrowth of the regenerates through EPRO composition treated tissue more neurite process is increased at least 70 % in length relative to effectively than through untreated tissues . According to the regrowth of a neurite process of a neuron that has not some such embodiments , the at least one dendrite regener been treated with the EPRO composition . According to ated extends at least twice as far through EPRO composition some embodiments, the regrowth of the neurite process is 15 treated tissue than at least one dendrite regenerating through increased at least 80 % in length relative to the regrowth of untreated tissues . a neurite process of a neuron that has not been treated with According to another embodiment, the at least one poly the EPRO composition . According to some embodiments , peptide of formula I regenerates at least one dendrite treated the regrowth of the neurite process is increased at least 90 % with the at least one polypeptide of formula I more effec in length relative to the regrowth of a neurite process of a 20 tively than at least one untreated dendrite . According to neuron that has not been treated with the EPRO composi- some such embodiments , the at least one dendrite treated tion . with the at least one polypeptide of formula I extends at least According to another embodiment, the EPRO composi - twice as far as at least one untreated dendrite . tion increases neurite regrowth by inhibiting expression of at According to another embodiment, the EPRO composi least one inflammatory cytokine from activated microglia . 25 tion is a pharmaceutical composition . According to another embodiment, the at least one inflam - According to another embodiment, the EPRO composi matory cytokine is at least one of IL - 1 beta , IL - 6 , and tion further comprises at least one additional active agent. TNF -alpha . 6 .Methods for Protecting Against Progression of a Neuronal According to another embodiment, axons regenerate Injury or Neuronal Degeneration through EPRO composition treated tissue more effectively 30 According to another aspect, the described invention than through untreated tissues. According to some such provides a method for protecting at least one neuron from embodiments , the axons regenerated extend at least twice as progression of a neuronal injury , the method comprising : ( a ) far through EPRO composition treated tissue than those providing a therapeutically effective amount of an EPRO axons regenerating through untreated tissues. composition , the composition comprising : ( i ) at least one According to another embodiment, the at least one poly - 35 polypeptide having an amino acid sequence according to peptide of formula I regenerates at least one axon treated Formula I : with the at least one polypeptide of formula I more effec tively than an untreated axon . According to some such 21- 01- X2- 03- 04- 25- 26- 27- 28- 29- 310- 32 embodiments , the at least one axon treated with the at least wherein Z1 and Z2 are independently absent or are one polypeptide of formula I extends at least twice as far as 40 transduction domains ; X1 is selected from the group con an untreated axon . sisting of A , KA , KKA , KKKA and RA , or is absent ; X2 is According to another embodiment, the neurite process is selected from the group consisting of G , L , A , V , I, M , Y , W at least one dendrite . According to some such embodiments, and F , or is an aliphatic amino acid ; X3 is selected from the the regrowth of the neurite process is increased at least 10 % group consisting of V , L , I, A , G , Q , N , S , T and C , or is an in length relative to at least one dendrite of the neurite 45 aliphatic amino acid ; X4 is selected from the group consist process that has not been treated with the EPRO composi - ing of Q , N , H , R and K ; X5 is selected from the group tion . According to some such embodiments , the regrowth of consisting of Q and N ; X6 is selected from the group the neurite process is increased at least 20 % in length consisting of C , A , G , L , V , I , M , Y , W and F or is an aliphatic relative to at least one dendrite of the neurite process that has amino acid ; X7 is selected from the group consisting of S , not been treated with the EPRO composition . According to 50 A , C , T and G or is an aliphatic amino acid ; X8 is selected some such embodiments , the regrowth of the neurite process from the group consisting of V , L , I and M ; X9 is absent or is increased at least 30 % in length relative to at least one is any amino acid ; X10 is absent or is any amino acid ; dendrite of the neurite process that has not been treated with wherein at least one of the following is true : (a ) X3 is N and the EPRO composition . According to some such embodi- X7 is not G ; ( b ) X7 is G and X3 is not N ; ( c ) X2 is not L ; ments , the regrowth of the neurite process is increased at 55 ( d ) X4 is not R ; ( e ) X5 is not Q ; ( f) X6 is not L ; ( g ) X8 is least 40 in length relative to at least one dendrite of the not V ; ( h ) X10 is absent; ( i ) X9 and X10 are absent; neurite process that has not been treated with the EPRO composition . According to some such embodiments , the ( ii ) a carrier; regrowth of the neurite process is increased at least 50 % in ( b ) administering the composition to a subject in need length relative to at least one dendrite of the neurite process 60 thereof; and that has not been treated with the EPRO composition . (c ) reducing or inhibiting at least one manifestation of According to some such embodiments , the regrowth of the progression of the neuronal injury in at least one neuronal neurite process is increased at least 60 % in length relative to cell population affected by the neuronal injury ; and at least one dendrite of the neurite process that has not been ( d ) increasing survival of the at least one neuronal cell treated with the EPRO composition . According to some such 65 population affected by the neuronal injury . embodiments , the regrowth of the neurite process is According to one embodiment, the injury is a neurapraxia increased at least 70 % in length relative to at least one type injury. According to another embodiment, the injury is US 9 ,890 , 195 B2 72 a axonotmesis type injury . According to another embodi KAFAKLAARLYRAAGC [SEQ ID NO : 21 ]; AAFAK ment, the injury is a neurtmesis type injury . According to LAARLYRKAGC [SEQ ID NO : 221; KAFAALAAR another embodiment, the injury results from an acute dis LYRKAGC [ SEQ ID NO : 23 ]; KAFAKLAAQLYRKAGC order. According to another embodiment, the acute disorder [ SEQ ID NO : 24 ]; AGGGGYGRKKRRRRRR [ SEQ ID is a stroke , a spinal cord injury, or a traumatic brain injury . 5 NO : 25 ]; YARAAARQARA [SEQ ID NO : 26 ] ; YGRK According to another embodiment, the injury results from a KRRORRR TSEQ ID NO : 271; WLRRIKAWLRRIKA SEQ chronic neurodegenerative disease . According to another ID NO : 28 ] ; WLRRIKAWLRRIKAWLRRIKA [ SEQ ID embodiment, the chronic neurodegenerative disease is Par NO : 291; FAKLAARLYRKA (SEQ ID NO : 30 ); KAF kinson ' s disease , Alzheimer ' s disease , Multiple Sclerosis , AALAARLYRKA [SEQ ID NO : 18 ] ; KAFAKLAAR Amyotrophic lateral sclerosis . or a neuropathy . According to 10 LYRAA [ SEQ ID NO : 16 ]; KAFAKLAARLYRA [SEQ ID another such embodiment, the neuropathy is a diabetic NO : 19 ] ; FAKLAARLYRAA [ SEQ ID NO : 31 ] ; and FAK neuropathy. According to another embodiment, the at leastLAARLYRA [ SEQ ID NO : 32 ). one manifestation of progression of the neuronal injury to at According to another embodiment, exemplary polypep least one neuronal cell population is apoptotic cell death . tides according to the invention include, but are not limited According to another embodiment, the at least one mani - 15 to any of those listed above , wherein one or both of Z1 and festation of progression of the neuronal injury to at least one Z2 are selected from the group consisting of: WLR neuronal cell population is microglial activation . According RIKAWLRRIKA [SEQ ID NO : 28 ] ; WLRRIKAWLR to another embodiment, the at least one manifestation of RIKAWLRRIKA [ SEQ ID NO : 29 ] ; YGRKKRRQRRR progression of the neuronal injury to at least one neuronal (SEQ ID NO : 271; YARAAARQARA (SEQ ID NO : 26 ) ; cell population is inflammation . According to another 20 RORRKKRG [ SEQ ID NO : 31; GRKKRROR [ SEQ ID NO : embodiment, the at least one manifestation of progression of 4 ) ; KAFAKLAARLYRKA [ SEQ ID NO : 15 ] ; FAKLAAR the neuronal injury to at least one neuronal cell population LYRKA [ SEQ ID NO : 301; KAFAALAARLYRKA [ SEQ ID is formation of a scar. According to another embodiment, the NO : 18 ]; KAFAKLAARLYRAA [ SEQ ID NO : 16 ] ; KAF scar is a glial scar. According to another embodiment, the AKLAARLYRA [ SEQ ID NO : 19 ] ; FAKLAARLYRAA neuronal cell population is a cortical cell population . 