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(12) United States Patent (10) Patent No.: US 8,617.534 B2 Sussman Et Al

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(12) United States Patent (10) Patent No.: US 8,617.534 B2 Sussman Et Al USOO8617534B2 (12) United States Patent (10) Patent No.: US 8,617.534 B2 Sussman et al. (45) Date of Patent: Dec. 31, 2013 (54) COMPOSITIONS AND METHOD FOR Bachmann, “The serine/threonine kinase Pim-1'. The International MANIPULATING PM-1 ACTIVITY IN Journal of Biochemistry & Cell Biology 37 (2005) 726-730. CIRCULATORY SYSTEM CELLS Bhattacharya, "Pim-1 associates with protein complexes necessary for mitosis”. Chromosoma (2002) 111:80-95. (75) Inventors: Mark A. Sussman, San Diego, CA Camper-Kirby, “Myocardial Akt Activation and Gender: Increased (US); John A. Muraski, San Clemente, Nuclear Activity in Females Versus Males'. Circulation Research CA (US) (2001), 88: 1020-1027. Fransioli, “Evolution of the c-kit-Positive Cell Respons to Pathologi (73) Assignee: San Diego State University (SDSU) cal Challenge in the Myocardium', StemCells (2008) 26:1315-1324. Foundation, San Diego, CA (US) Gude, "Akt Promotes Increased Cardiomyocyte Cycling and Expan sion of the Cardiac Progenitor Cell Population'. Circulation Research (2006) 99:381-388. (*) Notice: Subject to any disclaimer, the term of this Hammerman, "Pim and Akt oncogenes are independent regulators of patent is extended or adjusted under 35 hematopoietic cell growth and survival', (2005) 105:4477-4483. U.S.C. 154(b) by 419 days. Katakami, “Role of Pim-1 in Smooth Muscle Cell Proliferation'. The Journal of Biological Chemistry, vol. 279, No. 52, Issue of Dec. 24. (21) Appl. No.: 12/742,871 pp. 54742-54749, 2004. Kato, 'Atrial natriuretic peptide promotes cardiomyocyte Survival by (22) PCT Filed: Nov. 14, 2008 cGMP-dependent nuclear accumulation of Zyxin and Akt'. The Jour nal of Clinical Investigation, vol. 115, No. 10, Oct. 2005, pp. 2716 (86). PCT No.: PCT/US2O08/083693 2730. Lily, “The PIM-1 serine kinase prolongs survival and inhibits S371 (c)(1), apoptosis-related mitochondrial dysfunction in part through a bcl-2- (2), (4) Date: Jul. 21, 2010 dependent pathway”. Oncogene (1999) 18, 4022-4031. Macdonald, “Pim kinases phosphorylate multiple sites on Bad and (87) PCT Pub. No.: WO2009/065080 promote 14-3-3 binding and dissociation from Bcl-XL, BMC Cell Biology (2006) 7:1, pp. 1-14. PCT Pub. Date: May 22, 2009 Mikkers, "Mice Deficient for All PIM Kineses Display Reduced Body Size and Impaired Responses to Hematopoietic Growth Fac (65) Prior Publication Data tors’, Mol. Cell Biol. 2004, 24(13):6104–61 15. US 2010/0316701 A1 Dec. 16, 2010 Muraski, "Pim-1 regulates cardiomyocyte survival downstream of Akt, Nature Medicine, vol. 13, No. 12, Oct. 2007, pp. 1467-1475. Plank. “Calcium dynamics in the failing heart: restoration by Related U.S. Application Data B-adrenergic receptor blockade'. Am. J. Physiol. Heart Circ. Physiol. (60) Provisional application No. 61/091,698, filed on Aug. 285: H305-H315, 2003. 