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 compound comprising an oligomeric compound, wherein:
the oligomeric compound is complementary to a small non-coding RNA;
the oligomeric compound consists of 15 to 30 linked monomeric subunits; and
at least one monomeric subunit is a modified nucleoside or a nucleoside mimetic.
2 . The compound of claim 1 wherein the small non-coding RNA is selected from a pri-miRNA, a pre-miRNA and a miRNA.
3 . The compound of claim 1 wherein the oligomeric compound is at least 90% complementary to the small non-coding RNA.
4 . The compound of claim 1 wherein the oligomeric compound is at least 95% complementary to the small non-coding RNA.
5 . The compound of claim 1 wherein the oligomeric compound is 100% complementary to the small non-coding RNA.
6 . The compound of claim 1 wherein the oligomeric compound is 100% complementary to at least an 8-nucleobase portion of the small non-coding RNA.
7 . The compound of claim 1 wherein the oligomeric compound consists of 19 to 23 linked monomeric subunits.
8 . The compound of claim 1 wherein the oligomeric compound consists of an oligonucleotide.
9 . The compound of claim 8 wherein the oligonucleotide consists of 19 to 23 linked nucleosides.
10 . The compound of claim 1 comprising at least one modified sugar moiety.
11 . The compound of claim 10 wherein the modified sugar moiety is selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
12 . The compound of claim 11 wherein the bicyclic sugar moiety comprises a 4′-CH 2 —O-2′ bridge.
13 . The compound of claim 1 wherein the oligomeric compound comprises at least 3 LNA monomers.
14 . The compound of claim 1 wherein the oligomeric compound comprises at least one modified internucleoside linkage.
15 . The compound of claim 14 wherein the modified internucleoside linkage is a phosphorothioate linkage.
16 . The compound of claim 1 wherein each internucleoside linkage of the oligomeric compound is a phosphorothioate linkage.
17 . The compound of claim 1 wherein each monomeric subunit comprises a modified sugar moiety.
18 . The compound of claim 17 wherein at least one modified sugar moiety is 2′-O-methoxyethyl.
19 . The compound of claim 17 wherein at least one modified sugar moiety is 2′-O-methyl.
20 . The compound of claim 1 wherein the oligomeric compound does not comprise a deoxynucleotide region that is capable of supporting RNase H cleavage of an RNA target.
21 . The compound of claim 8 wherein the oligonucleotide comprises two or more chemically distinct regions.
22 . The compound of claim 21 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.
23 . The compound of claim 21 wherein each nucleoside of the two or more chemically distinct regions is independently selected from a 2′-deoxynucleoside and a bicyclic sugar nucleoside.
24 . The compound of claim 23 wherein the bicyclic nucleoside comprises a 4′-CH 2 —O-2′ bridge.
25 . The compound of claim 1 comprising at least one modified nucleobase.
26 . The compound of claim 25 wherein the modified nucleobase is 5-methylcytosine.
27 . The compound of claim 1 wherein the oligomeric compound is attached to a conjugate group.
28 . The compound of claim 27 wherein the conjugate group is cholesterol.
29 . A compound comprising an oligomeric compound complementary to a region of a protein-coding RNA, wherein the region is a miRNA binding site.
30 . The compound of claim 29 wherein the oligomeric compound is complementary to at least an 8-nucleobase portion of the miRNA binding site.
31 . The compound of claim 29 wherein the oligomeric compound is at least 90% complementary to the region of the protein-coding RNA.
32 . The compound of claim 29 wherein the oligomeric compound is at least 95% complementary to the region of the protein-coding RNA.
33 . The compound of claim 29 wherein the oligomeric compound is 100% complementary to the region of the protein-coding RNA.
34 . A composition comprising the compound of claim 1 and a pharmaceutically acceptable diluent or carrier.