25 [SEQ ID NO : 31 ] ; and FAKLAARLYRA [ SEQ ID NO : 32 ) . According to another embodiment, the neuronal cell popu - According to another embodiment, the at least one poly lation is a motor neuron cell population . According to peptide of formula I comprises YARAAARQARAKALAR another embodiment, the neuronal cell population is a sen QLGVAA [SEQ ID NO : 33 ]; YGRKKRRORRRKALAR sory neuron cell population . According to some embodi QLGVAA SEQ ID NO : 341; ments , the neuronal cell population is a mixed cortical cell 30 RQRRKKRGKALARQLGVAA [ SEQ ID NO : 35 ] ; GRK population . According to some such embodiments , the KRRQRKALARQLGVAA [SEQ ID NO : 36 ) ; WLR mixed cortical cell population comprises neurons, microglia , RIKAWLRRIKAKALARQLGVAA [SEQ ID NO : 37 ] ; and astrocytes . According to another embodiment, the at WLRRIKAWLRIKAWLRRIKAKALARQLGVAA (SEQ least one neuropathy is a peripheral neuropathy . According ID NO : 38 ]; YARAAARQARAKKKALARQLGVAA [ SEQ to another embodiment, the at least one neuropathy is a 35 ID NO : 391; YGRKKRRRRRRKKKALARQLGVAA (SEO autonomic peripheral neuropathy . ID NO : 40 ] ; RQRRKKRGKKKALARQLGVAA [SEQ ID According to another embodiment, in addition to the NO : 41 ] ; GRKKRRORKKKALARQLGVAA ( SEQ ID NO : recited amino acids, X2 , X3 , X6 and X7 can be any aliphatic 42 ]; WLRRIKAWLRRIKAKKKALARQLGVAA [SEQ ID amino acid (whether naturally occurring or not) , including , NO : 43 ]; WLRRIKAWLRRIKAWLRRIKAKKKALAR but not limited to , beta - alanine and 2 - aminocyclohexane - 1 - 40 QLGVAA [SEQ ID NO : 44 ); KAFAKLAARLYRKALAR carboxylic acid . QLGVAA [SEQ ID NO : 45 ]; FAKLAARLYRKALARQL According to another embodiment, X4 is R ; X5 is Q , GVAA SEQ ID NO : 461; and / or X8 is V . According to another embodiment, X3 is KAFAKLAARLYRAALARQLGVAA [SEQ ID NO : 47 ]; selected from the group consisting of V , L , I, A , G , Q and N . KAFAKLAARLYRALARQLGVAA SEQ ID NO : 48 ) ; According to another embodiment, X6 is selected from the 45 KAFAALAARLYRAALARQLGVAA (SEQ ID NO : 491; group consisting of C , A , G , L , V , I, M , Y , W and F . FAKLAARLYRAALARQLGVAA [SEQ ID NO : 50 ]; According to another embodiment, X7 is selected from the WLRRIKAWRRIKA - LNRQLGVAA ; YARAAAR group consisting of S , A , C , T and G . QARAKALNRQLGVA [ SEQ ID NO : 51] ; KAFAKLAAR According to another embodiment, at least one of Z1 and LYRKALNRQLAVAA [SEQ ID NO : 52 ]; FAKLAAR Z2 is a transduction domain . According to another embodi- 50 LYRKALNROLAVAA ( SEO ID NO : 531; ment, the transduction domain ( s ) is /are selected from the KAFALKAARLYRKA - LNRQLGVAA ; and FAKLAAR group consisting of: ( R )4 - 9 SEQ ID NO : 1 ] ; GRKKRROR - LYRKA -LNRQLGVAA . RRPPQ [SEQ ID NO : 2 ] ; RORRKKRG [SEQ ID NO : 3 ] ; Further exemplary peptides include WLRRIKAWR GRKKRROR [SEQ ID NO : 4 ] ; AYARAAARQARA [ SEQRIKALNRQLGVA [SEQ ID NO : 56 ] , KAFALKAAR ID NO : 51; DAATATRGRSAASRPTERPRAPARSASR - 55 LYRKALNRQLGVA [SEQ ID NO : 57 ] , and FAKLAAR PRRPVE ( SEQ ID NO : 6 ) ; GWTLNSAGYLLGLINLKA LYRKALNRQLGVA [ SEQ ID NO : 58 ] . LAALAKKIL [SEQ ID NO : 7 ]; PLSSIFSRIGDP [SEQ ID Further exemplary polypeptides according to the inven NO : 8 ] ; AAVALLPAVLLALLAP ( SEQ ID NO : 91; AAV tion include , but are not limited to , those comprising or LLPVLLAAP ( SEQ ID NO : 101; VTVLALGALAGVGVG consisting of: KALNRQLGVA [ SEQ ID NO : 54 ] , and SEQ ID NO : 11 ; GALFLGWLGAAGSTMGAWSOP 60 KALNROLGVA ( SEQ ID NO : 55 ) . ( SEQ ID NO : 12 ] ; GWTLNSAGYLLGLINLKALAALAK - According to another embodiment, the at least one poly KIL [ SEQ ID NO : 7 ); KLALKLALKALKAALKLA (SEQ peptide of formula I of the EPRO composition is a peptide ID NO : 13 ) ; KETWWETWWTEWSQPKKKRKV SEQ ID of amino sequence YARAAARQARAKALARQLGVAA NO : 14 ] ; KAFAKLAARLYRKA [ SEQ ID NO : 15 ); KAF [SEQ ID NO : 33 ] . According to another embodiment, the at AKLAARLYRAA ( SEQ ID NO : 16 ]; AAFAKLAAAR - 65 least one polypeptide of formula I of the EPRO composition LYRKA [SEQ ID NO : 17 ); KAFAALAARLYRKA [ SEQ ID is a peptide of amino acid sequence YARAAAR NO : 18 ]; KAFAKLAARLYRKAGC [SEQ ID NO : 20 ] ; QARAKALNRQLGVA [SEQ ID NO : 51] . According to US 9 ,890 , 195 B2 73 74 another embodiment, the at least one polypeptide of formula amino acid sequence FAKLAARLYRKALARQLGVAA I of the EPRO composition is a peptide of amino acid [SEQ ID NO : 46 ] . According to some embodiments , the at sequence FAKLAARLYRKALARQLGVAA (SEQ ID NO : least one polypeptide has at least about 80 % sequence 46 ] . identity to amino acid sequence FAKLAARLYRKALAR According to another embodiment, the at least one poly - 5 QLGVAA (SEQ ID NO : 46 ) . According to some embodi peptide of formula I of the EPRO composition is a peptide ments , the at least one polypeptide has at least about 85 % of amino acid sequence YARAAARQARAKALNRQL sequence identity to amino acid sequence FAKLAAR GVAA [SEQ ID NO : 59 ] . According to another embodi LYRKALARQLGVAA [ SEQ ID NO : 46 ] . ment, the at least one polypeptide of formula I of the EPRO According to some embodiments , the at least one poly composition is a peptide of amino acid sequence FAK - 10 peptide has at least about 70 % sequence identity to amino LAARLYRKLALRQLGVAA [SEQ ID NO : 60 ] . acid sequence FAKLAARLYRKLALRQLGVAA (SEO ID According to one embodiment, the at least one polypep NO : 60 ) . According to some embodiments, the at least one tide has an amino acid sequence of at least 70 % sequence polypeptide has at least about 75 % sequence identity to identity to an amino acid sequence according to Formula I. amino acid sequence FAKLAARLYRKLALRQLGVAA According to one embodiment, the at least one polypeptide 15 [SEQ ID NO : 60 ] . According to some embodiments , the at has an amino acid sequence of at least 75 % sequence least one polypeptide has at least about 80 % sequence identity to an amino acid sequence according to Formula I. identity to amino acid sequence FAKLAARLYRKLAL According to one embodiment , the at least one polypeptide RQLGVAA [ SEQ ID NO : 60 ] . According to some embodi has an amino acid sequence of at least 80 % sequence m ents , the at least one polypeptide has at least about 85 % identity to an amino acid sequence according to Formula I. 20 sequence identity to amino acid sequence FAKLAAR According to one embodiment, the at least one polypeptide LYRKLALRQLGVAA [ SEQ ID NO : 60 ] . has an amino acid sequence of at least 85 % sequence According to another embodiment , the reducing or inhib identity to an amino acid sequence according to Formula I. iting of the at least one manifestation of progression of the According to some embodiments , the at least one poly - neuronal injury is by at least 10 % relative to the manifes peptide has at least about 70 % sequence identity to amino 25 tation of progression of the neuronal injury within at least acid sequence YARAAARQARAKALARQLGVAA [ SEQ one neuronal cell population that has not been treated with ID NO : 33 ]. According to some embodiments , the at least the EPRO composition . According to another embodiment, one polypeptide has at least about 75 % sequence identity to the reducing or inhibiting of the at least one manifestation of amino acid sequence YARAAARQARAKALAROLGVAA progression of the neuronal injury is by at least 20 % relative [ SEQ ID NO : 33 ] . According to some embodiments , the at 30 to the manifestation of progression of the neuronal injury least one polypeptide has at least about 80 % sequence within at least one neuronal cell population that has not been identity to amino acid sequence YARAAARQARAKA - treated with the EPRO composition . According to another LARQLGVAA ( SEQ ID NO : 33 ) . According to some embodiment, the reducing or inhibiting of the at least one embodiments, the at least one polypeptide has at least about manifestation of progression of the neuronal injury is by at 85 % sequence identity to amino acid sequence YARAAAR - 35 least 30 % relative to the manifestation of progression of the QARAKALARQLGVAA [SEQ ID NO : 33 ] . neuronal injury within at least one neuronal cell population According to some embodiments , the at least one poly - that has not been treated with the EPRO composition . peptide has at least about 70 % sequence identity to amino According to another embodiment, the reducing or inhibit acid sequence YARAAARQARAKALNRQLGVA [ SEQ ID ing of the at least one manifestation of progression of the NO : 51 ] . According to some embodiments , the at least one 40 neuronal injury is by at least 40 % relative to the manifes polypeptide has at least about 75 % sequence identity to tation of progression of the neuronal injury within at least amino acid sequence YARAAARQARAKALNRQLGVA one neuronal cell population that has not been treated with [ SEQ ID NO : 51 ] . According to some embodiments , the at the EPRO composition . According to another embodiment, least one polypeptide has at least about 80 % sequence the reducing or inhibiting of the at least one manifestation of identity to amino acid sequence YARAAARQARAKALN - 45 progression of the neuronal injury is by at least 50 % relative RQLGVA [SEQ ID NO : 51 ] . According to some embodi - to the manifestation of progression of the neuronal injury ments , the at least one polypeptide has at least about 85 % within at least one neuronal cell population that has not been sequence identity to amino acid sequence YARAAAR - treated with the EPRO composition . According to another QARAKALNRQLGVA [SEQ ID NO : 51] . embodiment, the reducing or inhibiting of the at least one According to some embodiments , the at least one poly - 50 manifestation of progression of the neuronal injury is by at peptide has at least about 70 % sequence identity to amino least 60 % relative to the manifestation of progression of the acid sequence YARAAARQARAKALNRQLGVAA [SEQ n euronal injury within at least one neuronal cell population ID NO : 59 ]. According to some embodiments , the at least that has not been treated with the EPRO composition . one polypeptide has at least about 75 % sequence identity to According to another embodiment, the reducing or inhibit amino acid sequence YARAAARQARAKALNRQLGVAA 55 ing of the at least one manifestation of progression of the [SEQ ID NO : 59 ] . According to some embodiments , the at neuronal injury is by at least 70 % relative to the manifes least one polypeptide has at least about 80 % sequence tation of progression of the neuronal injury within at least identity to amino acid sequence YARAAARQARAKALN one neuronal cell population that has not been treated with RQLGVAA (SEQ ID NO : 59 ) . According to some embodi- the EPRO composition . According to another embodiment, ments , the at least one polypeptide has at least about 85 % 60 the reducing or inhibiting of the at least onemanifestation of sequence identity to amino acid sequence YARAAAR - progression of the neuronal injury is by at least 80 % relative QARAKALNRQLGVAA [ SEQ ID NO : 59 ] . to the manifestation of progression of the neuronal injury According to some embodiments , the at least one poly - within at least one neuronal cell population that has not been peptide has at least about 70 % sequence identity to amino treated with the EPRO composition . According to another acid sequence FAKLAARLYRKALARQLGVAA [SEQ ID 65 embodiment, the reducing or inhibiting of the at least one NO : 46 ) . According to some embodiments, the at least one manifestation of progression of the neuronal injury is by at polypeptide has at least about 75 % sequence identity to least 90 % relative to the manifestation