25, 2008, provisional application No. 60/988,753, Roh, "Overexpression of the Oncogenic Kinase Pim-1 Leads to filed on Nov. 16, 2007. Genomic Instability”, Cancer Res. (2003) 63:8079-8084. Rota, "Nuclear Targeting of Akt Enhances Ventricular Function and Myxocyte Contractility”, Circ. Res. (2005) 97:1332-1341. (51) Int. Cl. Shiraishi. "Nuclear Targeting of Akt Enhances Kinase Activity and A6 IK 4.8/00 (2006.01) Survival of Cardiomyocytes”, Circ. Res. (2004) 94:884-891. CI2N 15/63 (2006.01) Solarogu, "Anti-Apoptotic Effect of Granulocyte-Colony Stimulat A61 K3 L/70 (2006.01) ing Factor After Focal Cerebral Ischemia in the Rat'. Neuroscience (52) U.S. Cl. 143 (2006) 965-974. USPC ...................... 424/93.21: 435/455; 435/320.1 Sussman, “Myocardial Aging and Senescence: Where Have the Stem (58) Field of Classification Search Cells Gone?”, Annu. Rev. Physiol. (2004) 66:29-48. USPC ............................. 424/93.21: 435/455,320.1 Sussman, “Myofibril Degeneration Caused by Tropomodulin Overexpression Leads to Dilated Cardiomyopathy in Juvenile Mice'. See application file for complete search history. J. Clin. Invest., vol. 101, No. 1 Jan. 1998, 51-61. (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner — Quang Nguyen (74) Attorney, Agent, or Firm — Gregory P. Einhorn; 2002/0076395 A1* 6/2002 Crystal et al. ................ 424.93.2 2004/0258669 A1* 12/2004 Dzau et al. ...... 424.93.21 Gavrilovich, Dodd & Lindsey LLP 2007/003 1899 A1* 2/2007 Kobayashi etal 435/723 2008/0267921 A1* 10, 2008 Marban et al. ............... 424,93.7 (57) ABSTRACT 2012/O1286.31 A1 5/2012 Sussman The invention provides compositions (e.g., pharmaceutical OTHER PUBLICATIONS compositions) comprising nucleic acids encoding the serine/ Muraski et al. Pim-1 regulates cardiomyocyte Survival downstream threonine kinase PIM-1, and methods for making and using of Akt. Abstract #1523 in Circulation 114 (18, Suppl. S): p. 11-294. them; including methods for inducing cellular proliferation, Oct. 31 2006. and protecting cardiac cells from hypoxia and cellular apop Cottage, C et al. Pim-1 stimulates cardiac progenitor cell prolifera tosis. The invention provides compositions (e.g., pharmaceu tion and asymmetric division. Circulation 118(18, Suppl. 2): p. S321, tical compositions) comprising nucleic acids encoding PIM Abstract No. 1414, 2008).* 1, and methods for enhancing the regenerative potential of Aho et al., “Pim-1 kinase promotes inactivation of the pro-apoptotic stem cells in the heart. Bad protein by phosphorylating it on the Ser112 gatekeeper site'. FEBS Letter 571 (2004) 43-49. 8 Claims, 21 Drawing Sheets US 8,617.534 B2 Page 2 (56) References Cited Fischer et al., “Enhancement of Myocardial Regeneration Through Genetic Engineering of Cardiac Progenitor Cells Expressing Pim-1 OTHER PUBLICATIONS Kinase'. Circulation 2009, 120:2077-2087. Gnecchi et al., “Paracrine action accounts for marked protection of Tsujita, “Evaluation of Left Ventricular Function in Cardiomyopathic ischemic heart by Akt-modified mesenchymal stern cells'. Nature Mice by Tissue Doppler and Color M-Mode Doppler Medicine, vol. 11, No. 4, Apr. 2005, pp. 367-368. Echocardiography”, Echocardiography, A.Jml. of CV Ultrasound & Gnecchi et al., “Evidence Supporting paracrine hypothesis for Akt Allied Tech., vol. 22, No. 3, 2005, pp. 245-253. Tsujita, "Nuclear targeting of Akt antagonizes aspects of modified mesenchymal stem cell-mediated cardiac protection and cardiomyocyte