Enhanced antisense oligonucleotides

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.

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 linked nucleosides in length comprising:
 (a) a gap region having 12 to 18contiguous 2′-deoxyribonucleosides; and   (b) a first wing region having 1 to 4 contiguous nucleosides; and   (c) a second wing region having 1 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 region is a 2′modified nucleoside thereby reducing expression of said target RNA in said animal. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the target RNA is associated with a metabolic or a cardiovascular disease or condition. 
     
     
         5 . The method of  claim 1 , wherein the metabolic disease or condition is selected from metabolic syndrome, diabetes, obesity, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, Type 2 diabetes, diet-induced obesity, hyperglycemia, insulin resistance, hepatic steatosis, fatty liver disease, or non-alcoholic steatohepatitis. 
     
     
         6 . The method of  claim 1 , wherein the cardiovascular disease or condition is selected from familial hypercholesterolemia, nonfamilial hypercholesterolemia, mixed dyslipidemia, dysbetalipoproteinemia, atherosclerosis, coronary artery disease, myocardial infarction, hypertension, carotid artery diseases, carotid artery disease, stroke, cerebrovascular disease, peripheral vascular disease, thrombosis, or arterial aneurism. 
     
     
         7 . The method of  claim 1 , wherein the gap-widened antisense oligonucleotide has a wing-gap-wing motif selected from 2-16-2, 3-14-3, 2-14-2, 3-12-3 or 4-12-4. 
     
     
         8 . The method of  claim 1 , wherein the gap-widened antisense oligonucleotide has at least one phosphorothioate internucleotide linkage. 
     
     
         9 . The method of  claim 6 , wherein the gap-widened antisense oligonucleotide has all phosphorothioate internucleotide linkages. 
     
     
         10 . The method of  claim 1 , wherein gap-widened antisense oligonucleotide has at least one 5-methylcytosine. 
     
     
         11 .- 25 . (canceled) 
     
     
         26 . A method of modulating gene expression in an animal comprising the step of contacting said animal with the pharmaceutical composition comprising a gap-widened antisense oligoncuelotide 18-24 linked nucleosides in length comprising:
 (a) a gap region having 12 to 18 contiguous 2′-deoxyribonucleotides;   (b) a first wing region having 1 to 4 contiguous nucleosides; and   (c) a second wing region having 1 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 region is a 2′ modified nucleoside thereby modulating gene expression in said animal. 
     
     
         27 .- 28 . (canceled)