Claims for Patent: 9,789,074

Summary for Patent: 9,789,074

Title:	Composition and method for muscle repair and regeneration
Abstract:	The invention provides methods for muscle repair or regeneration comprising administering therapeutically effective amounts of RAR agonists or stem cells that are pretreated with contact with a RAR agonist to a subject at a site of muscle damage. Additionally, the invention provides compositions comprising RAR agonist treated stem cells and methods of use of said cells for muscle repair or regeneration. In one embodiment, the stem cells are mesenchymal stem cells. In one embodiment, the RAR agonist is an RARγ agonist. In one embodiment, administration of the RAR agonist is begun during a period of increased endogenous retinoid signaling in the subject resulting from incurrence of the damaged muscle tissue.
Inventor(s):	Masahiro Iwamoto, Maurizio Pacifici
Assignee:	Thomas Jefferson University
Application Number:	US13/819,914
Patent Claims:	1. A method of muscle repair or regeneration in a subject, comprising administering a therapeutically effective amount of an RARγ agonist to a subject with damaged muscle tissue, wherein the RARγ agonist is selected from the group consisting of CD-271 (6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); CD-394; CD-437 (6-(4-Hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); CD-1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid); CD-2247; palovarotene (4-[(1E)-2-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-2-naphthalenyl]-ethenyl]-benzoic acid); BMS-270394 (3-Fluoro-4-[(R)-2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid); BMS-189961 (3-Fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid); CH-55 (4-[(E)-3-(3,5-Di-tert-butyl-phenyl)-3-oxo-propenyl]-benzoic acid); 6-[3-(adamantan-1-yl)-4-(prop-2-ynyloxy)phenyl]naphthalene-2-carboxylic acid; 5-[(E)-3-oxo-3-(5,5,8,8-tetrahydronaphthalene-2-yl)propenyl]thiophene-2-carboxylic acid; and enantiomers, derivatives, prodrugs, and pharmaceutically acceptable salts thereof. 2. The method of claim 1, wherein the damaged muscle tissue is the result of a physical injury or accident, disease, infection, overuse, loss of blood circulation, or muscle atrophy or wasting. 3. The method of claim 1, wherein the damaged muscle tissue is dystrophic muscle or an ageing muscle. 4. The method of claim 1, wherein the subject is a mammal, a mouse or a human. 5. The method of claim 1, further comprising administering an anti-inflammatory agent to the subject. 6. The method of claim 1, wherein said subject in need thereof has a muscle damaging myopathy. 7. The method of claim 6, wherein the muscle damaging myopathy is an inflammatory myopathy. 8. The method of claim 7, wherein the muscle damaging myopathy is myositis ossificans. 9. The method of claim 6, wherein the muscle damaging myopathy is a muscular dystrophy. 10. The method of claim 1, wherein the subject has damage to skeletal muscle. 11. The method of claim 1, wherein said RARγ agonist is administered locally. 12. The method of claim 1, wherein said RARγ agonist is administered systemically. 13. A method of inducing progenitor stem cells to undergo myogenic differentiation in a subject with damaged muscle tissue, comprising administering a therapeutically effective amount of an RARγ agonist to the subject, wherein the RARγ agonist is selected from the group consisting of CD-271 (6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); CD-394; CD-437 (6-(4-Hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); CD-1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid); CD-2247; palovarotene (4-[(1E)-2-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-2-naphthalenyl]-ethenyl]-benzoic acid); BMS-270394 (3-Fluoro-4-[(R)-2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid); BMS-189961 (3-Fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)acetylamino]-benzoic acid); CH-55 (4-[(E)-3-(3,5-Di-tert-butyl-phenyl)-3-oxo-propenyl]-benzoic acid); 6-[3-(adamantan-1-yl)-4-(prop-2-ynyloxy)phenyl]naphthalene-2-carboxylic acid; 5-[(E)-3-oxo-3-(5,5,8,8-tetrahydronaphthalene-2-yl)propenyl]thiophene-2-carboxylic acid; and enantiomers, derivatives, prodrugs, and pharmaceutically acceptable salts thereof. 14. A method for reducing muscle tissue damage in a subject with a muscle damaging myopathy, said method comprising administering to said subject an RARγ agonist in amount sufficient to reduce said muscle tissue damage, wherein the RARγ agonist is selected from the group consisting of CD-271 (6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); CD-394; CD-437 (6-(4-Hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid); CD-1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid); CD-2247; palovarotene (4-[(1E)-2-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-3-(1H-pyrazol-1-ylmethyl)-2-naphthalenyl]-ethenyl]-benzoic acid); BMS-270394 (3-Fluoro-4-[(R)-2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid); BMS-189961 (3-Fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)acetylamino]-benzoic acid); CH-55 (4-[(E)-3-(3,5-Di-tert-butyl-phenyl)-3-oxo-propenyl]-benzoic acid); 6-[3-(adamantan-1-yl)-4-(prop-2-ynyloxy)phenyl]naphthalene-2-carboxylic acid; 5-[(E)-3-oxo-3-(5,5,8,8-tetrahydronaphthalene-2-yl)propenyl]thiophene-2-carboxylic acid; and enantiomers, derivatives, prodrugs, and pharmaceutically acceptable salts thereof. 