MicroRNA compounds and methods for modulating miR-122

Patent metadata

Field	Value
Publication number	US-9574194-B2
Application number	US-201615056534-A
Country	US
Kind code	B2
Filing date	Feb 29, 2016
Priority date	May 1, 2013
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Described herein are compositions and methods for the inhibition of miR-122 activity. The compositions have certain nucleoside modifications that yield potent inhibitors of miR-122 activity. The compounds may comprise conjugates to facilitate delivery to the liver. The compositions may be administered to subjects infected with hepatitis C virus, as a treatment for hepatitis C virus and related conditions.

First claim

What is claimed:

1. A compound comprising a modified oligonucleotide consisting of 16 to 22 linked nucleosides, wherein the nucleobase sequence of the modified oligonucleotide is complementary to miR-122 (SEQ ID NO: 1) and wherein the modified oligonucleotide comprises at least 16 contiguous nucleosides of the following nucleoside pattern I in the 5′ to 3′ orientation:

(R) X -N Q -N Q -N B -N B -N Q -N B -N Q -N B -N Q -N B -N B -(NZ) Y

wherein each R is, independently, a non-bicyclic nucleoside or a bicyclic nucleoside;
X is from 4 to 10;
each N B is, independently, a bicyclic nucleoside;
each N Q is, independently, a non-bicyclic nucleoside;
Y is 0 or 1; and
N Z is a modified nucleoside or an unmodified nucleoside.

2. The compound of claim 1 , wherein the modified oligonucleotide comprises at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, or 22 contiguous nucleosides of nucleoside pattern I.

3. The compound of claim 1 wherein each bicyclic nucleoside is independently selected from an LNA nucleoside, a cEt nucleoside, and an ENA nucleoside.

4. The compound of claim 1 , wherein each bicyclic nucleoside is a cEt nucleoside.

5. The compound of claim 1 wherein each non-bicyclic nucleoside is independently selected from a β-D-deoxyribonucleoside, a β-D-ribonucleoside, 2′-O-methyl nucleoside, a 2′-O-methoxyethyl nucleoside, and a 2′-fluoronucleoside.

6. The compound of claim 1 wherein each non-bicyclic nucleoside is independently selected from a β-D-deoxyribonucleoside, and a 2′-O-methoxyethyl nucleoside.

7. The compound of claim 1 , wherein X is 4, 7, or 10.

8. The compound of claim 1 , wherein Y is 0.

9. The compound of claim 1 wherein:
a. X is 7;
each R is a 2′-O-methoxyethyl nucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside; and Y is 0;

b. X is 4; (R) x is N R1 —N R2 —N R3 —N R4 , wherein each of N R1 and N R3 is a S-cEt nucleoside and each of N R2 and N R4 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside;
Y is 1; and N Z is a β-D-deoxyribonucleoside

c. X is 4; (R) x is N R1 —N R2 —N R3 —N R4 , wherein each of N R1 and N R4 is a S-cEt nucleoside and each of N R2 and N R3 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside;
Y is 1; and N Z is a 2′-O-methoxyethyl nucleoside

d. X is 7; (R) x is N R1 —N R2 —N R3 —N R4 —N R5 —N R6 —N R7 , wherein each of N R1 , N R2 , N R3 , and N R4 and is a 2′-O-methoxyethyl nucleoside, each of N R5 and N R7 is a β-D-deoxyribonucleoside, and N R6 is S-cEt nucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside; and Y is 0;

e. X is 7; (R) x is N R1 —N R2 —N R3 —N R4 —N R5 —N R6 —N R7 , wherein each of N R1 , N R2 , N R3 , N R4 , and N R5 is a 2′-O-methoxyethyl nucleoside, N R6 is S-cEt nucleoside, and N R7 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside; and Y is 0;

f. X is 7; (R) x is N R1 —N R2 —N R3 —N R4 —N R5 —N R6 —N R7 , wherein each of N R1 , N R2 , N R3 , N R4 , N R5 , and N R6 is 2′-O-methoxyethyl nucleoside, and N R7 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside; and Y is 0;

