Microrna compounds and methods for modulating mir-122
AssigneeRegulus Therapeutics Inc.
InventorsBalkrishen Bhat, Daniel Hogan
Life of this patent
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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.
Claims62
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-NQ-NQ-NB-NB-NQ-NB-NQ-NB-NQ-NB-NB-(NZ)y
- wherein each R is, independently, a non-bicyclic nucleoside or a bicyclic nucleoside;
- X is from 4 to 10;
- each NB is, independently, a bicyclic nucleoside;
- each NQ is, independently, a non-bicyclic nucleoside;
- Y is 0 or 1;
- and
- NZ is a modified nucleoside or an unmodified nucleoside.
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A compound comprising a modified nucleotide and a conjugate moiety, wherein the modified oligonucleotide has the structure CLCALTTGLTLCACLACLTCLCL, wherein the subscript “L” indicates an LNA and nucleosides not followed by a subscript are β-D-deoxyribonucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage, and wherein the conjugate moiety is linked to the 3′ terminus of the modified oligonucleotide and has the structure:
- wherein each N is, independently, a modified or unmodified nucleoside and m is from 1 to 5;
- X1 and X2 are each, independently, a phosphodiester linkage or a phosphorothioate linkage;
- and MO is a modified oligonucleotide.
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A compound comprising a modified nucleotide and a conjugate moiety, wherein the modified oligonucleotide has the structure AEMeCEAEMeCEMeCEAETETGUSCSACSACSTCSCS, wherein nucleosides not followed by a subscript are β-D-deoxyribonucleosides, nucleosides followed by a subscript “E” are 2′-MOE nucleosides, nucleosides followed by a subscript “S” are S-cEt nucleosides, and each internucleoside linkage is a phosphorothioate internucleoside linkage;
- and wherein the conjugate moiety is linked to the 3′ terminus of the modified oligonucleotide and has the structure:
- wherein X is a phosphodiester linkage;
- m is 1;
- N is a β-D-deoxyriboadenosine;
- Y is a phosphodiester linkage;
- and MO is the modified oligonucleotide.
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Dependencies are inferred from the claim text.