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 treating, or reducing the risk of developing, a myocardial infarction or chronic heart failure in a subject, the method comprising:
identifying a subject in need of treatment for a myocardial infarction or chronic heart failure; and
administering to the subject a therapeutically effective amount of an microRNA (miR)-19a/19b oligonucleotide.
2 . The method of claim 1 , wherein the subject is over the age of 65; does not yet have chronic heart failure; or has not yet had a myocardial infarction.
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 amount of cardiomyocyte proliferation is sufficient to improve cardiac function, increase cardiac contractile force, or increase the thickness of the myocardium; and wherein the method optionally includes detecting an improvement in cardiac function, an increase in cardiac contractile force, or an increase in 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 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; and
an optional linker therebetween.
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 using a virus; a nanoparticle or microparticle delivery; 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.