of progression of the US 9 ,890 , 195 B2 75 76 neuronal injury within at least one neuronal cell population publication provided may be different from the actual pub that has not been treated with the EPRO composition . lication dates which may need to be independently con According to another embodiment, the reducing or inhibit - firmed . ing of the at least one manifestation of progression of the neuronal injury is by at least 95 % relative to the manifes - 5 EXAMPLES tation of progression of the neuronal injury within at least one neuronal cell population that has not been treated with The following examples are put forth so as to provide the EPRO composition . those of ordinary skill in the art with a complete disclosure According to another embodiment, the EPRO composi and description of how to make and use the present inven tion protects at least one neuron from progression of a 10 tion , and are not intended to limit the scope of what the neuronal injury by inhibiting expression of at least one inflammatory cytokine from activated microglia . According inventors regard as their invention nor are they intended to to another embodiment, the at least one inflammatory represent that the experiments below are all or the only cytokine is at least one of IL - 1 beta , IL - 6 , and TNF -alpha . experiments performed . Efforts have been made to ensure According to another embodiment, the EPRO composi- 15 accuracy with respect to numbers used ( e . g . amounts, tem tion is a pharmaceutical composition . perature , etc .) but some experimental errors and deviations should be accounted for. Unless indicated otherwise , parts General methods in molecular genetics and genetic engi are parts by weight, molecular weight is weight average neneering useful in the present invention are described in the current editions of Molecular Cloning : A Laboratory molecular weight, temperature is in degrees Centigrade , and Manual ( Sambrook , et al. , 1989 , Cold Spring Harbor Labo - 20 pressure is at or near atmospheric . ratory Press) , Gene Expression Technology (Methods in Enzymology , Vol. 185 , edited by D . Goeddel, 1991. Aca Example 1 . Peptide Synthesis and Purification demic Press , San Diego , Calif .) , “ Guide to Protein Purifi cation ” in Methods in Enzymology ( M . P . Deutshcer, ed .. The MAPKAP kinase 2 inhibitor (MK2i ) peptide having ( 1990 ) Academic Press, Inc . ) ; PCR Protocols : A Guide to 25 sequence [ SEQ ID NO : 33 ] was synthesized on Rink - amide Methods and Applications (Innis , et al. 1990 . Academic resin using standard fluorenyl methyloxy carboxyl (FMOC ) Press, San Diego , Calif . ) , Culture of Animal Cells : A Manual chemistry on a Protein Technologies Symphony Peptide of Basic Technique , 2nd Ed. ( R . I. Freshney. 1987 . Liss , Inc. Synthesizer (Protein Technologies , Inc. , Tucson , Ariz . ). Fol New York , N . Y .) , and Gene Transfer and Expression Pro - lowing synthesis, the peptide was cleaved from the resin tocols , pp . 109 - 128 , ed . E . J . Murray, The Humana Press 30 with a trifluoroacetic acid ( TFA ) -based cocktail, precipitated Inc ., Clifton , N . J . ) . Reagents , cloning vectors , and kits for in ether , and recovered by centrifugation . The recovered genetic manipulation are available from commercial ven peptide was dried overnight in vacuum , re -suspended in dors such as BioRad , Stratagene , Invitrogen , ClonTech and MilliQ -purified water , then purified using an fast protein Sigma - Aldrich Co . liquid chromatography (FPLC ) system ( AKTA Explorer ,GE Where a range of values is provided , it is understood that 35 Healthcare ) equipped with a 22 / 250 C18 prep - scale column each intervening value , to the tenth of the unit of the lower (Grace Davidson , Deerfield , Ill . ) . An acetonitrile gradient limit unless the context clearly dictates otherwise , between was used to achieve separation . A small sample of peptide the upper and lower limit of that range and any other stated was solubilized in TFA ( 0 . 1 % ) , water ( 50 % ) and acetonitrile or intervening value in that stated range is encompassed (about 50 % ) and the molecular weight confirmed by time within the invention . The upper and lower limits of these 40 of- flight matrix - assisted laser desorption / ionization smaller ranges which may independently be included in the (MALDI ) mass spectrometry . Synthesis and concentration smaller ranges is also encompassed within the invention of the peptides were confirmed using quantitative amino subject to any specifically excluded limit in the stated range . acid analysis . Where the stated range includes one or both of the limits , ranges excluding either both of those included limits are also 45 Example 2 . Effect of MAPKAP Kinase 2 Inhibition included in the invention . (MK2i ) on Neurite Outgrowth Unless defined otherwise , all technical and scientific terms used herein have the same meaning as commonly The effect of an MAPKAP Kinase 2 inhibitor (MK2i ) on understood by one of ordinary skill in the art to which this neurite outgrowth was studied using mixed cortical cells invention belongs . Although any method and materials 50 (neurons , microglia , astrocytes ) isolated from E18 Sprague similar or equivalent to those described herein can also be Dawley rat cortices. Briefly , the tissue was dissociated and used in the practice or testing of the present invention , the the isolated cortical cells were cultured in polylysine -coated preferred methods and materials are now described . All 96 -well plates. After culture for 24 hours , the cortical cells publications mentioned herein are incorporated herein by were exposed to 100 mM MK2i peptide YARAAAR reference to disclose and described the methods and /or 55 QARAKALARQLGVAA [SEQ ID NO : 33 ] or to regular materials in connection with which the publications are media ( control) for 5 hours . Phase contrast images of cited . individual neurons were acquired and neurite length was It must be noted that as used herein and in the appended quantified by tracing individual neurons using ImageJ soft claims , the singular forms " a " , " and ” , and “ the ” include ware ( Collins , T J ( July 2007 ) ; " Image for microscopy ” , plural references unless the context clearly dictates other - 60 Biotechniques. 43 ( 1 Suppl) : 25 -30 ) . wise . All technical and scientific terms used herein have the FIG . 1 shows a graph of the mean neurite length (um ) of same meaning . the control neurons ( n = 160 neurites ) and of the MK2i The publications discussed herein are provided solely for peptide YARAAARQARAKALARQLGVAA [SEQ ID NO : their disclosure prior to the filing date of the present appli - 33 ] exposed neurons ( n = 113 neurites ). Statistical evaluation cation . Nothing herein is to be considered as an admission 65 included a Kolmogorov - Smirnov test to confirm the distri that the present invention is not entitled to antedate such bution was normal, as well as a t - test with an alpha value of publication by virtue of prior invention . Further , the dates of 0 .01 . The statistical evaluation shows that the mean of the US 9 ,890 , 195 B2 77 78 neurite lengths of MK2i- treated neurites was significantly sion objectives. Image channels were collected sequentially larger than that of the control. (p < 0 .01 ) using 488 nm , 543 nm , and 633 nm laser lines, along with a tunable MaiTai laser (Spectra Physics ) set to 740 nm . Example 3 . Effect of MAPKAP Kinase 2 Inhibition Two -photon excitation of Hoescht 33342 was driven by this (MK2i ) on Neuronal Cell Death and Microglial 5 740 nm excitation , and the emission was collected by an Activation external PMT (R3896 , Hamamatsu ) equipped with a 405 /40 nm filter (Chroma ) ) . Internal detectors collected all other The effect of MK2i on neuronal cell death and microglical channels . A wide aperture setting (400 um ) was used to activation was investigated by treating 1 -week old mixed capture representative images from the labeled 2D cultures ; cortical cultures comprising neurons , astrocytes , and micro - 10 laser power and PMT voltage settings were held constant. glia with the MK2i peptide YARAAARQARAKALARQL Related image channels levels were set equal, allowing GVAA [SEQ ID NO : 33 ] . Primary Cortical Cell Culture visual comparison of fluorescent intensity, using Olympus Embryonic rat cortical tissue was obtained immediately Fluoview V1 . 7 software . Scale bars were added and figures following removal of embryos from the rat' s abdomen . E17 were designed using Photoshop CS2 ( Adobe ). Sprague -Dawley rat cortical tissue was placed in a 50 ml 15 Live -Dead Assay conical tube containing 5 ml of Solution 1 (NaCl 7 .24 g /L ; Live -dead assays were conducted using Molecular KCl 0 . 4 g / L ; NaH , PO , 0 . 14 g / L ; Glucose 2 .61 g / L ; Hepes Probe ' s LIVE /DEAD® Viability /Cytotoxicity Kit for Mam 5 . 96 g / L ; MgSO4 0 . 295 g / L ; Bovine Serum Albumin 3 g / L ) . malian Cells to quantify the change in toxicity in cortical cell Under sterile conditions, 18 ul of trypsin solution (7 . 5 mg/ ml cultures following the MK2i peptide YARAAAR in 0 . 9 % saline ) was added and tissue was passed through a 20 QARAKALARQLGVAA [SEQ ID NO : 33 ] treatment . Prior 5 -ml pipet several times to disassociate tissue . After the to experiments , optimal concentration of the live cell dye , conical tube was placed in a 37° C . water bath for 20 Calcein - AM (CA ) , and the dead cell dye (Ethidium - 1 ) was minutes , 100 ul of trypsin inhibitor /DNAse solution ( 2 . 5 determined to be 6 mM . Also , optimal time for dye incu mg /ml trypsin inhibitor, 400 ug /ml DNase in 0 . 9 % saline ) bation was 30 minutes . was added to the tube and tissue was pipetted several times 25 One -half hour before the 24 - hour time point, untreated with a 5 -ml pipet. Tissue was centrifuged at 1 , 000 rpm for cultures were killed with a 30 -minute 70 % ethanol treat 5 minutes at room temperature and supernatant was poured ment . One group of control dead cells received 100 ul of the off . Cells were re - suspended in 16 ml of HibernateE 6 mM CA solution to determine the background fluores (BrainBits , Springfield , 111 . ) and 100 ul of trypsin inhibitor/ cence of CA . A second group of control dead cells received DNAse solution and pipetted up and down several times. 