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(12) United States Patent (10) Patent No.: US 9.248,185 B2 Rubin Et Al

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(12) United States Patent (10) Patent No.: US 9.248,185 B2 Rubin Et Al USOO9248185B2 (12) United States Patent (10) Patent No.: US 9.248,185 B2 Rubin et al. (45) Date of Patent: Feb. 2, 2016 (54) METHODS OF INCREASING SATELLITE (2013.01); A61 K3I/485 (2013.01); A61 K CELL PROLIFERATION 3 I/553 (2013.01); A61 K3I/58 (2013.01); A61K3I/7076 (2013.01); G0IN33/5044 (75) Inventors: Lee L. Rubin, Wellesley, MA (US); (2013.01); C07D498/22 (2013.01) Amanda Gee, Alexandria, VA (US); (58) Field of Classification Search Amy J. Wagers, Cambridge, MA (US) None (73) Assignee: President and Fellows of Harvard See application file for complete search history. College, Cambridge, MA (US) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this U.S. PATENT DOCUMENTS patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. 2003/018151.0 A1* 9, 2003 Baker et al. ................... 514,432 2005/0281788 A1 12/2005 de Bari et al. (21) Appl. No.: 14/126,716 2010.0048534 A1 2/2010 Dziki et al. .............. 514, 21108 (22) PCT Filed: Jun. 18, 2012 FOREIGN PATENT DOCUMENTS (86). PCT No.: PCT/US2O12/042964 RU 2368398 9, 2009 S371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: Jun. 13, 2014 Shea et al (2010. Cell Stem Cell. 6: 117-129).* Strocket al., 2003. Cancer Research. 63:5559-5563.* (87) PCT Pub. No.: WO2012/174537 Mulligan et al., 2004. Nature Reviews: Cancer, 14: 173-186.* PCT Pub. Date: Dec. 20, 2012 Carlson, et al. “Relative roles of TGF-B1 and Wnt in the systemic regulation and aging of Satellite cell responses'. Aging Cell 8: 676 (65) Prior Publication Data 689 (2009). Consalvi, et al., “Histone Deacetylase Inhibitors in the Treatment of US 2014/O294.855A1 Oct. 2, 2014 Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases”, O O Mol. Med. 17(5-6): 457-465 (2011). Related U.S. Application Data Bentzinger, et al., “Extrinsic regulation of satellite cell specification' (60) Provisional application No. 61/497,708, filed on Jun. StemCell Research & Therapy, 2010, 1:27 online Retrieved from 16, 2011. the Internet: <URL: http:www.ncbi.nlm.nih.gov/pubmed/ 20804582>. (51) Int. Cl. Elia, et al., “Sonic hedgehog promotes proliferation and differentia A 6LX3/553 (2006.01) tion of adult muscle cells: Involvement of MAPK/ERK and PI3K/Akt A6IP 2L/00 (2006.01) pathways" Biochimica et Biophysica Acta 1773. 