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 15, 16, 17, 18, or 19 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 15 contiguous nucleosides of the following nucleoside pattern VII in the 5′ to 3′ orientation:
N M -(N B -N M -N M ) 2 -N M -(N B -N Q -N Q -N Q ) 2 -N B -N B -N Z
wherein each N M is a 2′-O-methoxyethyl nucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside; and
N Z is an S-cEt nucleoside.
2. The compound of claim 1 , wherein at least one internucleoside linkage is a phosphorothioate linkage.
3. The compound of claim 1 , wherein each internucleoside linkage is a phosphorothioate linkage.
4. The compound of claim 1 , wherein the modified oligonucleotide has 1 or 2 mismatches with respect to the nucleobase sequence of miR-21.
5. The compound of claim 1 , wherein the modified oligonucleotide has 0 mismatches with respect to the nucleobase sequence of miR-21.
6. The compound of claim 1 , wherein modified oligonucleotide has a nucleobase sequence selected from SEQ ID NOs: 3, 5, 6, 7, 8, 9, and 10, wherein each T is independently selected from T and U.
7. The compound of claim 1 , wherein the modified oligonucleotide has the structure:
A E C S A E T E C S A E G E T E C S TGAU S AAGC S U S A S ,
(SEQ ID NO: 3)
wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-MOE nucleosides; and nucleosides followed by a subscript “S” are S-cEt nucleosides.
8. The compound of claim 7 , wherein at least one internucleoside linkage is a phosphorothioate linkage.
9. The compound of claim 7 , wherein each internucleoside linkage is a phosphorothioate linkage.
10. A compound comprising a modified oligonucleotide having the structure:
A E C S A E T E C S A E G E T E C S TGAU S AAGC S U S A S ,
(SEQ ID NO: 3)
wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-MOE nucleosides; and nucleosides followed by a subscript “S” are S-cEt nucleosides; and wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
11. 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.
12. 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.
13. The compound of claim 10 , wherein the modified oligonucleotide is conjugated to one or more moieties that enhance the activity, cellular distribution or cellular uptake.
14. The compound of claim 10 , wherein the modified oligonucleotide is conjugated to a moiety selected from a lipid, cholesterol, a carbohydrate, a phospholipid, biotin, phenazine, and folate.
15. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable carrier.