30 100 ul of the 6 mM EthD - 1 solution to determine the Cells were filtered through a cell strainer and centrifuged at maximum fluorescence for EthD - 1 . Conversely , one group 1 ,400 rpm for 5 minutes at room temperature . Supernatant of control live cells received 100 ul of the 6 mM EthD - 1 was poured off and cells were re -suspended in media . solution to determine the background fluorescence of EthD Primary cells were then plated in poly - D - lysine coated 1 , while a second group of control live cells received 100 ul 96 -well plates at a seeding density of 625 , 000 cells / cm and 35 of the 6 mM CA solution to determine the maximum incubated for 7 - 9 days at 37° C . After 7 - 9 days , cortical cells fluorescence for CA . were treated with 5 ng/ ml or 10 ng /ml of TNF - a to activate At the 24 hour time point, cultures were washed twice microglia . Cells then were treated with 0 , 0 . 5 , 1 , or 3 mM with 250 ul 1xPBS . Then , 100 ul of a 6 mM EthD - 1 /6 mM MK2i peptide YARAAARQARAKALARQLGVAA ( SEQ C A working solution was added to each treated well. Fluo ID NO : 33 ] for 4 hours , 8 hours, and 24 hours. After 40 rescence was measured then using a Spectramax M5 treatment, media was removed and stored at - 20° C . Microplate Reader (Molecular Devices ) . EthD - 1 required an Immunocytochemistry excitation wavelength of 530 nm and an emission wave In preparation for staining mixed cortical cells , cellmedia length of 645 nm . CA required an excitation wavelength of was replaced with phosphate -buffered 4 % formaldehyde 485 nm and an emission wavelength of 530 nm . solution for 5 minutes, followed by three washes using 45 The MK2i Peptide YARAAARQARAKALARQLGVAA HBHS solution ( HEPES -buffered Hank ' s saline containing [ SEQ ID NO : 33 ] Reduces Cell Death and Microglial 10 mg/ L sodium azide , pH 7 . 4 ) . Blocking solution , consist Activation ing of 10 % normal goat serum in HBHS, then was applied Immunohistochemical images confirmed the presence of for 30 minutes , followed by three washes with HBHS . neurons, astrocytes , and microglia in 1 -week old mixed Microglia , astrocytes , and neurons were labeled using anti - 50 cortical cultures (FIGS . 2A and 2B ) , which was maintained bodies against ionized calcium binding adaptor molecule 1 following the MK2i peptide YARAAARQARAKALARQL ( Ibal , Wako ) , glial fibrillary acidic protein (GFAP , Milli - GVAA ( SEQ ID NO : 33 ] treatment. FIG . 3 shows micro pore ), and B - 3 - tubulin (B3tub , Covance ) , respectively . Anti - graphs of neurons ( ß - 3 - tub ), astrocytes (GFAP ) , and micro bodies were applied for 2 hours , at a dilution of 1 :400 in glia ( Ibal ) , treated with 0 mM MK2i HBHS . After two 10 minute washes and one 30 minute 55 ( YARAAARQARAKALARQLGVAA ( SEQ ID NO : 33 ]) , wash , secondary antibodies were applied . Alexafluor 488 0 .5 mM MK2i, 1 . 0 mM MK2i, and 3 mM MK2i . Minimal goat -anti -mouse , Alexafluor 555 goat -anti -chicken , and morphological effects were observed until 3 mM treatment, Alexafluor 635 goat anti - rabbit ( all from Invitrogen , Carls which increased neuronal and astrocytic cell damage, as well bad , Calif . ) were applied at 1 : 400 along with Hoescht 33342 as microglial proliferation . FIG . 4 shows micrographs of at approximately 1 : 10000 ( Invitrogen , Carlsbad , Calif . ) in 60 neurons treated with MK2i ( YARAAARQARAKALARQL HBHS for 2 hours . All immunocytochemistry procedures GVAA [ SEQ ID NO : 33 ] ) and TNF - a . Row 1 shows neurons were performed at room temperature, and stored at 4° C . in treated with 0 mM MK2i and 0 ng/ ml TNF - a , 5 ng /ml HBHS + sodiumazide prior to imaging . TNF - a , and 10 ng/ ml TNF - a , respectively ; Row 2 shows Cell Imaging neurons treated with 0 . 5 mM MK2i and 0 ng /ml TNF - a , 5 Cell imaging was accomplished using an Olympus IX81 65 ng/ ml TNF - a , and 10 ng /ml TNF- a , respectively ; Row 3 microscope equipped with an Olympus FV1000 laser con - shows neurons treated with 1 mM MK2i and 0 ng /ml focal system through Olympus 10x / 0 .40x /0 .80 water emer - TNF- a , 5 ng/ ml TNF- a , and 10 ng/ ml TNF - a , respectively ; US 9 ,890 , 195 B2 79 80 and Row 4 shows neurons treated with 3 mM MK2i and 0 assays were conducted using the Rat IL - 1B ELISA Devel ng/ ml TNF - a , 5 ng/ ml TNF - a , and 10 ng/ ml TNF - a , respec opment Kit (Peprotech Inc ., Rocky Hill , N . J .) . 100 ul of 2 tively . FIG . 4 shows the effect of TNF - a - and MK2i on ug/ ml antigen -affinity purified goat anti- rat IL - 1ß was added neurons, indicating that 5 ng /ml and 10 ng /ml TNF - a to ELISA microplate wells (NuncMaxisorp ) and incubated treatment resulted in significant neuronal cell damage , 5 at room temperature overnight. Wells were washed 4 times which was suppressed by 0 .5 and 1 mM MK2i . However, with 300 ul wash buffer ( 0 .05 % Tween - 20 in 1xPBS ) . 300 this suppression was not maintained at 3 mM MK2i treat - ul block buffer ( 1 % BSA in 1xPBS ) was added to each well ment, which also resulted in neuronal cell damage . FIG . 5 and incubated for 1 hour at room temperature . Block buffer shows micrographs of microglia treated with TNF - a and was aspirated and wells were washed 4 times with wash MK2i ( YARAAAROARAKALARQLGVAA (SEO ID NO : 10 buffer . 3 ng/ ml recombinant IL - 1B was then diluted to zero 33 ]) , where Row 1 shows non -MK2i - treated microglia ( con in diluent ( 0 .05 % Tween - 20 , 0 . 1 % BSA in 1xPBS ) . 100 ul trol) exposed to 0 ng/ ml TNF - a and 10 ng /ml TNF - a ; and of diluted recombinant IL - 1ß solutions were added in trip Row 2 shows 1 mM MK2i - treated microglia exposed toO licate into microplate wells . 100 ul of media from MK2i ng /ml TNF - a and 10 ng /ml TNF - a . FIG . 5 indicates that treatments also were added to microplate wells . Microplates 24 -hr TNF - a treatment induces microglial spreading within 15 were then incubated at room temperature for 2 hours, mixed cortical cultures , and that 24 hour TNF - a and MK2i aspirated and washed 4 times with wash buffer . 100 ul of 0 . 5 treatment induces microglial swelling , but suppresses the ug/ ml biotinylated antigen - affinity purified goat anti -rat microglial spreading caused by TNF - a . IL - 1B was added to microplate wells and incubated for 2 FIG . 6 shows micrographs of astrocytes treated with hours . Microplates were aspirated and washed 4 times with TNF - a and MK2i (YARAAAROARAKALAROLGVAA 20 wash buffer . 5 . 5 ul Avidin Peroxidase 1 :2000 was diluted in [ SEQ ID NO : 33 ]) . Row 1 shows non -MK2i - treated astro 11 ml diluent. 100 ul of this solution was added to wells and cytes exposed to 0 ng /ml , 5 ng /ml and 10 ng /ml TNF - a , incubated for 30 minutes at room temperature, aspirated , and respectively ; Row 2 shows 0 . 5 mM MK2i - treated astrocytes washed 4 times with wash buffer . 100 ul of ABTS Liquid exposed to 0 ng /ml , 5 ng/ ml and 10 ng/ ml TNF - a , respec - Substrate Solution (Sigma ) was added to each well . Absor tively ; Row 3 shows 1 mM MK2i- treated astrocytes exposed 25 bance was then measured using a Spectramax M5 to 0 ng /ml , 5 ng /ml and 10 ng /ml TNF - a , respectively ; and Microplate Reader (Molecular Devices ) . Absorbance values Row 4 shows 3 mm MK2i- treated astrocytes exposed to 0 were monitored at 5 -minute intervals for 25 minutes . ng /ml , 5 ng /ml and 10 ng /ml TNF - a , respectively . FIG . 6 The MK2i Peptide ( YARAAARQARAKALARQL shows damage to astrocytes treated with 3 mM MK2i. GVAA [SEQ ID NO : 33 ] ) Significantly Reduces Mean IL - 6 30 and IL - B Concentration Example 4 . The Effect of MAPKAP Kinase 2 Dunnett 's method was used to compare the effect of Inhibition (MK2i ) on IL - 6 and IL - 1B Expression TNF - a +MK2i ( YARAAARQARAKALARQLGVAA [SEQ ID NO : 33 ] ) treatment on IL - 6 concentration to TNF - a IL - 6 ELISA Assays treatment. For the 5 ng /ml and 10 ng /ml TNF - a controls , In order to investigate the effect of MK2i inhibition on 35 analysis showed that mean IL - 6 concentrations significantly IL - 6 production , IL - 6 ELISA assays were conducted to decreased following 0 . 5 mM , 1 mM , and 3 mM MK2i quantify changes in inflammatory cytokine production using ( YARAAARQARAKALARQLGVAA [ SEQ ID NO : 33 ] ) the Rat IL - 6 ELISA Development Kit (Peprotech Inc. , treatment for 4 hours , 8 hours , or 24 hours (FIG . 7 , A - C ). Rocky Hill, N . J . ) . 100 ul of 1 ug /ml antigen -affinity purified Dunnett ' s method also was used to compare the effect of goat anti - rat IL -6 was added to ELISA microplate wells 40 TNF - a +MK2i (YARAAARQARAKALARQLGVAA (SEQ (NuncMaxisorp ) and incubated at room temperature over ID NO : 33 ]) treatment on IL - 1ß concentration to TNF - a night. Wells were washed 4 times with 300 ul wash buffer treatment alone ( FIG . 7 , D - F ) . For the 5 ng /ml TNF - a ( 0 . 05 % Tween -20 in 1xPBS ) . 300 ul block buffer ( 1 % BSA controls , analysis showed that after 4 hours , 8 hours and 24 in 1xPBS ) was added to each well and incubated for 1 hour hours, mean IL - 1B concentrations significantly decreased at room temperature . Block buffer was aspirated and wells 45 after 0 . 5 mm , 1 mM , and 3 mM MK2i ( YARAAAR were washed 4 times with wash buffer. 8 ng /ml recombinant QARAKALARQLGVAA (SEQ ID NO : 33 ]) treatment. For IL - 6 was then diluted to zero in diluent ( 0 .05 % Tween - 20 , the 10 ng /ml TNF - a controls , analysis showed that after 4 0 . 1 % BSA in 1xPBS ). 100 ul of diluted recombinant IL - 6 hours and 8 hours , mean IL - 1ß concentrations significantly solutions were added in triplicate into microplate wells. 100 decreased after 0 . 5 mM , 1 mM , and 3 mM MK2i ul of media from MK2i treatments also were added to 50 (YARAAARQARAKALARQLGVAA (SEQ ID NO : 331) microplate wells . Microplates then were incubated at room treatment. After 24 hours , mean IL - 1B concentrations also temperature for 2 hours , aspirated and washed 4 times with decreased after 0 .5 mm , 1 mM , and 3 mM MK2i wash buffer. 