hypertrophy, PNAS, Aug. 8, 2006, vol. 103, No. 32. functional improvement'. The FASEB Journal, vol. 20, Apr. 2006, 11946-11951. pp. 661-669. Wang, “Pim-1: A serine/threonine kinase with a role in cell survival, Mangi et al., “Mesenchymal stem cells modified with Akt prevent proliferation, differentiation and tumorigenesis”. J. Vet. Sci. (2001), remodeling and restore performance of infarcted hearts'. Nature 2(3), 167-179. Medicine, vol. 9, No. 9, Sep. 2003, pp. 1195-1201. Welch, “Cardiac-Specific IGF-1 Expression Attenuates Dilated Mirotsou et al., “Secreted frizzled related protein 2 (Sfrp2) is the key Cardiomyopathy in Tropomodulin-Overexpressing Transgenic Akt-mesenchymal stem cell-released paracrine factor mediating Mice". Circ. Res. (2002)90:641-648. Yan, “The PIM-2 Kinase Phosphorylates BAD on Serine 112 and myocardial survival and repair', PNAS, Jan. 30, 2007, vol. 104, No. Reverses BAD-induced Cell Death'. The Journal of Biological 5, pp. 1643-1648. Chemistry, vol. 278, No. 46, Issue of Nov. 14, pp. 45358-45367, Mohsin et al., “Human Cardiac Progenitor Cells Engineered with 2003. Pim-I Kinase Enhance Myocardial Repair'. Journal of the American Fox et al., “The serine/threonine kinase Pim-2 is a transcriptionally College of Cardiology, vol. 60, No. 14, 2012, pp. 1278-1287. regulated apoptotic inhibitor.” Genes Dev. 2003 17:1841-1854. Noiseux et al., “Mesenchymal Stemn Cells Overexpressing Akt Dra Fischer, et al., “Cardiac Progenitor Cell Commitment is Inhibited by matically Repair Infarcted Myocardium and Improve Cardiac Func Nuclear Akt Expression.” Circulation Research, 2011; 108:960-970. tion Despite Infrequent Cellular Fusion or Differentiation'. Molecu Sussman, et al., “Pathogenesis of dilated cardiomyopathy: molecular, lar Therapy, vol. 14, No. 6, Dec. 2006. pp. 840-850. structural, and population analyses in tropomodulin-overexpressing transgenic mice”, Am J Pathol. Dec 1999; 155(6):2101-13. * cited by examiner U.S. Patent Dec. 31, 2013 Sheet 1 of 21 US 8,617.534 B2 Figure 1 U.S. Patent Dec. 31, 2013 Sheet 2 of 21 US 8,617.534 B2 z9.InáH U.S. Patent Dec. 31, 2013 Sheet 4 of 21 US 8,617.534 B2 ?6eJOSX33M U.S. Patent Dec. 31, 2013 Sheet 5 of 21 US 8,617.534 B2 S9.InáH U.S. Patent Dec. 31, 2013 Sheet 6 of 21 US 8,617.534 B2 U.S. Patent Dec. 31, 2013 Sheet 7 of 21 US 8,617.534 B2 i U.S. Patent Dec. 31, 2013 Sheet 8 of 21 US 8,617.534 B2 Akt Pim-1 GAPDH is tos. Figure 8 (A) SarCOmeric Pr- actin Nuclei overlay NTG AKT Figure 8 (B) U.S. Patent Dec. 31, 2013 Sheet 9 of 21 US 8,617.534 B2 A phalloidin Pin overlay Non-infected Figure 9 U.S. Patent Dec. 31, 2013 Sheet 10 of 21 US 8,617.534 B2 8 - s & A - CD i 21 U.S. Patent Dec. 31, 2013 Sheet 11 of 21 US 8,617.534 B2 6LQM-uuld U.S. Patent CVS U.S. Patent Dec. 31, 2013 Sheet 13 of 21 US 8,617.534 B2 Untreated 200 Figure 13 U.S. Patent Dec. 31, 2013 Sheet 14 of 21 US 8,617.534 B2 AWOd b PWDd 0.14 0.15 Pim-wit Sh 0.13 t " 0.4 wn-Pim-wit Sham Pi-wt TAC 0.3 a-NG Sham reserNTGAC e are Pim-WAC 9. 0.12 iNTGTAC to 0.11 O, 1 3 0,1 0.09 O,09 0.08 0.08 0.07 0.07 2 3 4 5 is 7 8 9 10 1 12 13 14 2 3 4 5 6 8 9 O 1 12 13 4 weeks post-op d weeks post-op 0,45 re--Pin-wtsham EDD 0.34 ESD --MTG sham kick El Pin-wit TAC 3 aimwTac ck 0.
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