15. The method of claim 1, wherein the RARγ agonist is CD-271 (6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid) or a pharmaceutically acceptable salt thereof. 16. The method of claim 1, wherein the RARγ agonist is CD-394 or a pharmaceutically acceptable salt thereof. 17. The method of claim 1, wherein the RARγ agonist is CD-437 (6-(4-Hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid) or a pharmaceutically acceptable salt thereof. 18. The method of claim 1, wherein the RARγ agonist is CD-1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid) or a pharmaceutically acceptable salt thereof. 19. The method of claim 1, wherein the RARγ agonist is CD-2247 or a pharmaceutically acceptable salt thereof. 20. The method of claim 1, wherein the RARγ agonist is BMS-270394 (3-Fluoro-4-[(R)-2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid) or a pharmaceutically acceptable salt thereof. 21. The method of claim 1, wherein the RARγ agonist is BMS-189961 (3-Fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid) or a pharmaceutically acceptable salt thereof. 22. The method of claim 13, wherein the RARγ agonist is CD-271 (6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid) or a pharmaceutically acceptable salt thereof. 23. The method of claim 13, wherein the RARγ agonist is CD-394 or a pharmaceutically acceptable salt thereof. 24. The method of claim 13, wherein the RARγ agonist is CD-437 (6-(4-Hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid) or a pharmaceutically acceptable salt thereof. 25. The method of claim 13, wherein the RARγ agonist is CD-1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid) or a pharmaceutically acceptable salt thereof. 26. The method of claim 13, wherein the RARγ agonist is CD-2247 or a pharmaceutically acceptable salt thereof. 27. The method of claim 13, wherein the RARγ agonist is BMS-270394 (3-Fluoro-4-[(R)-2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid) or a pharmaceutically acceptable salt thereof. 28. The method of claim 13, wherein the RARγ agonist is BMS-189961 (3-Fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid) or a pharmaceutically acceptable salt thereof. 29. The method of claim 14, wherein the RARγ agonist is CD-271 (6-(4-Methoxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid) or a pharmaceutically acceptable salt thereof. 30. The method of claim 14, wherein the RARγ agonist is CD-394 or a pharmaceutically acceptable salt thereof. 31. The method of claim 14, wherein the RARγ agonist is CD-437 (6-(4-Hydroxy-3-tricyclo[3.3.1.13,7]dec-1-ylphenyl)-2-naphthalenecarboxylic acid) or a pharmaceutically acceptable salt thereof. 32. The method of claim 14, wherein the RARγ agonist is CD-1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid) or a pharmaceutically acceptable salt thereof. 33. The method of claim 14, wherein the RARγ agonist is CD-2247 or a pharmaceutically acceptable salt thereof. 34. The method of claim 14, wherein the RARγ agonist is BMS-270394 (3-Fluoro-4-[(R)-2-hydroxy-2-(5, 5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid) or a pharmaceutically acceptable salt thereof. 35. The method of claim 14, wherein the RARγ agonist is BMS-189961 (3-Fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-acetylamino]-benzoic acid) or a pharmaceutically acceptable salt thereof. 36. The method of claim 13, wherein said subject in need thereof has a muscle damaging myopathy. 37. The method of claim 36, wherein the muscle damaging myopathy is an inflammatory myopathy. 38. The method of claim 37, wherein the muscle damaging myopathy is myositis ossificans. 39. The method of claim 36, wherein the muscle damaging myopathy is a muscular dystrophy. 40. The method of claim 13, wherein the subject has damage to skeletal muscle. 41. The method of claim 13, wherein said RARγ agonist is administered locally. 42. The method of claim 13, wherein said RARγ agonist is administered systemically. 43. The method of claim 14, wherein the subject has damage to skeletal muscle. 44. The method of claim 14, wherein the muscle damaging myopathy is an inflammatory myopathy. 45. The method of claim 44, wherein the muscle damaging myopathy is myositis ossificans. 46. The method of claim 14, wherein the muscle damaging myopathy is a muscular dystrophy. 47. The method of claim 14, wherein said RARγ agonist is administered locally. 48. The method of claim 14, wherein said RARγ agonist is administered systemically.