# US 11,433,039 B2 · Composition and method for muscle repair and regeneration

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- Number: US 11,433,039 B2
- Document ID: US11433039B2
- Status: Granted
- Kind: B2
- Application number: 16/379,178
- Filed: 2019-04-09
- Published: 2020-03-05
- Granted: 2022-09-06
- Earliest claimed: 2010-09-01
- Assignees: Thomas Jefferson University
- Applicants: Thomas Jefferson University
- Inventors: Masahiro Iwamoto; Maurizio Pacifici
- Web page: https://patentgrep.com/patent/US11433039B2

## CPC

- A61K 31/203: Retinoic acids {; Salts thereof}
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61K 31/185: Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids (hydroxamic acids A61K31/16; peroxy acids A61K31/327)
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/415: 1,2-Diazoles
- A61K 35/12: Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells (vaccines or medicinal preparations containing antigens or antibodies A61K39/00)
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

A method of muscle repair or regeneration in a subject, comprising (i) providing pre-treated stem cells produced by contacting mesenchymal stem cells with an amount of a retinoic acid receptor gamma (RARγ) agonist effective to induce or stimulate myogenic differentiation; and (ii) administering said pre-treated stem cells to a subject at a site of muscle injury to repair or regenerate muscle at the site, 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-1530 (4-(6-Hydroxy-7-tricyclo[3.3.1.13,7]dec-1-yl-2-naphthalenyl)benzoic acid); CD-2247; 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.

### Claim 2 (depends on 1)

The method of claim 1, wherein the muscle injury is a compound tissue injury.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound tissue injury comprises an injury to muscle and bone.

### Claim 4 (depends on 1)

The method of claim 1, wherein the pre-treated stem cells are administered in combination with non-treated stem cells.

### Claim 5 (depends on 4)

The method of claim 4, wherein the pre-treated stem cells and non-treated stem cells are administered at a ratio of 1:1.

### Claim 6 (depends on 1)

The method of claim 1, wherein the pre-treated stem cells have been pre-treated with the RARγ agonist for a period of about 3 days.

### Claim 7 (depends on 1)

The method of claim 1, wherein the administering is local.

### Claim 8 (depends on 1)

The method of claim 1, wherein the administering is by transplantation of the cells into the subject.

### Claim 9 (depends on 1)

The method of claim 1, wherein the mesenchymal stem cells are autologous or heterologous to the subject.

### Claim 10 (depends on 1)

The method of claim 1, wherein the mesenchymal stem cells are mammalian.

### Claim 11 (depends on 1)

The method of claim 1, wherein the mesenchymal stem cells are human.

### Claim 12 (depends on 1)

The method of claim 1, further comprising administering an antiinflammatory agent to the subject.

### Claim 13 (depends on 1)

The method of claim 1, wherein the injured muscle results from physical injury or accident, disease, infection, over-use, loss of blood circulation, or muscle atrophy or wasting.

### Claim 14 (depends on 1)

The method of claim 1, wherein the injured muscle tissue is dystrophic muscle or an ageing muscle.

### Claim 15 (depends on 1)

The method of claim 1, wherein the injured muscle is the result of muscle atrophy/wasting.