MICRORNA INDUCTION OF CARDIAC REGENERATION

• US 20170096671A1
• Filed: 05/15/2015
• Published: 04/06/2017
• Est. Priority Date: 05/16/2014
• Status: Active Grant

• Current Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: MORRISEY, Edward E.
• Granted Patent: US 10,590,419 B2
• Time in Patent Office: Days
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0375 Animal model for cardiovascular diseases
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• CPC Class Codes: A61K 48/0058 Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct
• CPC Class Codes: A61K 48/0075 characterised by an aspect of the delivery route, e.g. oral, subcutaneous
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific
• CPC Class Codes: C12N 2320/35 based on a specific dosage / administration regimen
• CPC Class Codes: C12N 2501/65 MicroRNA
• CPC Class Codes: C12N 2510/00 Genetically modified cells
• CPC Class Codes: C12N 2740/15043 viral genome or elements thereof as genetic vector
• CPC Class Codes: C12N 5/0657 Cardiomyocytes; Heart cells
• CPC Class Codes: C12N 5/0662 Stem cells

Abstract

The invention relates to compostions and methods for promoting cellular proliferation and de-differentiation of cells into stem cells to foster tissue regeneration. Specifically, the invention relates to transiently administering a microRNA (miR) or its mimic for promoting cardiomyocyte proliferation and cardiac regeneration.

Claims

1. A method for promoting cellular proliferation and de-differentiation of cells into stem cells for cardiac tissue regeneration, the method comprising:

transiently contacting said cells with a composition comprising a microRNA (miR) 302-367 cluster or a miR 302-367 cluster mimic, wherein said transient contact is sufficient to transiently activate cardiomyocyte proliferation, but not to reactivate the cell cycle of postnatal cardiomyocytes.

2. The method of claim 1, wherein said transient contact comprises a single administration of the composition.

3. The method of claim 1, wherein the composition comprises valproic acid.

4. The method of claim 1, wherein said miR is operably linked to a regulatory sequence.

5. The method of claim 4, wherein said regulatory sequence is an inducible promoter.

6. The method of claim 5, wherein said inducible promoter is a doxycycline inducible promoter.

7. The method of claim 1, wherein said miR is encoded by a nucleic acid sequence present within a vector.

8. The method of claim 7, wherein the vector is a viral vector.

9. The method of claim 8, wherein the viral vector is a lentivirus vector.

10. The method of claim 7, wherein the vector is a plasmid vector.

11. A method for promoting cardiac repair and regeneration in a subject, the method comprising:

transiently administering to said subject a composition comprising a microRNA (miR) 302-367 cluster or a miR 302-367 cluster mimic, wherein said transient administration is sufficient to transiently activate cardiomyocyte proliferation, but not to reactivate the cell cycle of postnatal cardiomyocytes.

12. The method of claim 11, wherein the transient administration is systemic administration.

13. The method of claim 11, wherein the transient administration is intravenous administration.

14. The method of claim 11, wherein the transient administration comprises a single administration of the composition to the subject.

15. The method of claim 11, wherein the composition comprises valproic acid.

16. The method of claim 11, wherein said miR is operably linked to a regulatory sequence.

17. The method of claim 16, wherein said regulatory sequence is an inducible promoter.

18. The method of claim 17, wherein said inducible promoter is a doxycycline inducible promoter.

19. The method of claim 11, wherein said miR is encoded by a nucleic acid sequence present within a vector.

20. The method of claim 19, wherein the vector is a viral vector.

21. The method of claim 20, wherein the viral vector is a lentivirus vector.

22. The method of claim 19, wherein the vector is a plasmid vector.

23. A method for promoting cardiomyocyte proliferation in a subject, the method comprising:

transiently administering to said subject a composition comprising a microRNA (miR) 302-367 cluster or a miR 302-367 cluster mimic, wherein said transient administration is sufficient to transiently activate cardiomyocyte proliferation, but not to reactivate the cell cycle of postnatal cardiomyocytes.

24. The method of claim 23, wherein the transient administration is systemic administration.

25. The method of claim 23, wherein the transient administration is intravenous administration.

26. The method of claim 23, wherein the transient administration comprises a single administration of the composition to the subject.

27. The method of claim 23, wherein the composition comprises valproic acid.

28. The method of claim 23, wherein said miR is operably linked to a regulatory sequence.

29. The method of claim 28, wherein said regulatory sequence is an inducible promoter.

30. The method of claim 29, wherein said inducible promoter is a doxycycline inducible promoter.

31. The method of claim 23, wherein said miR is encoded by a nucleic acid sequence present within a vector.

32. The method of claim 31, wherein the vector is a viral vector.

33. The method of claim 31, wherein the viral vector is a lentivirus vector.

34. The method of claim 31, wherein the vector is a plasmid vector.

35. A method for promoting cellular proliferation and de-differentiation of cells into stem cells for cardiac tissue regeneration, the method comprising:

transiently contacting said cells with a composition comprising a microRNA (miR) cluster or its mimic, wherein said cluster comprises one or more of miR302b, miR302c, and miR367, and wherein said transient contact is sufficient to transiently activate cardiomyocyte proliferation, but not to reactivate the cell cycle of postnatal cardiomyocytes.

36. A method for promoting cardiac repair and regeneration in a subject, the method comprising:

transiently administering to said subject a composition comprising a microRNA (miR) cluster or its mimic, wherein said cluster comprises one or more of miR302b, miR302c, and miR367, and wherein said transient administration is sufficient to transiently activate cardiomyocyte proliferation, but not to reactivate the cell cycle of postnatal cardiomyocytes.

37. A method for promoting cardiomyocyte proliferation in a subject, the method comprising:

transiently administering to said subject a composition comprising a microRNA (miR) cluster or its mimic, wherein said cluster comprises one or more of miR302b, miR302c, and miR367, and wherein said transient administration is sufficient to transiently activate cardiomyocyte proliferation, but not to reactivate the cell cycle of postnatal cardiomyocytes.