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 having the structure:
(SEQ ID NO: 3)
A E C S ATC S AGTC S TGAU S AAGC S TA E ,
wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-methoxyethyl (2′-MOE) nucleosides; and nucleosides followed by a subscript “S” are S-constrained ethyl (S-cEt) nucleosides.
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 is conjugated to one or more moieties that enhance the activity, cellular distribution or cellular uptake.
5. 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.
6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
7. A compound comprising a modified oligonucleotide having the structure:
(SEQ ID NO: 3)
A E C S ATC S AGTC S TGAU S AAGC S TA E ,
wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides; nucleosides followed by a subscript “E” are 2′-methoxyethyl (2′-MOE)nucleosides; and nucleosides followed by a subscript “S” are S-constrained ethyl (S-cEt) nucleosides; and wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate linkage.
8. The compound of claim 7 , wherein the modified oligonucleotide is conjugated to one or more moieties that enhance the activity, cellular distribution or cellular uptake.
9. The compound of claim 7 , wherein the modified oligonucleotide is conjugated to a moiety selected from a lipid, cholesterol, a carbohydrate, a phospholipid, biotin, phenazine, and folate.
10. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.