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 modified oligonucleotide consisting of 16, 17, or 18 linked nucleosides of the structure:
(SEQ ID NO: 3)
5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′
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 is a phosphorothioate linkage.
2. The modified oligonucleotide of claim 1 , consisting of 18 linked nucleosides of the structure:
(SEQ ID NO: 3)
5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′.
3. The modified oligonucleotide of claim 2 , consisting of 18 linked nucleosides and having the structure:
5′-A E C S ATC S AGTC S TGAU S AAGC S T-3′
(nucleobases 1-18 of SEQ ID NO: 3).
4. The modified oligonucleotide of claim 2 , consisting of 18 linked nucleosides and having the structure:
5′-C S ATC S AGTC S TGAU S AAGC S TA E -3′
(nucleobases 2-19 of SEQ ID NO: 3).
5. The modified oligonucleotide of claim 1 , consisting of 17 linked nucleosides of the structure:
(SEQ ID NO: 3)
5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′.
6. The modified oligonucleotide of claim 5 , consisting of 17 linked nucleosides and having the structure:
5′-A E C S ATC S AGTC S TGAU S AAGC S -3′
(nucleobases 1-17 of SEQ ID NO: 3).
7. The modified oligonucleotide of claim 5 , consisting of 17 linked nucleosides and having the structure:
5′-C S ATC S AGTC S TGAU S AAGC S T-3′
(nucleobases 2-18 of SEQ ID NO: 3).
8. The modified oligonucleotide of claim 5 , consisting of 17 linked nucleosides and having the structure:
5′-ATC S AGTC S TGAU S AAGC S TA E -3′
(nucleobases 3-19 of SEQ ID NO: 3).
9. The modified oligonucleotide of claim 1 , consisting of 16 linked nucleosides of the structure:
(SEQ ID NO: 3)
5′-A E C S ATC S AGTC S TGAU S AAGC S TA E -3′.
10. The modified oligonucleotide of claim 9 , consisting of 16 linked nucleosides and having the structure:
5′-A E C S ATC S AGTC S TGAU S AAG-3′
(nucleobases 1-16 of SEQ ID NO: 3).
11. The modified oligonucleotide of claim 9 , consisting of 16 linked nucleosides and having the structure:
5′-C S ATC S AGTC S TGAU S AAGC S -3′
(nucleobases 2-17 of SEQ ID NO: 3).
12. The modified oligonucleotide of claim 9 , consisting of 16 linked nucleosides and having the structure:
5′-ATC S AGTC S TGAU S AAGC S T-3′
(nucleobases 3-18 of SEQ ID NO: 3).
13. The modified oligonucleotide of claim 9 , consisting of 16 linked nucleosides and having the structure:
5′-TC S AGTC S TGAU S AAGC S TA E -3′
(nucleobases 4-19 of SEQ ID NO: 3).
14. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 and a pharmaceutically acceptable diluent.
15. The pharmaceutical composition of claim 14 , which is a sterile aqueous solution.