Methods and compositions for enhancing cardiomyocyte maturation and engraftment

Patent metadata

Field	Value
Publication number	US-11752176-B2
Application number	US-201816493888-A
Country	US
Kind code	B2
Filing date	Mar 15, 2018
Priority date	Mar 15, 2017
Publication date	Sep 12, 2023
Grant date	Sep 12, 2023

Abstract

Provided herein are methods and compositions comprising cardiomyocytes and epicardial cells for the treatment of cardiac disease.

First claim

The invention claimed is:

1. A transplant composition comprising human cardiomyocytes and in vitro-differentiated human epicardial cells or the differentiated progeny of such human epicardial cells, wherein upon administration to cardiac tissue of a subject in need thereof, the cardiomyocytes, the epicardial cells and/or their differentiated progeny engraft into the cardiac tissue.

2. The transplant composition of claim 1 , wherein the human cardiomyocytes are in vitro-differentiated.

3. The transplant composition of claim 1 , wherein the epicardial cells or their progeny, the cardiomyocytes, or both, are differentiated from embryonic stem cells or from induced pluripotent stem cells.

4. The transplant composition of claim 1 , wherein the epicardial cells express fibronectin.

5. The transplant composition of claim 1 , further comprising at least one of: cyclosporine A, pinacidil, or IGF-1.

6. The transplant composition of claim 1 , wherein the cardiomyocytes are present at a ratio of 2:1, 1.5:1, 2.25:1, 2.5:1, 2.75:1, 3:1, 3.5:1, 4:1, 5:1, 7.5:1, 10:1, 15:1, 20:1, 1:1.5, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.5, 1:4, 1:5, 1:7.5, 1:10, 1:15, or 1:20 relative to the epicardial cells or progeny thereof.

7. A tissue particle comprising a human cardiomyocyte in physical association with an in vitro-differentiated human epicardial cell or differentiated progeny thereof, in a culture medium or a cocktail comprising at least one of: cyclosporine A, pinacidil, or IGF-1, wherein upon administration to cardiac tissue of a subject in need thereof, the cardiomyocyte, the epicardial cell and/or their differentiated progeny engraft into the cardiac tissue.

8. The tissue particle of claim 7 , wherein the particle comprises from 2 to 2500 cells.

9. The tissue particle of claim 7 , wherein the ratio of cardiomyocytes to epicardial cells or differentiated progeny thereof is 2:1, 1.5:1, 2.25:1, 2.5:1, 2.75:1, 3:1, 3.5:1, 4:1, 5:1, 7.5:1, 10:1, 15:1, 20:1, 1:1.5, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.5, 1:4, 1:5, 1:7.5, 1:10, 1:15, or 1:20.

10. The tissue particle of claim 7 , wherein the epicardial cell, the cardiomyocyte, or both is/are differentiated from an embryonic stem cell(s) or an induced pluripotent stem cell(s).

11. A method of promoting engraftment of cardiomyocytes into cardiac tissue, comprising administering to cardiac tissue of a subject in need thereof a transplant composition of claim 1 or a tissue particle of claim 7 .

12. The method of claim 11 , wherein the subject has suffered a cardiac infarction.

13. A method of promoting a mature phenotype of transplanted human cardiomyocytes, the method comprising administering to cardiac tissue of a subject in need thereof a transplant composition of claim 1 or a tissue particle of claim 7 .

14. The method of claim 13 , wherein the subject has suffered a cardiac infarction.

15. The method of claim 13 , wherein the cardiomyocyte maturity is indicated by at least one of: an increase in sarcomere length, an increase in cardiomyocyte diameter or length, expression of the cardiac isoform, cTnT, of troponin, or connexin 43 expression when cardiomyocytes are transplanted in admixture with epicardial cells, relative to cardiomyocyte transplantation alone.

Assignees

• Univ Washington
• Cambridge Entpr Ltd

Inventors

• Murry Charles E
• Sinha Sanjay
• Bargehr Johannes

Classifications

• A61K35/34 Primary

  Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes (vascular smooth muscle A61K35/44) · CPC title

• A61K35/545

  Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K31/4409

  only substituted in position 4, e.g. isoniazid, iproniazid · CPC title

• A61K38/13

  Cyclosporins · CPC title