Micro-RNA for the regulation of cardiac apoptosis and contractile function
The present invention relates to treating or preventing age-related cardiomyopathy by modulating the expression or activity of a miR-34 family member and/or PNUTS. Methods of treating or preventing age-related cardiomyopathy include administering an inhibitor of miR-34 expression or activity or an agonist of PNUTS expression or activity. Also provided herein are methods of treating or preventing cardiac fibrosis and myocardial infarction by administering an inhibitor of miR-34 expression or activity or an agonist of PNUTS expression or activity.
1. A method of treating acute myocardial infarction in a subject in need thereof comprising administering to the subject an inhibitor of a miR-34 family member, wherein the inhibitor of the miR-34 family member is an antisense oligonucleotide having a sequence that is at least partially complementary to a mature miR-34a sequence.
2. The method of claim 1 , wherein the miR-34 family member is miR-34a, miR-34b, miR-34c or combinations thereof.
3. The method of claim 1 , wherein the antisense oligonucleotide comprises a sequence that is at least partially complementary to a sequence of 5′-UGGCAGUGUCUUAGCUGGUUGU-3′ (SEQ ID NO: 1).
4. The method of claim 1 , wherein the antisense oligonucleotide comprises at least one sugar and/or backbone modification.
5. The method of claim 4 , wherein the at least one sugar modification is a 2′-O-alkyl modification or a bicyclic sugar nucleoside modification.
6. The method of claim 5 , wherein the bicyclic sugar nucleoside modification is a locked nucleic acid.
7. The method of claim 4 , wherein the backbone modification is a phosphorothioate linkage.
8. The method of claim 1 , wherein the antisense oligonucleotide is about 8 to about 18 nucleotides in length.
9. The method of claim 1 , wherein the antisense oligonucleotide is about 12 to about 16 nucleotides in length.
10. The method of claim 1 , wherein the inhibitor is administered to the subject by an intravenous or subcutaneous route of administration.
11. The method of claim 1 , wherein apoptosis of cardiomyocytes is reduced in the subject following administration of the inhibitor as compared to an untreated subject.
12. The method of claim 1 , wherein contractile function is increased in the subject following administration of the inhibitor as compared to an untreated subject.
13. The method of claim 1 , wherein the expression of PNUTS is increased in the subject following administration of the inhibitor as compared to an untreated subject.
14. The method of claim 1 , wherein the subject is a human.
15. The method of claim 1 , wherein the antisense oligonucleotide comprises a sequence that is complementary to a seed region of a mature miR-34a sequence.
16. The method of claim 15 , wherein the seed region spans bases 2-8 from a 5′ portion of a mature miR-34a sequence.
17. The method of claim 15 , wherein the antisense oligonucleotide comprises a sequence that is complementary to the sequence of 5′-GGCAGUG-3′.