Oligomeric compounds and compositions for use in modulation of small non-coding RNAs
Compounds, compositions and methods are provided for modulating the expression and function of small non-coding RNAs. The compositions comprise oligomeric compounds, targeted to small non-coding RNAs. Methods of using these compounds for modulation of small non-coding RNAs as well as downstream targets of these RNAs and for diagnosis and treatment of disease associated with small non-coding RNAs are also provided.
1. A method of inhibiting the activity of a microRNA comprising contacting a cell comprising the microRNA with a compound comprising an oligomeric compound, wherein:
the oligomeric compound is at least 90% complementary to a miRNA or a precursor thereof;
the oligomeric compound consists of 15 to 30 linked monomeric subunits;
at least one monomeric subunit is a modified nucleoside; and
the miRNA is selected from miR-33a (SEQ ID NO: 227) and miR-33b (SEQ ID NO: 286).
2. The method of claim 1 wherein the oligomeric compound is at least 95% complementary to the miRNA.
3. The method of claim 1 wherein the oligomeric compound is 100% complementary to the miRNA.
4. The method of claim 1 wherein the oligomeric compound is 100% complementary to at least an 8-nucleobase portion of the miRNA.
5. The method of claim 1 wherein the miRNA is miR-33a (SEQ ID NO: 227).
6. The method of claim 1 wherein the miRNA is miR-33b (SEQ ID NO: 286).
7. The method of claim 1 wherein the oligomeric compound is 100% complementary to at least an 8-nucleobase portion of miR-33a (SEQ ID NO: 227).
8. The method of claim 1 wherein the oligomeric compound is 100% complementary to at least an 8-nucleobase portion of miR-33b (SEQ ID NO: 286).
9. The method of claim 1 wherein the oligomeric compound consists of an oligonucleotide.
10. The method of claim 9 wherein the oligonucleotide consists of 19 to 24 linked nucleosides.
11. The method of claim 1 wherein the oligomeric compound comprises at least one modified sugar moiety.
12. The method of claim 1 wherein the modified sugar moiety is selected from a 2′-F sugar moiety, a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, and a bicyclic sugar moiety.
13. The method of claim 12 wherein the bicyclic sugar moiety comprises a 4′-CH 2 —O-2′ bridge.
14. The method of claim 10 wherein the oligonucleotide comprises at least one modified sugar moiety.
15. The method of claim 14 wherein the modified sugar moiety is selected from a 2′-F sugar moiety, a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, and a bicyclic sugar moiety.
16. The method of claim 15 wherein the bicyclic sugar moiety comprises a 4′-CH 2 —O-2′ bridge.
17. The method of claim 1 wherein the oligomeric compound comprises at least one modified internucleoside linkage.
18. The method of claim 17 wherein the modified internucleoside linkage is a phosphorothioate linkage.
19. The method of claim 18 wherein each internucleoside linkage of the oligomeric compound is a phosphorothioate linkage.
20. The method of claim 1 wherein each monomeric subunit comprises a modified sugar moiety.
21. The method of claim 20 wherein each modified sugar moiety is independently selected from a 2′-F sugar moiety, a 2′-O-methyl sugar moiety, a 2′-O-methoxyethyl sugar moiety, and a bicyclic sugar moiety.
22. The method of claim 1 wherein the oligonucleotide comprises two or more chemically distinct regions.
23. The method of claim 22 wherein the sugar moiety of each nucleoside of a first chemically distinct region is the same and is selected from a 2′-fluoro nucleoside, a 2′-O-methyl nucleoside, a 2′-O-methoxyethyl nucleoside, a 2′-deoxynucleoside, and a bicyclic sugar nucleoside.
24. The method of claim 22 wherein the sugar moiety of each nucleoside of a first chemically distinct region is the same and is selected from a 2′-deoxynucleoside and a bicyclic sugar nucleoside.
25. The method of claim 24 wherein the bicyclic nucleoside comprises a 4′-CH 2 —O-2′ bridge.
26. The method of claim 1 wherein the oligomeric compound comprises at least one modified nucleobase.
27. The method of claim 26 wherein the modified nucleobase is 5-methylcytosine.
28. A composition comprising a compound comprising an oligomeric compound, wherein:
the oligomeric compound is at least 90% complementary to a miRNA or a precursor thereof;
the oligomeric compound consists of 15 to 30 linked monomeric subunits;
at least one monomeric subunit is a modified nucleoside; and
the miRNA is miR-33b (SEQ ID NO: 286);
and a pharmaceutically acceptable diluent or carrier.