Inhibitors of MYH7B and uses thereof
The present invention provides nucleic acid inhibitors of MYH7B and compositions thereof. The present invention also provides methods of treating or preventing a cardiac disorder such as cardiac hypertrophy, myocardial infarction, or heart failure in a subject by administering to the subject an inhibitor of MYH7B. The present invention further provides methods of modulating the activity or expression of β-MHC in cardiac cells of a subject by administering to the subject an inhibitor of MYH7B.
1. An antisense oligonucleotide inhibitor of MYH7B containing at least one modified nucleotide, wherein the antisense oligonucleotide is 12 to 18 nucleotides and wherein the sequence of the antisense oligonucleotide is completely complementary to a sequence of SEQ ID NO: 6 from nucleotides 511-538, or nucleotides 1226-1243, or nucleotides 4280-4300.
2. The antisense oligonucleotide inhibitor of claim 1 , wherein the antisense oligonucleotide is 14 nucleotides and the sequence of the antisense oligonucleotide is completely complementary to a sequence of SEQ ID NO: 6 from nucleotides 511-538.
3. The antisense oligonucleotide inhibitor of claim 1 , wherein the antisense oligonucleotide is 14 nucleotides and the sequence of the antisense oligonucleotide is completely complementary to the sequence of SEQ ID NO: 6 from nucleotides 1226-1243.
4. The antisense oligonucleotide inhibitor of claim 1 , wherein the antisense oligonucleotide is 14 nucleotides and the sequence of the antisense oligonucleotide is completely complementary to the sequence of SEQ ID NO: 6 from nucleotides 4280-4300.
5. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide comprises the sequence of 5′-lGslTslTsmdCsdAsmdCsdTsmdCsdAsmdCsdAslTslCslC-3′ (SEQ ID NO: 188).
6. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide comprises the sequence of 5′-lAslGslTsdTsmdCsdAsmdCsdTsmdCsdAsmdCslAslTslC-3′ (SEQ ID NO: 190).
7. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide comprises the sequence of 5′-lAslGslTsdTsdAsdTsmdCsdAsdTsdTsmdCslCslTslC-3′ (SEQ ID NO: 370).
8. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide comprises the sequence of 5′-lCslTslTsdAsdGsmdCsdTsdGsdAsdTsmdCslCslTslC-3′ (SEQ ID NO: 568).
9. The antisense oligonucleotide inhibitor of claim 1 , wherein said modified nucleotide includes a sugar, base, and/or a backbone modification.
10. The antisense oligonucleotide inhibitor of claim 1 , wherein said modified nucleotide is a locked nucleotide.
11. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide contains one to six locked nucleotides.
12. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide contains at least three locked nucleotides at the 5′ end.
13. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide contains at least three locked nucleotides at the 3′ end.
14. The antisense oligonucleotide inhibitor of claim 12 , wherein the at least three locked nucleotides at the 5′ end are ribonucleotides.
15. The antisense oligonucleotide inhibitor of claim 13 , wherein the at least three locked nucleotides at the 3′ end are ribonucleotides.
16. The antisense oligonucleotide inhibitor of claim 1 , wherein said antisense oligonucleotide contains at least one deoxyribonucleotide.
17. The antisense oligonucleotide inhibitor of claim 16 , wherein said antisense oligonucleotide contains two to eight deoxyribonucleotides.
18. The antisense oligonucleotide inhibitor of claim 9 , wherein the sugar modification is selected from the group consisting of 2′-O, 4′-C methylene bridge, 2′-O, 4′-C ethylene bridge, 2′-CH 2 —NH—CH 2 —4′ bridge, 2′-deoxy, 2′-O-alkyl, and 2′-halo modifications.
19. The antisense oligonucleotide inhibitor of claim 9 , wherein the backbone modification is a phosphorothioate linkage.
20. The antisense oligonucleotide inhibitor of claim 19 , wherein said antisense oligonucleotide contains two or more phosphorothioate linkages.
21. The antisense oligonucleotide inhibitor of claim 19 , wherein said antisense oligonucleotide is fully phosphorothioate linked.
22. The antisense oligonucleotide inhibitor of claim 1 , wherein said modified nucleotide is 5′-methyl cytidine.
23. A pharmaceutical composition comprising the antisense oligonucleotide inhibitor of MYH7B of claim 1 and a pharmaceutically acceptable excipient.
24. The pharmaceutical composition of claim 23 , further comprising a second therapeutic agent, wherein the second therapeutic agent is an antisense oligonucleotide inhibitor of miR-208a, miR-208b, miR-499, miR-15a, miR-15b, miR-16, miR-195, or a mixture thereof.