100 ul of 0 .25 ug/ ml biotinylated antigen - (YARAAARQARAKALARQLGVAA [SEQ ID NO : 33 ]) affinity purified goat anti - rat IL - 6 was added to microplate treatment; however, only 3 mM MK2i (YARAAAR wells and incubated for 2 hours. Microplates were aspirated 55 QARAKALARQLGVAA [ SEQ ID NO : 33 ]) produced a and washed 4 times with wash buffer. 6 ul Avidin Peroxidase statistically significant decrease . Results suggest that MK2i 1 :2000 was diluted in 12 ml diluent. 100 ul of this solution treatment is an effective method for down -regulating , but not was added to wells and incubated for 30 minutes at room eliminating , cytokine production following microglial acti temperature, aspirated , and washed 4 times with wash buffer. vation . 100 ul of ABTS Liquid Substrate Solution (Sigma ) was 60 added to each well. Absorbance was then measured using a Example 5 . The Effect of MAPKAP Kinase 2 Spectramax M5 Microplate Reader (Molecular Devices ) . Inhibition (MK2i ) on Cortical Cell Viability Absorbance values were monitored at 5 -minute intervals for 50 minutes . Dunnett ' s method was used to compare the effect of IL - 1B ELISA Assays 65 TNF - a + MK2i ( YARAAARQARAKALARQLGVAA [SEQ In order to quantify changes in inflammatory cytokine ID NO : 33 ] ) treatment to TNF - a treatment on the percentage ( IL - 1B ) production upon MK2i inhibition , IL - 1B ELISA of dead cortical cells . FIG . 8 shows a graph of the net % dead US 9 ,890 , 195 B2 81 82 cells versus 24 treatments of 1 ) 5 ng /ml TNF - a plus 500 um thereafter to prevent urinary tract infections. Animals will be MK2i ( YARAAARQARAKALARQLGVAA [ SEQ ID NO : sacrificed at two time points to provide assessment of the 331) : 2 ) 5 ng /ml TNF - a plus 1 mM MK2i: 3 ) 5 ng /ml TNF - a onset and sustained regeneration of axons ( typically in cohorts of 6 and 16 on days 7 and 56 respectively . The day plus 3 mM MK2i; 4 ) 10 nm /ml TNF -a plus 500 uM MK2i; 5 7 time allows determination of the extent of proliferation of 5 ) 10 ng /ml TNF- a plus 1 mM MK2i; and 6 ) 10 ng/ ml 5 astrocytes and if there is a chronic immune response . Day 56 TNF - a plus 3 mM MK2i. In FIG . 8 , % dead values for will provide information on axonal regeneration ( Coumans , TNF - a + MK2i ( YARAAARQARAKALARQLGVAA SEQ J . V . , T . T . - S . Lin , et al . ( 2001) . “ Axonal regeneration and ID NO : 33 ]) treatments were normalized to TNF - a only functional recovery after complete spinal cord transection in treatments . After 24 hours , 5 ng/ ml TNF - a + MK2i rats by delayed treatment with transplants and neurotro ( YARAAARQARAKALARQLGVAA [SEQ ID NO : 33 ]) 10 phins” The Journal of Neuroscience 21 (23 ): 9334 - 9344 ). A treatment significantly decreased % dead cells . 10 ng/ ml Targer number of animals is needed for day 56 animals so TNF - a +MK2i (YARAAARQARAKALARQLGVAA [SEQ that longitudinal and axonal sectioning as well as neuroana ID NO : 33 ]) treatment also decreased % dead values. tomical tracing can be done (Woerly , Doan Woerly , S . , V . D . However , this decrease was not statistically significant. FIG . Doan , et al. ( 2001) . " Spinal cord reconstruction using Neu 4 shows a decreased neuronal population when cells are 15 rogelTM Implants and functional recovery after chronic treated with 10 ng /ml TNF - a . This effect was not observed injury . ” Journal of Neuroscience Research 66 : 1187 - 1197 ) . in cultures simultaneously treated with 10 ng/ ml TNF - a Spinal Cord Histology : along with MK2i (both 0 .5 mM and 1 mM concentration ) . Animals will be euthanized by CO , inhalation according This suggests that treatment with MK2i exerts a neuropro - to AVMA recommendations (Andrews , E . J ., B . T . Bennett , tective effect. These results also suggest that MK2i 20 et al. ( 1993 ) . “ Report of the AVMA panel on Euthanasia .” ( YARAAARQARAKALARQLGVAA [SEQ ID NO : 33 ]) Journal of the American Veterinary Association 202 ( 2 ) : treatment creates a more viable cellular environment, poten 229 - 249 ) . Cardiac perfusion using 2 % paraformaldehyde in tially through avoiding TNF - a - induced neuroinflammation PBS , followed by 10 % sucrose precedes cord dissection to ( see , for example , Lee et al 1999 , Oh et al. , 1999 , Tambuyzer optimize histology (Andrew , D . and A . D . Craig , Spinotha et al. , 2009 ) . 25 lamic lamina I neurons selectively sensitive to histamine : a central neural pathway for itch . Nature Neuroscience , 2001 . Example 6 . The Effect of the MK2i Peptide 4 ( 1 ) : p . 72 -77 ) . From the four animals not receiving neural YARAAARQARAKALARQLGVAA ( SEQ ID NO : tracing , the cord in the region of injury will be recovered , 33 ] on MK2 Expression then processed by longitudinal cryostat sectioning (14 um ) 30 along the injured axis . For assessment of proliferative cells Western blot analysis was used to determine the effect of in the injury site , anti -PCNA antibodies are applied accord the MK2i peptide YARAAARQARAKALARQLGVAA ing to supplier 's instruction . Cell - type staining for occupa [ SEQ ID NO : 33 ] on MK2 expression . FIG . 9 shows a graph tion of the matrix in the context of spinal repair will include of normalized intensity of the expression level of the MK2 astrocytes ( glial fibrillary acidic protein , GFAP ), oligoden protein by cultured cortical cells following 24 hour MK2i 35 drocytes (myelin proteolipid protein , mPLP ) , neurons ( neu ( YARAAARQARAKALARQLGVAA [SEQ ID NO : 33 ] ) ron specific enolase , NSE ) , GAP -43 ( found in the growth ( 500 uM ) treatment. The upper right corner of the figure cone of extending axons ), monocytes/ macrophages ( CD45 ) , shows a western blot analysis of the MK2 protein following lymphocytes (CD16 ) , and endothelial cells ( factor VIII ) . MK2i (500 uM ) treatment. Comparison of control blots to Cervical Contusion Injury . treatment blots showed no significant reduction in MK2 40 A contusion injury will be created using an electromag expression following 24 hr 0 . 5 mM MK2i ( YARAAAR - netic SCI device . Animals first will be anesthetized and then QARAKALARQLGVAA [ SEQ ID NO : 33 ] ) treatment. a vertical incision will be made along the cervical vertebra These results support MK2i' s mechanism of action , i . e ., and the superficial muscle and skin retracted . A laminectomy MK2i interferes with substrate binding to MK2, but does not will be used to expose at cervical vertebra C5 and the spinal reduce MK2 activity (FIG . 9 ) or phosphorylation (data not 45 cord underneath (C5 ) while maintaining an intact dura shown ) . mater. The cervical contusion injury will be created with a force of 3 Kdyn . The exposed C5 spinal cord will be rated Example 7 . Animal Models as either mildly, moderately or severely injured as deter mined by displacement of the spinal cord by 0 .80 mm , 0 . 95 In another aspect, the present invention further describes 50 mm , or 1 . 10 mm , respectively , with a single , brief displace experiments in animal models of human disease that will be ment of 20 msec . After injury , the muscles and skin will be used to determine the effect of the polypeptides of the sutured in layers. The rats will recover in a warmed cage present invention . with water and food easily accessible . Gentamicin ( 5 mg/ kg , Spinal Cord Models intramuscular ) will be administered immediately post- sur Spinal cord experiments : Sprague Dawley rats (200 - 300 55 gery and then daily for seven days . The analgesic , Buprenex mg) will be subjected to spinal cord injury using transection ( 0 .01 mg /kg of 0 . 3 mg/ mL , subcutaneous ) will be delivered (Widenfalk , Lundstromer et al. 2001 ) . Following halothane post- surgery and daily for 2 days to minimize animal dis anesthesia , dorsal laminectomies at T9 expose the cord . comfort . The rats will be maintained for 1 week or 9 weeks Complete transection leaving a 2 mm gap will be achieved after injury . For each time point and severity of injury, 20 using an iris scalpel. Peptide concentrations ranging from 60 animals will be treated and 10 animals will serve as controls. 0 .01 - 1 mM peptide or saline ( control) will be applied to the Harvested tissues will be examined for cavitation , gliosis injured cord is achieved using 50 - 100 ul volumes . Closure and axonal regeneration . will be done using absorbable suture material, and the animals recover on warmed blankets . Prophylactic antibiot Example 8 . Animal Models ics will be administered for one week , and subsequently if 65 needed . Urinary bladders will be emptied thrice daily by Adult Sprague -Dawley rats were anesthetized with intra mechanical expression for the first week , and twice daily peritoneal injection of ketamine /xylazine and their dorsal US 9 ,890 , 195 B2 83 84 thoracic skin scrubbed with an aspetic betadine solution . A reduction in the amount of MPO activity using the 5 M T9 - 10 laminectomy was performed under sterile conditions MK2i dose ( I . V . ) compared to the higher doses and the to expose the spinal cord without disrupting the dura . FIG . saline control . 10 shows a graph of the MPO activity . A moderate spinal cord injury was delivered with a MASCIS impactor (Keck 5 While the present invention has been described with Center for Collaborative Research , Piscataway , NJ. ) at a reference to the specific embodiments thereof, it should be level of 25 cm . Immediately after the surgery the incision understood by those skilled in the art that various changes was closed in multiple layers . Thirty minutes following may be made and equivalents may be substituted without injury the animals were dosed with 0 . 5 ml YARAAAR - departing from the true spirit and scope of the Invention . In QARAKALARQLGVAA ( SEQ ID NO : 33 ] (500 uM , 50 1 addition , many modifications may be made to adapt a uM , or 5 uM ) in 0 . 9 % NaCl. After 4 hours, the animals were particular situation , material, composition of matter , pro sacrificed via a lethal dose of pentobarbital. The injured cess, process step or steps, to the objective , spirit and scope spinal cord was dissected out. Myeloperoxidase enzyme of the present invention . All such modifications are intended (MPO ) activity was measured . There was a significant to be within the scope of the claims appended hereto .