1438-1446 (2007). A6IP2/06 (2006.01) International Search Report for International Application PCT/ A 6LX39/395 (2006.01) US 12/42964, dated Dec. 20, 2012. A6 IK3I/36 (2006.01) * cited by examiner A6 IK3I/404 (2006.01) 3. 7. 3.08: Primary Examiner — Zachary Howard A6 IK3I/47 (2006.015 (74) Attorney, Agent, or Firm — Lisa M. Warren, Esq.; A6 IK3I/4706 (2006.01) Morse, Barnes-Brown & Pendleton, PC. A6 IK3I/485 2006.O1 A6 IK3I/58 3:08: (57) ABSTRACT A 6LX3L/7076 (2006.01) The invention provides methods for inducing, enhancing or GOIN33/50 (2006.01) increasing satellite cell proliferation, and an assay for screen CO7D 498/22 (2006.01) ing for a candidate compound for inducing, enhancing or (52) U.S. Cl. increasing satellite cell proliferation. Also provided is a CPC ........... A61K 39/3955 (2013.01); A61 K31/136 method for repairing or regenerating a damaged muscle tissue (2013.01); A61 K3I/404 (2013.01); A61 K of a subject. 31/4164 (2013.01); A61 K3I/4439 (2013.01); A6 IK3I/47 (2013.01); A61 K3I/4706 9 Claims, 25 Drawing Sheets U.S. Patent Feb. 2, 2016 Sheet 1 of 25 US 9.248,185 B2 U.S. Patent Feb. 2, 2016 Sheet 2 of 25 US 9.248,185 B2 U.S. Patent Feb. 2, 2016 Sheet 3 of 25 US 9.248,185 B2 FIG. 2C U.S. Patent Feb. 2, 2016 Sheet 4 of 25 US 9.248,185 B2 FIG. 2D Fit3 KINASE INHIBITOR s 4. 9 3.5 g 3 2.5 er 2 / 1.5 3. S 0.5 o Ksus 2 O ww. 0.08M 0,16 0.31 0.625 1.25 2.5 S 10 CMPD CONC(M) FIG. 3A U.S. Patent Feb. 2, 2016 Sheet 5 of 25 US 9.248,185 B2 ADENOSINE RECEPTORAGONIST 3 2 4.5 S 4 3.53 2. m: 2 / as 1.5- &-> & 2.5 3.75 5 7.5 10 15 20 30 CMPD CONC(M) FIG. 3B Ft3 KINASE INHIBITOR ECMPD ONLY T CMPD+FGF DMSO 1 2 3 FGF DAYS IN COMPOUND FIG. 4 U.S. Patent Feb. 2, 2016 Sheet 6 of 25 US 9.248,185 B2 FIG. 5B U.S. Patent Feb. 2, 2016 Sheet 7 of 25 US 9.248,185 B2 1OO 90 8O 60 50 40 30 - - 2O 10 CEP DMSO TREATMENT INTERWAL: d-d3.5 FIG. 6 U.S. Patent Feb. 2, 2016 Sheet 8 of 25 US 9.248,185 B2 U.S. Patent Feb. 2, 2016 Sheet 9 of 25 US 9.248,185 B2 FRESHLY SOLATED CEP1 O 102 103 104 105 O 102 103 104 105 CXCR4 CXCR4 CEP2 CEP3 5 10 te t loy s is A 103 is 103 102) 102 O 0. 102 103 104 105 O 102 103 104 105 CXCR4 CXCR4 Y U.S. Patent Feb. 2, 2016 Sheet 10 of 25 US 9.248,185 B2 FRESHLY DMSO1 SOLATED te 108 to: 104 is te is 103 1. 