Methods for inducing cardiomyocyte proliferation
Methods for inducing cardiomyocyte proliferation, e.g., in vivo, by administering a composition comprising miRNA17-92 cluster oligonucleotides, e.g., miR-19a oligonucleotides, miR-19b oligonucleotides, or both miR-19a and miR-19b oligonucleotides.
1. A method of improving cardiac function in a subject, the method comprising:
identifying and selecting a subject in need of improving cardiac function; and
administering to the selected subject a therapeutically effective amount of a microRNA (miR)-19a/19b oligonucleotide.
2. The method of claim 1 , wherein, prior to administering to the selected subject a therapeutically effective amount of a miR-19a/19b oligonucleotide, the subject is treated with a cardiotoxic compound.
3. The method of claim 1 , wherein the therapeutically effective amount is an amount sufficient to induce cardiomyocyte proliferation.
4. The method of claim 3 , wherein the cardiomyocyte proliferation is sufficient to increase cardiac contractile force, or increase the thickness of the myocardium.
5. The method of claim 1 , wherein the miR-19a/b oligonucleotide is a single stranded DNA or RNA that is at least 18, 19, or 20 nucleotides long, but less than 24 nucleotides long, and is at least 80% identical to SEQ ID NO:1 or 3, with 100% identity to nucleotides 1-8 of SEQ ID NO:1 or 3.
6. The method of claim 5 , wherein the miR-19a/b oligonucleotide comprises at least one modification selected from the group consisting of: 5′-phosphorylation; at least one 2′-fluoro ribose modification; and a cholesterol moiety.
7. The method of claim 5 , wherein the miR-19a/b oligonucleotide comprises SEQ ID NO:1 or 3.
8. The method of claim 1 , wherein the miR-19a/b oligonucleotide is a double stranded DNA or RNA, comprising:
a first strand comprising a sequence that is at least 80% identical to 18, 19, or 20 consecutive nucleotides of SEQ ID NO:1 or 3, with 100% identity to nucleotides 1-8 of SEQ ID NO:1 or 3;
a second strand comprising a sequence that is complementary to the first strand.
9. The method of claim 8 , wherein the double stranded DNA or RNA comprises SEQ ID NO:2 or 4.
10. The method of claim 8 , wherein the double stranded DNA or RNA comprises at least one modification selected from the group consisting of: 5′-phosphorylation; and 2′-O-methyl ribosyl substitution at position 2 in the first strand.
11. The method of claim 1 , wherein the miR-19a/b oligonucleotide is administered locally to the heart of the subject.
12. The method of claim 1 , wherein the miR-19a/b oligonucleotide is administered via a viral vector; a nanoparticle or microparticle; or a gelfoam.
13. The method of claim 1 , wherein the subject is a post-neonatal, adolescent, or adult mammal.
14. The method of claim 13 , wherein the subject is a human.
15. The method of claim 1 , wherein the miR-19a/b oligonucleotide comprises at least 18, 19, or 20 nucleotides with at least 80% identity to SEQ ID NO:1 or 3, including a region with 100% identity to nucleotides 1-8 of SEQ ID NO:1 or 3.
16. The method of claim 4 , wherein the method includes detecting an improvement in cardiac function, an increase in cardiac contractile force, or an increase in the thickness of the myocardium.
17. The method of claim 8 , wherein the first stand and the second strand is linked by a linker therebetween.