SEQUENCE LISTING

< 160 > NUMBER OF SEO ID NOS : 60 < 210 > SEQ ID NO 1 < 211 > LENGTH : 9 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : 223 > OTHER INFORMATION : MAMMALIAN < 220 > FEATURE : < 221??MF > NAME / KEY : MISC _ FEATURE < 222 > LOCATION : ( 4 ) . . ( 9 ) < 223 > OTHER INFORMATION : WHERE UP TO FIVE ARG ARE ABSENT < 400 > SEQUENCE : 1 Arg Arg Arg Arg Arg Arg Arg Arg Arg

< 210O > SEQ ID NO 2 < 211 > LENGTH : 13 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 2 Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg Pro Pro Gin 5 10

?.< 210 > SEQ ID NO 3 ?< 211 > LENGTH : 8 ?< 212 > TYPE : PRT ?< 213 > ORGANISM : Unknown ? 220 > FEATURE : ?< 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 3 Arg Gin Arg Arg Lys Lys Arg Gly 5

?.< 210 > SEQ ID NO 4 ?< 211 > LENGTH : 8 ?< 212 > TYPE : PRT ?< 213 > ORGANISM : Unknown ?< 220 > FEATURE : ?< 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 4 Gly Arg Lys Lys Arg Arg Gin Arg