102 O O -- mir-rrm-t-t-Tim-Trim-r -T-1 tim- 1 TTT-TTTTTT-1-1 Trini-t- O 102 103 104 105 O 102 103 104 105 CXCR4 CXCR4 DMSO2 DMSO3 105 105 104 104 5103 is 103 102 1: O 102 103 104 105 0 102 103 104 105 CXCR4 CXCR4 U.S. Patent Feb. 2, 2016 Sheet 11 of 25 US 9.248,185 B2 SU 11248 (SUNTINIB) O.O8 0.15 O.31 O.625 1.25 2.5 5 10 CONC(M) FIG. 9A SUNTINIB 1 S2 234.5 0.08 O.16 O.31 0.63 1.25 2.5 5.OO 10.00 CONC(uM) FIG. 9B U.S. Patent Feb. 2, 2016 Sheet 12 of 25 US 9.248,185 B2 JAK3INHIBW s 2 se 0.02 0.04 0.08 O. 16 O.31 O.625 1.25 2.5 S 10 CMPD CONC(uM) FIG. 10A JAK3i V 5 - ... " -3. 3 N c 1. N 2 3- --- X-1 X-O X o O.O3 O,OI 0.15 O.3 0.625 125 2.5 5 CMPD CONC(uM) FIG. IOB U.S. Patent Feb. 2, 2016 Sheet 13 of 25 US 9.248,185 B2 LESTAURTINIB (CEPTO1) 0.02 0.04 0.08 0.16 0.31 0.625 1.25 2.5 10 CMPD CONC(M) FIG. 11A LESTAURTINIB (CEP 701), 300 CELLS/WELL 0.005 0.01 .02 0.05 O. CMPD CONC(uM) FIG. IIB U.S. Patent Feb. 2, 2016 Sheet 14 of 25 US 9.248,185 B2 BOSUTINIB 2 1.5 s 1 - &as KX K> 5: 0.5 & 0 -T-I-T-I-T-I-T-YKXXX "|0.02 0.04 0.08 0.16 0.31 0.625 125 2.5 s 10 CMPD CONC(uM) FIG. 12 SU1652 0.08 O.15 0.31 O.625 1.25 2.5 5 O CONC(uM) FIG. 13 U.S. Patent Feb. 2, 2016 Sheet 15 of 25 US 9.248,185 B2 0.05uMCEPTO1 AND bFGFSYNERGY TEST, 4DIV, CMPDADDED 1 DV, MEDIA CHANGEDAT 3 DIV, 300Cells/well 10 8 6 2 4 O W DMSO CEP CEP + bFGF FGF CULTURE CONDITION FIG. 14 CEP701, 0.05uM CMPD ONLY 7 CMPD+bFGF 6 t 5 c 4 E. 3 - 1 O DAYS IN COMPOUND FIG. I5 U.S. Patent Feb. 2, 2016 Sheet 16 of 25 US 9.248,185 B2 ECMPD ONLY JAK, 0.06uM CMPD+bFGF 3 5 DMSO 2 3 FGF DAYS IN COMPOUND FIG. 16 CMPD ONLY SUNTINIB CMPD+bFGF DAYS IN COMPOUND FIG. 17 U.S. Patent Feb. 2, 2016 Sheet 17 of 25 US 9.248,185 B2 U.S. Patent Feb. 2, 2016 Sheet 18 of 25 US 9.248,185 B2 KS IN VI, CAG-GFPMyC. HOECHST FIG. 20 TGF-B SYNERGY TEST, WITHSOMCEPTO1 Ak.5i ONLY 4. WITH5On MCEPTO1 DMSO O.3 0.6 12 2.5 O bFGF CONCOFAIk5 INHIB. FIG. 21 U.S. Patent Feb. 2, 2016 Sheet 19 of 25 US 9.248,185 B2 ST) 66 50IJI U.S. Patent Feb. 2, 2016 Sheet 20 of 25 US 9.248,185 B2 EFFECT OF 4 DAY, 5OnMCEPEXPOSURE ON PRIMARY FIBROBLASS 100 S 80 in 60 s g 40 : 20 a -------Morala---------------- 500 CELLS/WELL 500 CELLS/WELL 3000 CELLSWELL 3000 CELLS/WELL, DMSO CEP DMSO CEP CONDITION FIG. 23 U.S. Patent Feb. 2, 2016 Sheet 21 of 25 US 9.248,185 B2 Þ3°50IJI ce ced re en ed ? Zl I-HI 2!!! U.S. Patent Feb. 2, 2016 Sheet 22 of 25 US 9.248,185 B2 50nMCEPTO1, YOUNG ANIMAL 6 DAYS IN CULTURE TOTAL 12 St. a 10 g 8 3 6 4 2 o ?l- I DMSO 1d 2d 3d 4d bfgf # DAYS EXPOSURE TO CEP FIG. 25 N6-CYCLOPENTYLADENOSINE CMPD CONC(M) FIG. 26 U.S. Patent Feb. 2, 2016 Sheet 23 of 25 US 9.248,185 B2 BUDESONIDE 2.5 3.75 5 75 10 15 20 30 CMPD CONC(uM) FIG. 27 30, MCPA CMPDALONE 12 5O CMPD + bFGF DMSO 1 2 3 DAYS INCMPD FIG.
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