Enhanced antisense oligonucleotides
First Claim
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1. A method of reducing expression of a target RNA in an animal, in need of reducing expression of said target RNA, comprising administering to said animal a gap-widened antisense oligonucleotide 18-24 nucleotides in length targeting a preselected RNA target in the liver, wherein said oligonucleotide comprises:
- (a) a gap region having 12 to 18 contiguous 2′
-deoxyribonucleotides;
(b) a first wing region having 2 to 4 contiguous nucleosides; and
(c) a second wing region having 2 to 4 contiguous nucleosides;
wherein the gap region is located between said first wing region and said second wing region and, wherein each nucleoside of said first and second wing regions comprises a 2′
-O-(2-methoxyethyl) modification;
thereby reducing expression of said preselected RNA target in the liver of said animal.
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Abstract
Described herein are gap-widened antisense oligonucleotides having improved therapeutic index as compared to 5-10-5 MOE gapmer antisense oligonucleotides of the same sequence. Also described are methods of reducing a target RNA in an animal using the gap-widened antisense oligonucleotides of the present invention. Further, are methods for selecting a gap-widened antisense oligonucleotides.
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Citations
20 Claims
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1. A method of reducing expression of a target RNA in an animal, in need of reducing expression of said target RNA, comprising administering to said animal a gap-widened antisense oligonucleotide 18-24 nucleotides in length targeting a preselected RNA target in the liver, wherein said oligonucleotide comprises:
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(a) a gap region having 12 to 18 contiguous 2′
-deoxyribonucleotides;(b) a first wing region having 2 to 4 contiguous nucleosides; and (c) a second wing region having 2 to 4 contiguous nucleosides;
wherein the gap region is located between said first wing region and said second wing region and, wherein each nucleoside of said first and second wing regions comprises a 2′
-O-(2-methoxyethyl) modification;thereby reducing expression of said preselected RNA target in the liver of said animal. - View Dependent Claims (2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14)
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8. A method of modulating gene expression in an animal comprising the step of contacting said animal with a pharmaceutical composition comprising a gap-widened antisense oligonucleotide 18-24 nucleotides in length targeting a preselected RNA target in the liver in the manufacture of a medicament for the treatment of disorders and diseases related to said RNA, wherein the antisense oligonucleotide comprises:
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(a) a gap region having 12 to 18 contiguous 2′
-deoxyribonucleotides;(b) a first wing region having 2 to 4 contiguous nucleosides; and (c) a second wing region having 2 to 4 contiguous nucleosides;
wherein the gap region is located between said first wing region and said second wing region and, wherein each nucleoside of said first and second wing regions comprises a 2′
-O-(2-methoxyethyl) modification;thereby modulating the expression of said preselected RNA target in the liver of said animal. - View Dependent Claims (15, 16, 17, 18, 19, 20)
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Specification