g. X is 10; (R) x is N R1 —N R2 —N R3 —N R4 —N R5 —N R6 —N R7 —N R8 —N R9 —N R10 , wherein each of N R1 , N R2 , N R3 , N R4 , N R5 , and N R6 is 2′-O-methoxyethyl nucleoside, each of N R7 and N R9 is a an S-cEt nucleoside; each of N R8 and N R10 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside; and Y is 0;

h. X is 10; (R) x is N R1 —N R2 —N R3 —N R4 —N R5 —N R6 —N R7 —N R8 —N R9 —N R10 , wherein each of N R1 , N R2 , N R3 , N R4 , N R5 , and N R6 is 2′-O-methoxyethyl nucleoside, each of N R7 and N R9 is a an S-cEt nucleoside; and each of N R8 and N R10 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside;
Y is 1 and Nz is a 2′-O-methoxyethyl nucleoside;

i. X is 4; (R) x is N R1 —N R2 —N R3 —N R4 wherein each of N R1 and N R4 is an S-cEt nucleoside, and each of N R1 and N R3 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside;
Y is 1 and N Z is a β-D-deoxyribonucleoside;

j. X is 4; (R) x is N R1 —N R2 —N R3 —N R4 , wherein N R1 is a 2′-O-methoxyethyl nucleoside, each of N R2 and N R4 is an S-cEt nucleoside, and N R3 is a β-D-deoxyribonucleoside;
each N B is an S-cEt nucleoside;
each N Q is a β-D-deoxyribonucleoside;
Y is 1 and N Z is a 2′-O-methoxyethyl nucleoside.

10. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the nucleobase sequence of miR-122 (SEQ ID NO: 1).

11. The compound of claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage.

12. The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is selected from SEQ ID NOs: 3 to 6, wherein each T is independently selected from T and U.

13. The compound of claim 1 , wherein the compound comprises a conjugate moiety linked to the 5′ terminus or the 3′ terminus of the modified oligonucleotide.

14. The compound of claim 13 , wherein the conjugate moiety comprises at least one ligand selected from a carbohydrate, cholesterol, a lipid, a phospholipid, an antibody, a lipoprotein, a hormone, a peptide, a vitamin, a steroid, and a cationic lipid.

15. The compound of claim 13 , wherein the compound has the structure:
L n -linker-MO
wherein each L is, independently, a ligand and n is from 1 to 10; and MO is a modified oligonucleotide.

16. The compound of claim 13 , wherein the compound has the structure:
L n -linker-X-MO
wherein each L is, independently, a ligand and n is from 1 to 10; X is a phosphodiester linkage or a phosphorothioate linkage; and MO is a modified oligonucleotide.

17. The compound of claim 13 , wherein the compound has the structure:
L n -linker-X 1 —N m —X 2 -MO

wherein each L is, independently, a ligand and n is from 1 to 10; each N of N m is, independently, a modified or unmodified nucleoside and m is from 1 to 5; X 1 and X 2 are each, independently, a phosphodiester linkage or a phosphorothioate linkage; and MO is a modified oligonucleotide.

18. The compound of claim 17 , wherein if n is greater than 1, La-linker has the structure:
(L-Q′ n S-Q″—

wherein each L is, independently, a ligand; n is from 1 to 10; S is a scaffold; and Q′ and Q″ are, independently, linking groups.

19. The compound of claim 18 , wherein Q′ and Q″ are each independently selected from a peptide, an ether, polyethylene glycol, an alkyl, a C 1 -C 20 alkyl, a substituted C 1 -C 20 alkyl, a C 2 -C 20 alkenyl, a substituted C 2 -C 20 alkenyl, a C 2 -C 20 alkynyl, a substituted C 2 -C 20 alkynyl, a C 1 -C 20 alkoxy, a substituted C 1 -C 20 alkoxy, amino, amido, a pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate, and 6-aminohexanoic acid.

20. The compound of claim 18 , wher

Assignees

• Regulus Therapeutics Inc

Inventors

• Bhat Balkrishen
• Hogan Daniel

Classifications

• C12N15/1131 Primary

  against viruses · CPC title

• C12N2310/321

  2'-O-R Modification · CPC title

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• C12N2310/3515

  Lipophilic moiety, e.g. cholesterol · CPC title