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 .- 2 . (canceled)
3 . A method of inhibiting the activity of miR-27a (SEQ ID NO: 1187) and/or miR-27b (SEQ ID NO: 1059), comprising contacting a cell comprising the microRNA with a compound comprising an oligonucleotide, wherein:
the oligonucleotide is at least 90% complementary to miR-27a and/or miR-27b;
the oligonucleotide consists of 15 to 30 linked monomeric subunits; and
at least one monomeric subunit comprises a modified sugar moiety.
4 . The method of claim 3 , wherein the oligonucleotide is at least 95% complementary to miR-27a and/or miR-27b.
5 . The method of claim 3 , wherein the oligonucleotide is 100% complementary to miR-27a and/or miR-27b.
6 . The method of claim 3 , wherein the oligonucleotide consists of 18, 19, 21, or 22 linked monomeric subunits.
7 . The method of claim 3 , wherein each modified sugar moiety is independently selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
8 . The method of claim 7 , wherein the bicyclic sugar moiety comprises a 4′-CH 2 —O-2′ bridge.
9 . The method of claim 3 , wherein the oligonucleotide comprises at least one modified internucleoside linkage.
10 . The method of claim 3 , wherein each internucleoside linkage of the oligonucleotide is a phosphorothioate linkage.
11 . The method of claim 3 , wherein each monomeric subunit comprises a modified sugar moiety.
12 . The method of claim 11 , wherein each modified sugar moiety is independently selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, 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 3 , wherein the oligonucleotide comprises two or more chemically distinct regions.
15 . The method of claim 14 , 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.
16 . The method of claim 15 , wherein the bicyclic nucleoside comprises a 4′-CH 2 —O-2′ bridge.
17 . The method of claim 3 , wherein the oligonucleotide comprises at least one modified nucleobase.
18 . The method of claim 3 , wherein the oligonucleotide comprises at least one 5-methylcytosine.
19 . The method of claim 3 , wherein the oligonucleotide is attached to a conjugate group.
20 . The method of claim 3 , wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 1 to 8 of miR-27a and/or miR-27b.
21 . The method of claim 3 , wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 2 to 9 of miR-27a and/or miR-27b.
22 . The method of claim 3 , wherein the modified oligonucleotide is complementary to a target region comprising nucleobases 3 to 10 of miR-27a and/or miR-27b.
23 . The method of claim 3 , wherein the contacting comprises administering the compound to a subject.