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 double-stranded miRNA mimic comprising a first strand and a second strand, wherein the first strand and the second strand each consists of 17 to 25 linked nucleosides, wherein
a) the first strand comprises a nucleobase sequence identical to at least 17 contiguous nucleobases of the nucleobase sequence of a mature miRNA;
b) the second strand comprises a nucleobase sequence that is at least 90% complementary to the nucleobase sequence of the first strand that is identical to the nucleobase sequence of the mature miRNA;
c) the second strand comprises at least one nucleoside with a modified sugar moiety.
2. The double-stranded miRNA mimic of claim 1 , wherein the first strand and/or the second strand comprises a one or two nucleoside overhang at the 5′ end and/or the 3′ end.
3. The double-stranded miRNA mimic of claim 2 , wherein the second strand comprises a one or two nucleoside overhang on the 3′ end.
4. The double-stranded miRNA mimic of claim 2 , wherein the first strand comprises a one or two nucleoside overhang on the 3′ end.
5. The double-stranded miRNA mimic of claim 3 , wherein the first strand comprises a one or two nucleoside overhang on the 3′ end.
6. The double-stranded miRNA mimic of claim 1 , which is blunt-ended.
7. The double-stranded miRNA mimic of claim 1 , wherein the second strand comprises a terminal modification at the 5′ end or the 3′ end.
8. The double-stranded miRNA mimic of claim 7 , wherein the terminal modification is a 5′ or 3′ cap.
9. The double-stranded miRNA mimic of claim 7 , wherein the terminal modification is a conjugate group.
10. The double-stranded miRNA mimic of claim 1 , wherein at least one nucleoside with a modified sugar moiety is selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
11. The double-stranded miRNA mimic of claim 1 , wherein each nucleoside with a modified sugar moiety is independently selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
12. The double-stranded miRNA mimic of claim 11 , wherein each nucleoside with a modified sugar moiety is 2′-O-methyl.
13. The double-stranded miRNA mimic of claim 1 , wherein the second strand has an alternating motif comprising alternating unmodified nucleosides and nucleoside with a modified sugar moiety.
14. The double-stranded miRNA mimic of claim 13 , wherein the modified sugar moiety is selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
15. The double-stranded miRNA mimic of claim 14 , wherein the modified sugar moiety is 2′-O-methyl.
16. The double-stranded miRNA mimic of claim 1 , wherein the second strand has an alternating motif comprising alternating a first nucleoside with a first modified sugar moiety and a second nucleoside with a second modified sugar moiety, wherein the first modified sugar moiety and the second modified sugar moiety are different.
17. The double-stranded miRNA mimic of claim 16 , wherein the first modified sugar moiety and the second modified sugar moiety are each independently selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
18. The double-stranded miRNA mimic of claim 1 , wherein each nucleoside of the second strand has a modified sugar moiety.
19. The double-stranded miRNA mimic of claim 18 , wherein each modified sugar moiety is independently selected from 2′-F, 2′-O-methyl, 2′-O-methoxyethyl, and a bicyclic sugar moiety.
20. The double-stranded miRNA mimic of claim 1 , wherein the second strand is a blockmer.