< 210 > SEQ ID NO 5 < 211 > LENGTH : 12 US 9 ,890 , 195 B2 85 86 - continued < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 5 Ala Tyr Ala Arg Ala Ala Ala Arg Gin Ala Arg Ala 10

< 210 > SEQ ID NO 6 < 211 > LENGTH : 34 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 6 Asp Ala Ala Thr Ala Thr Arg Gly Ara Ser Ala Ala Ser Ara Pro Thr 10 15 Glu Arg Pro Arg Ala Pro Ala Arg Ser Ala Ser Arg Pro Arg Arg Pro 20 25 30 Val Glu

?< 210 > SEQ ID NO 7 ?< 211 > LENGTH : 27 ?< 212 ?> TYPE : PRT ?< 213 ?> ORGANISM : Unknown ?< 220 > FEATURE : ?< 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 7 Gly Trp Thr Leu Asn Ser Ala Gly Tyr Leu Leu Gly Leu Ile Asn Leu 10 15 Lys Ala Leu Ala Ala Leu Ala Lys Lys Ile Leu 20 25

< 210 > SEQ ID NO 8 < 211 > LENGTH : 12 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 8 Pro Leu Ser Ser Ile Phe Ser Arg Ile Gly Asp Pro 10

< 210 > SEQ ID NO 9 < 211 > LENGTH : 16 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 9 Ala Ala Val Ala Leu Leu Pro Ala Val Leu Leu Ala Leu Leu Ala Pro 2 10 15

< 210 > SEQ ID NO 10 < 211 > LENGTH : 12 < 212 > TYPE : PRT < 213??? > ORGANISM : Unknown < 220 > FEATURE : < 223??? > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 10 US 9 ,890 , 195 B2 87 88 - continued

Ala Ala Val Leu Leu Pro Val Leu Leu Ala Ala Pro 10

< 210 > SEQ ID NO 11 < 211 > LENGTH : 15 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown V 20 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 11 Val Thr Val Leu Ala Leu Gly Ala Leu Ala Gly Val Gly Val Gly 10 15

< 210 > SEQ ID NO 12 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 2 20 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 12 Gly Ala Leu Phe Leu Gly Trp Leu Gly Ala Ala Gly Ser Thr Met Gly 10 15 Ala Trp Ser Gin Pro 20

< 210 > SEQ ID NO 13 < 211 > LENGTH : 18 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 13 Lys Leu Ala Leu Lys Leu Ala Leu Lys Ala Leu Lys Ala Ala Leu Lys 10 15

Leu Ala

< 210 > SEQ ID NO 14 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 14 Lys Glu Thr Trp Trp Glu Thr Trp Trp Thr Glu Trp Ser Gin Pro Lys 1 10 15 Lys Lys Arg Lys Val 20

< 210 > SEQ ID NO 15 < 211 > LENGTH : 14 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 15 Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala 10

< 210 > SEO ID NO 16 US 9 ,890 , 195 B2 89 - continued < 211 > LENGTH : 14 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 16

Lys Ala Phe Ala Lys Leu Ala Ala Arq Leu Tyr Arg Ala Ala 10

< 210 > SEQ ID NO 17 < 211 > LENGTH : 15 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220M > FEATURE : < 223M > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 17 Ala Ala Phe Ala Lys Leu Ala Ala Ala Arg Leu Tyr Arg Lys Ala 5 10 15

< 210 > SEQ ID NO 18 < 211 > LENGTH : 14 < 212 > TYPE : PRT ?< 213 > ORGANISM : Unknown ?< 220 > FEATURE : ?< 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 18 Lys Ala Phe Ala Ala Leu Ala Ala Arg Leu Tyr Arg Lys Ala 1 10

< 210 > SEQ ID NO 19 < 211 > LENGTH : 13 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 19 Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Ala 1 ala Arg Leu10 Tyr Arg Ala

< 210 > SEQ ID NO 20 < 211 > LENGTH : 16 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 20 Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Gly Cys 1 10 15

< 210 > SEQ ID NO 21 < 211 > LENGTH : 16 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 21 Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Ala Ala Gly Cys 10 15

< 210 > SEQ ID NO 22 < 211 > LENGTH : 16 US 9 ,890 , 195 B2 91 - continued < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 22 Ala Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Gly Cys 10 15

< 210 > SEQ ID NO 23 < 211 > LENGTH : 16 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 23 Lys Ala Phe Ala Ala Leu Ala Ala Arg Leu Tyr Arg Lys Ala Gly Cys 10 15

< 210 > SEQ ID NO 24 < 211 > LENGTH : 16 < 212 > TYPE : PRT ? 13 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 24 Lys Ala Phe Ala Lys Leu Ala Ala Gln Leu Tyr Arg Lys Ala Gly Cys 1 10 15

< 210 > SEQ ID NO 25 < 211 > LENGTH : 16 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 25 Ala Gly Gly Gly Gly Tyr Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg 10 15

< 210 > SEQ ID NO 26 < 211 > LENGTH : 11

? < 212M?? > TYPE : PRT ?< 213 > ORGANISM : Unknown ?< 220 > FEATURE : ?< 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 26 Tyr Ala Arg Ala Ala Ala Ara Gln Ala Ara Ala 10

< 210 > SEO ID NO 27 < 211 > LENGTH : 11 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 27 Tyr Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg 10

< 210 > SEQ ID NO 28 < 211 > LENGTH : 14 < 212 > TYPE : PRT US 9 ,890 , 195 B2 93 94 - continued < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 28 Trp Leu Arg Arg Ile Lys Ala Trp Leu Arg Arg Ile Lys Ala 1 5 10

< 210 > SEQ ID NO 29 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 29 Trp Leu Arg Arg Ile Lys Ala Trp Leu Arg Arg Ile Lys Ala Trp Leu 10 15 Arg Arg Ile Lys Ala 20

< 210 > SEQ ID NO 30 < 211 > LENGTH : 12 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown 20 > FEATURE : 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 30 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala 10

< 210 > SEQ ID NO 31 < 211 > LENGTH : 12 < 212 > TYPE : PRT < 213ME??? > ORGANISM : Unknown 20 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 31 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Ala Ala 5 10

< 210 > SEQ ID NO 32 < 211 > LENGTH : 11 < 212 > TYPE : PRT ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 32 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Ala 10

< 210 > SEQ ID NO 33 < 211 > LENGTH : 22 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 33 Tyr Ala Arg Ala Ala Ala Arg Gin Ala Arg Ala Lys Ala Leu Ala Arg 10 15 Gin Leu Gly Val Ala Ala 20 US 9 ,890 , 195 B2 95 96 - continued

< 210 > SEQ ID NO 34 < 211 > LENGTH : 22 < 212 > TYPE : PRT ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 34 Tyr Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg Lys Ala Leu Ala Arg 5 10 15 Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 35 < 211 > LENGTH : 19 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown 20 > FEATURE : VV< 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 35 Arg Gin Arg Arg Lys Lys Arg Gly Lys Ala Leu Ala Arg Gin Leu Gly 10 15

Val Ala Ala

< 210 > SEQ ID NO 36 < 211 > LENGTH : 19 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 36 Gly Arg Lys Lys Arg Arg Gin Arg Lys Ala Leu Ala Arg Gin Leu Gly 10 15 Val Ala Ala

< 210 > SEQ ID NO 37 < 211 > LENGTH : 25 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 37 Trp Leu Arg Arg Ile Lys Ala Trp Leu Arg Arg Ile Lys Ala Lys Ala 10 15 Leu Ala Arg Gin Leu Gly Val Ala Ala 20 25

< 210 > SEQ ID NO 38 < 211 > LENGTH : 31 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 38 Trp Leu Arg Arg Ile Lys Ala Trp Leu Arg Ile Lys Ala Trp Leu Arg 1 5 10 15 Arg Ile Lys Ala Lys Ala Leu Ala Arg Gin Leu Gly Val Ala Ala 20 25 30 US 9 ,890 , 195 B2 97 98 - continued

< 210 > SEQ ID NO 39 < 211 > LENGTH : 24 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 39 Tyr Ala Arg Ala Ala Ala Arg Gin Ala Arg Ala Lys Lys Lys Ala Leu 1 10 15 Ala Arg Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 40 < 211 > LENGTH : 24 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 40 Tyr Gly Arg Lys Lys Arg Arg Gin Arg Arg Arg Lys Lys Lys Ala Leu 1 10 15 Ala Arg Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 41 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 41 Arg Gin Arg Arg Lys Lys Arg Gly Lys Lys Lys Ala Leu Ala Arg Gin 10 15 Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 42 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223NNPP > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 42 Gly Arg Lys Lys Arg Arg Gin Arg Lys Lys Lys Ala Leu Ala Arg Gin 10 15 Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 43 < 211 > LENGTH : 27 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 43 Trp Leu Arg Arg Ile Lys Ala Trp Leu Arg Arg Ile Lys Ala Lys Lys 10 15

Lys Ala Leu Ala Ara Gln Leu G Ly Val Ala Ala 20 moeten25 US 9 ,890 , 195 B2 99 100 - continued

