MICRORNA COMPOUNDS AND METHODS FOR MODULATING MIR-21 ACTIVITY

1 . A compound comprising a modified oligonucleotide consisting of 8 to 22 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 8 contiguous nucleosides of the following nucleoside pattern I in the 5′ to 3′ orientation:

(R) X -N B -N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Q -N Z

wherein each R is, independently, a non-bicyclic nucleoside; X is from 1 to 4;

each N B is, independently, a bicyclic nucleoside;

each N Q is, independently, a non-bicyclic nucleoside; and

each N Z is, independently, a modified nucleoside.

2 . The compound of claim 1 , wherein the modified oligonucleotide consists of 8 to 19 linked nucleosides, and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following nucleoside pattern II in the 5′ to 3′ orientation:

N M -N B -N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Q -N Z

wherein N M is a modified nucleoside that is not a bicyclic nucleoside.

3 . A compound comprising a modified oligonucleotide consisting of 8 to 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 8 contiguous nucleosides of the following nucleoside pattern III in the 5′ to 3′ orientation:

(R) X -N B -N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Y -N Z

wherein each R is a non-bicyclic nucleoside; X is from 1 to 4;

each N B is a bicyclic nucleoside;

each N Q is a non-bicyclic nucleoside;

N Y is a modified nucleoside or an unmodified nucleoside; and

each N Z is a modified nucleoside.

4 . The compound of claim 3 , wherein the modified oligonucleotide consists of 8 to 19 linked nucleosides, and wherein the modified oligonucleotide comprises at least 8 contiguous nucleosides of the following nucleoside pattern IV in the 5′ to 3′ orientation:

N M -N B -N Q -N Q -N B -(N Q -N Q -N Q -N B ) 3 -N Y -N Z

wherein N M is a modified nucleoside that is not a bicyclic nucleoside.

5 . A compound comprising a modified oligonucleotide consisting of 8 to 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 8 contiguous nucleosides of the following nucleoside pattern V in the 5′ to 3′ orientation:

N M -N B -(N Q -N Q -N B -N B ) 4 -N Z

wherein N M is a modified nucleoside that is not a bicyclic nucleoside;

each N B is a bicyclic nucleoside;

each N Q is a non-bicyclic nucleoside; and

N Z is a modified nucleoside.

6 . (canceled)

7 . The compound of claim 2 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary is at least 95% complementary, or is 100% complementary to the nucleobase sequence of miR-21 (SEQ ID NO: 1).

8 . (canceled)

9 . The compound of claim 2 , wherein each bicyclic nucleoside is an S-cEt nucleoside.

10 . The compound of claim 2 , wherein each bicyclic nucleoside is an LNA nucleoside.

11 . The compound of claim 2 wherein each non-bicyclic nucleoside is independently selected from a β-D-deoxyribonucleoside and a 2′-O-methoxyethyl nucleoside.

12 . The compound of claim 11 wherein each non-bicyclic nucleoside is a β-D-deoxyribonucleoside.

13 . The compound of claim 11 wherein each non-bicyclic nucleoside is a 2′-O-methoxyethyl nucleoside.

14 . The compound of claim 1 wherein the modified oligonucleotide consists of 15, 16, 17, 18, 19, 20, 21, or 22 linked nucleosides of nucleoside pattern I or II.

15 . The compound of claim 2 wherein each internucleoside linkage is a modified internucleoside linkage.

16 . The compound of claim 2 wherein at least one cytosine is a 5-methyl cytosine.

17 . The compound of claim 1 wherein:

a. R consists of four linked nucleosides N R1 -N R2 -N R3 -N R4 , wherein N R1 is a 2′-O-methoxyethyl nucleoside and each of N R2 -N R3 -N R4 is a β-D-deoxyribonucleoside;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside;

b. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside;

c. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an S-cEt nucleoside;

each N Q is a 2′-O-methoxyethyl nucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside;

d. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is an S-cEt nucleoside;

e. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an LNA nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside; or

f. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an LNA nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is an LNA nucleoside.

18 . The compound of claim 2 wherein:

a. 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 a 2′-O-methoxyethyl nucleoside;

b. N M is a 2′-O-methoxyethyl nucleoside;

each N B is an S-cEt nucleoside;

each N Q is a 2′-O-methoxyethyl nucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside;

c. N M is a 2′-O-methoxyethyl nucleoside;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside;

each N is a β-D-deoxyribonucleoside; and

N Z is an S-cEt nucleoside;

d. N M is a 2′-O-methoxyethyl nucleoside;

each N B is an LNA nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside; or

e. N M is a 2′-O-methoxyethyl nucleoside;

each N B is an LNA nucleoside;

each N Q is a β-D-deoxyribonucleoside; and

N Z is an LNA nucleoside.

19 . The compound of claim 3 wherein:

a. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside;

N Y is a β-D-deoxyribonucleoside; and

N Z is a 2′-O-methoxyethyl nucleoside;

b. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside;

N Y is a β-D-deoxyribonucleoside; and

N Z is an S-cEt nucleoside; or

c. each R is a 2′-O-methoxyethyl nucleoside; X is 1;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside;

N Y is an S-cEt nucleoside; and

N Z is an S-cEt nucleoside.

20 . The compound of claim 4 wherein:

a. N M is a 2′-O-methoxyethyl nucleoside;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside;

N Y is a β-D-deoxyribonucleoside;

N Z is a 2′-O-methoxyethyl nucleoside; and

b. N M is a 2′-O-methoxyethyl nucleoside;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside;

N Y is a β-D-deoxyribonucleoside; and

N Z is an S-cEt nucleoside;

c. N M is a 2′-O-methoxyethyl nucleoside;

each N B is an S-cEt nucleoside;

each N Q is a β-D-deoxyribonucleoside;

N Y is an S-cEt nucleoside; and

N Z is an S-cEt nucleoside.

21 . The compound of claim 5 wherein:

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 a 2′-O-methoxyethyl nucleoside.

22 . The compound of claim 1 wherein the modified oligonucleotide has the nucleobase sequence of SEQ ID NO: 3 or wherein the modified oligonucleotide has the nucleobase sequence of SEQ ID NO: 4, and wherein each T in the sequence is independently selected from a T and a U.

23 . (canceled)

24 . (canceled)

25 . (canceled)

26 . A method of decreasing collagen expression in a cell comprising contacting a cell with a compound of claim 2 .

27 . A method of treating, preventing or delaying the onset of a disease associated with miR-21 comprising administering to a subject having a disease associated with miR-21 a compound of claim 2 .

28 . The method of claim 27 , wherein the disease is fibrosis.

29 . The method of claim 28 , wherein the fibrosis is selected from kidney fibrosis, lung fibrosis, liver fibrosis, cardiac fibrosis, skin fibrosis, age-related fibrosis, spleen fibrosis, scleroderma, and post-transplant fibrosis.

30 . (canceled)

31 . A method of treating a fibroproliferative disorder in a subject comprising administering to the subject a compound of claim 2 .

32 . The method of claim 27 comprising selecting a subject having elevated miR-21 expression in one or more tissues.

33 . (canceled)

34 . (canceled)

35 . (canceled)

36 . The method of claim 27 , wherein the disease is cancer.

37 . The method of claim 36 wherein the cancer is liver cancer, breast cancer, bladder cancer, prostate cancer, colon cancer, lung cancer, brain cancer, hematological cancer, pancreatic cancer, head and neck cancer, cancer of the tongue, stomach cancer, skin cancer, or thyroid cancer.

38 .- 51 . (canceled)