MicroRNA compounds and methods for modulating miR-21 activity
Described herein are compositions and methods for the inhibition of miR-21 activity. The compositions have certain nucleoside modification patterns that yield potent inhibitors of miR-21 activity. The compositions may be used to inhibit miR-21, and also to treat diseases associated with abnormal expression of miR-21, such as fibrosis and cancer.
1. A compound comprising a modified oligonucleotide consisting of 12, 13, 14, or 15 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-21 (SEQ ID NO: 1) and wherein the modified oligonucleotide comprises at least 12 contiguous nucleosides of the following nucleoside pattern VI in the 5′ to 3′ orientation:
N Q —N B —N B —N Q —(N B —N B —N Q —N Q ) 2 —N B —N Q —N B
wherein each N Q is a non-bicyclic nucleoside; and
each N B is a bicyclic nucleoside.
2. The compound of claim 1 , wherein each bicyclic nucleoside is independently selected from an LNA nucleoside, a cEt nucleoside, and an ENA nucleoside.
3. The compound of claim 1 , wherein each non-bicyclic nucleoside is independently selected from a β-D-deoxyribonucleoside, a 2′-O-methyl, and a 2′-O-methoxyethyl nucleoside.
4. The compound of claim 1 , wherein each non-bicyclic nucleoside is independently selected from a β-D-deoxyribonucleoside and a 2′-O-methoxyethyl nucleoside.
5. The compound of claim 1 wherein:
a. each N B is an S-cEt nucleoside; and
each N Q is a 2′-O-methoxyethyl nucleoside; or
b. each N B is an S-cEt nucleoside; and
each N Q is a β-D-deoxyribonucleoside.
6. The compound of claim 1 , wherein at least one internucleoside linkage is a phosphorothioate linkage.
7. The compound of claim 1 , wherein each internucleoside linkage is a phosphorothioate linkage.
8. The compound of claim 1 , wherein the modified oligonucleotide has 1 or 2 mismatches with respect to the nucleobase sequence of miR-21.
9. The compound of claim 1 , wherein the modified oligonucleotide has 0 mismatches with respect to the nucleobase sequence of miR-21.
10. The compound of claim 1 , wherein the modified oligonucleotide has a nucleobase Sequence of SEQ ID NO: 5 or 7, wherein each T is independently selected from T and U.
11. The compound of claim 1 , wherein the modified oligonucleotide has the structure:
Me C E A S A S T E C S U S A E A E U S A S A E G E C S T E A S (SEQ ID NO: 7);
wherein nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides; and superscript “Me” indicates a 5-methyl group on the base of the nucleoside.
12. The compound of claim 11 , wherein at least one internucleoside linkage is a phosphorothioate linkage.
13. The compound of claim 11 , wherein each internucleoside linkage is a phosphorothioate linkage.
14. A modified oligonucleotide of structure:
Me C E A S A S T E C S U S A E A E U S A S A E G E C S T E A S (SEQ ID NO: 7);
wherein nucleosides followed by a subscript “E” are 2′-MOE nucleosides; nucleosides followed by a subscript “S” are S-cEt nucleosides; superscript “Me” indicates a 5-methyl group on the base of the nucleoside; and wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
15. A pharmaceutical composition comprising the modified oligonucleotide of claim 14 and a pharmaceutically acceptable carrier.
16. The compound of claim 1 , wherein the modified oligonucleotide is conjugated to one or more moieties that enhance the activity, cellular distribution or cellular uptake.
17. The compound of claim 1 , wherein the modified oligonucleotide is conjugated to a moiety selected from a lipid, cholesterol, a carbohydrate, a phospholipid, biotin, phenazine, and folate.
18. The compound of claim 11 , wherein the modified oligonucleotide is conjugated to one or more moieties that enhance the activity, cellular distribution or cellular uptake.
19. The compound of claim 11 , wherein the modified oligonucleotide is conjugated to a moiety selected from a lipid, cholesterol, a carbohydrate, a phospholipid, biotin, phenazine, and folate.
20. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable carrier.
21. The compound of claim 1 , wherein the modified oligonucleotide consists of 15 contiguous nucleosides of nucleoside pattern VI.