< 210 > SEQ ID NO 44 < 211 > LENGTH : 34 < 212 > TYPE : PRT ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 44 Trp Leu Arg Arg Ile Lys Ala Trp Leu Arg Arg Ile Lys Ala Trp Leu 1 15 Arg Arg Ile Lys Ala Lys Lys Lys Ala Leu Ala Arg Gin Leu Gly Val 20 25 core 30 Ala Ala

< 210 > SEQ ID NO 45 < 211 > LENGTH : 23 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 45 Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Leu Ala 10 15 Arg Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 46 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213NMOM > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 46 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Leu Ala Arg Gin 10 15 Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 47 < 211 > LENGTH : 23 < 212 > TYPE : PRT ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 47 Lys Ala Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Ala Ala Leu Ala 10 15 Arg Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 48 < 211 > LENGTH : 22 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown ? 20 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 48 Lys Ala Phe Ala Lys Leu Ala Ala Arq Leu Tyr Arg Ala Leu Ala Arg 5 10 15 US 9 ,890 , 195 B2 101 102 - continued

Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 49 < 211 > LENGTH : 23 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown A 20 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 49 Lys Ala Phe Ala Ala Leu Ala Ala Arq Leu Tyr Arg Ala Ala Leu Ala 10 15 Arg Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 50 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 2 3 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 50 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Ala Ala Leu Ala Arg Gin 10 15 Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 51 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220NMOM > FEATURE : < 223HN > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 51 Tyr Ala Arq Ala Ala Ala Arg Gln Ala Arg Ala Lys Ala Leu Asn Arq 10 15 Gin Leu Gly Val Ala 20

< 210 > SEQ ID NO 52 < 211 > LENGTH : 23 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 52 Lys Ala Phe Ala Lys Leu Ala Ala Arq Leu Tyr Arg Lys Ala Leu Asn 10 15 Arg Gin Leu Ala Val Ala Ala 20

< 210 > SEQ ID NO 53 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 2 20 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 53 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Leu Asn Arg Gin US 9 ,890 , 195 B2 103 104 - continued 10 15 Leu Ala Val Ala Ala 20

< 210 > SEQ ID NO 54 < 211 > LENGTH : 10 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 2 20 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 54 Lys Ala Leu Asn Arg Gin Leu Gly val Ala 10

< 210 > SEQ ID NO 55 < 211 > LENGTH : 10 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 55 Lys Ala Leu Asn Arg Gin Leu Gly Val Ala 10

< 210 > SEQ ID NO 56 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 56 Trp Leu Arg Arg Ile Lys Ala Trp Arg Arg Ile Lys Ala Leu Asn Arg 10 15 Gin Leu Gly Val Ala 20

< 210 > SEQ ID NO 57 < 211 > LENGTH : 22 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 57 Lys Ala Phe Ala Leu Lys Ala Ala Arg Leu Tyr Arg Lys Ala Leu Asn 1 10 15 Arg Gin Leu Gly Val Ala 20

< 210 > SEQ ID NO 58 < 211 > LENGTH : 20 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 58 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Ala Leu Asn Arg Gin 1 10 15 Leu Gly Val Ala 20 US 9 ,890 , 195 B2 105 106 - continued

< 210 > SEQ ID NO 59 < 211 > LENGTH : 22 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 59 Tyr Ala Arg Ala Ala Ala Arg Gin Ala Arg Ala Lys Ala Leu Asn Arg 5 10 15 Gin Leu Gly Val Ala Ala 20

< 210 > SEQ ID NO 60 < 211 > LENGTH : 21 < 212 > TYPE : PRT < 213 > ORGANISM : Unknown < 220 > FEATURE : < 223 > OTHER INFORMATION : MAMMALIAN < 400 > SEQUENCE : 60 Phe Ala Lys Leu Ala Ala Arg Leu Tyr Arg Lys Leu Ala Leu Arg Gin 10 15 Leu Gly Val Ala Ala 2020

What is claimed is : 30 9 . The method according to claim 1 , wherein the compo 1 . A method for improving or enhancing neurite out- sition is in a unit - dosage container or in a multi -dosage container. growth following a nerve injury in a subject in need thereof, 10 . A method for improving or enhancing nerve regen the method comprising: eration following a nerve injury in a subject in need thereof, (a ) providing a therapeutic amount of a composition 35 the method comprising : comprising : ( a ) providing a therapeutic amount of a composition (i ) a MAPKAP kinase 2 inhibitor peptide of amino acid comprising : sequence YARAAARQARAKALARQLGVAA ( i) a MAPKAP kinase 2 inhibitor peptide of amino acid [SEQ ID NO : 33 ] ; sequence of YARAAARQARAKALARQLGVAA ( ii ) a carrier ; and 80 [SEQ ID NO : 33 ]; ( b ) administering the composition to the subject in needod ( ii ) a carrier; and thereof; ( b ) administering the composition to the subject in need wherein the therapeutic amount is effective thereof; 1 . to enhance or improve outgrowth of at least one wherein the therapeutic amount is effective neurite process from a neuron cell body ; and 45 1 . to enhance or improve outgrowth of at least one 2 . to increase neurite length by at least 10 % relative to neurite process from a neuron cell body ; and neurite length of a neuron that has not been treated 2 . to increase regrowth of a neurite process of a neuron with the composition . by at least 10 % in length relative to regrowth of a 2 . The method according to claim 1 , wherein the compo neurite process of a neuron that has not been treated sition is a pharmaceutical composition . 50 with the composition . 3 . The method according to claim 1 , wherein the neurite 11 . The method according to claim 10 , wherein the process is an axon . composition increases neurite regrowth by inhibiting 4 . The method according to claim 1 , wherein the neurite expression of at least on inflammatory cytokine from acti process is a dendrite . vated microglia . 5 . The method according to claim 1 , wherein the compo - 55 12 . The method according to claim 11 , wherein the at least sition inhibits production of at least one inflammatory one inflammatory cytokine is at least one of IL - 1 beta , IL - 6 , cytokine following the nerve injury . and TNF - alpha. 6 . The method according to claim 5 , wherein the at least 13. The method according to claim 11, wherein the at least one inflammatory cytokine is at least one of IL - 1 beta , IL - 6 , one inflammatory cytokine is produced by activated micro and TNF - alpha . 60 glia and astrocytes following nerve injury . 7 . The method according to claim 5 , wherein the at least 14 . The method according to claim 10 , wherein the one inflammatory cytokine is produced by activated micro - concentration of the MAPKAP kinase 2 inhibitor peptide in glia and astrocytes following the nerve injury . the therapeutic composition is from 0 .001 nM to less than 3 8 . The method according to claim 1 , wherein the concen - mM . tration of the MAPKAP kinase 2 inhibitor peptide in the 65 15 . A method for protecting against progression of a therapeutic composition is from 0 . 001 nM to less than 3 neuronal injury in a subject in need thereof, the method mM . comprising: US 9 ,890 , 195 B2 107 108 ( a ) providing a therapeutic amount of a composition 21. The method according to claim 15 , wherein the at least comprising : one manifestation of progression of the neuronal injury in at ( i) a MAPKAP kinase 2 inhibitor peptide of amino acid least one neuronal cell population is apoptotic cell death . sequence of YARAAARQARAKALARQLGVAA 22 . The method according to claim 15 , wherein the at least [ SEQ ID NO : 33 ]; and 5 one manifestation of progression of the neuronal injury in at ( ii) a carrier ; and least one neuronal cell population is microglial activation . ( b ) administering the composition to the subject in need 23 . The method according to claim 15 , wherein the at least thereof; one manifestation of progression of the neuronal injury in at wherein the therapeutic amount is effective least one neuronal cell population is inflammation . 1 . to enhance or improve outgrowth of at leastotom one 10 24 . The method according to claim 15 , wherein the at least neurite process form a neuron cell body ; one manifestation of progression of the neuronal injury in at 2 . to reduce or inhibit at least one manifestation of least one neuronal cell population is formation of a scar. progression of the neuronal injury in at least one 25 . The method according to claim 15 , wherein the neuronal cell population affected by the neuronal 5 neuronal cell population is a cortical cell population . injury ; and 26 . The method according to claim 15 , wherein the 3 . to increase survival of the at least one neuronal cell population affected by the neuronal injury . neuronal cell population is a mixed cortical cell population . 16 . The method according to claim 15 , wherein the 27. The method according to claim 26 , wherein the mixed neuronal injury is a neurapraxia type injury . cortical cell population comprises neurons , microglia , and 17 . The method according to claim 15 , wherein the injury 20 astrocytes . is an axonotmesis type injury . 28 . The method according to claim 15 , wherein the 18 . The method according to claim 15 , wherein the injury composition protects at least one neuron from progression of is a neurotmesis type injury . a neuronal injury by inhibiting expression of at least one 19. The method according to claim 15 , wherein the injury inflammatory cytokine from activated microglia . results from an acute disorder. 25 29 . The method according to claim 28 , wherein the at least 20 . The method according to claim 19 , wherein the acute one inflammatory cytokine is at least one of IL - 1 beta , IL - 6 , disorder is a stroke, a spinal cord injury, or a traumatic brain and TNF - alpha . injury . * * * * *