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 miR-21 (SEQ ID NO: 236), comprising contacting a cell comprising miR-21 with a compound comprising an oligonucleotide, wherein:
the oligonucleotide is at least 90% complementary to miR-21;
the oligonucleotide consists of 15 to 30 linked monomeric subunits; and
at least one monomeric subunit comprises a modified sugar moiety.
2. The method of claim 1 , wherein the oligonucleotide is at least 95% complementary to miR-21.
3. The method of claim 1 , wherein the oligonucleotide is 100% complementary to miR-21.
4. The method of claim 1 , wherein the oligonucleotide consists of 18, 19, 20, 21, or 22 linked monomeric subunits.
5. The method of claim 1 , wherein each modified sugar moiety is independently selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
6. The method of claim 5 , wherein the bicyclic sugar moiety comprises a 4′-CH 2 —O-2′ bridge.
7. The method of claim 1 , wherein the oligonucleotide comprises at least one modified internucleoside linkage.
8. The method of claim 1 , wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage.
9. The method of claim 1 , wherein each monomeric subunit comprises a modified sugar moiety.
10. The method of claim 9 , wherein each modified sugar moiety is independently selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
11. The method of claim 10 , wherein the bicyclic sugar moiety comprises a 4′-CH 2 —O-2′ bridge.
12. The method of claim 1 , wherein the oligonucleotide comprises two or more chemically distinct regions.
13. The method of claim 12 , wherein each nucleoside of the two or more chemically distinct regions is independently selected from a 2′-fluoro nucleoside, a 2′-O-methyl nucleoside, a 2′-O-methoxyethyl nucleoside, a 2′-deoxynucleoside, and a bicyclic sugar nucleoside.
14. The method of claim 13 , wherein the bicyclic nucleoside comprises a 4′-CH 2 —O-2′ bridge.
15. The method of claim 1 , wherein the oligonucleotide comprises at least one 5-methylcytosine.
16. The method of claim 1 , wherein the oligonucleotide is attached to a conjugate group.
17. The method of claim 1 , wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 1 to 8 of miR-21.
18. The method of claim 1 , wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 2 to 9 of miR-21.
19. The method of claim 1 , wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 3 to 10 of miR-21.
20. The method of claim 1 , wherein the contacting comprises administering the compound to a subject.