Antisense compounds

Abstract

Provided herein are gapmer oligomeric compounds for reduction of target RNA in vivo comprising different nucleotide modifications within one or both wing regions. Also provided are methods of using such oligomeric compounds, including use in animals. In certain embodiments, such compound have desirable potency and toxicity characteristics.

1 . An oligomeric compound comprising a gapmer oligonucleotide consisting of 10 to 25 linked nucleosides wherein the gapmer oligonucleotide has a 5′ wing region positioned at the 5′ end of a deoxynucleotide gap, and a 3′ wing region positioned at the 3′ end of the deoxynucleotide gap, wherein at least one nucleoside of at least one of the wing regions is a 4′ to 2′ bicyclic nucleoside and at least one of the remaining wing nucleosides is a non-bicyclic 2′-modified nucleoside, wherein the non-bicyclic 2′-modified nucleoside is substituted at the 2′ position with a substituted or unsubstituted —O-(2-acetylamide). 
     
     
         2 . An oligomeric compound comprising a gapmer oligonucleotide consisting of 10 to 25 linked nucleosides wherein the gapmer oligonucleotide has a 5′ wing region positioned at the 5′ end of a deoxynucleotide gap, and a 3′ wing region positioned at the 3′ end of the deoxynucleotide gap, wherein at least one nucleoside of at least one of the wing regions is a 4′ to 2′ bicyclic nucleoside and at least one of the remaining wing nucleosides is a non-bicyclic 2′-modified nucleoside, wherein the non-bicyclic 2′-modified nucleoside is substituted at the 2′ position with a substituted or unsubstituted —O-alkyl. 
     
     
         3 .- 6 . (canceled) 
     
     
         7 . The oligomeric compound of  claim 1 , wherein the 4′ to 2′ bicyclic nucleoside is a methyleneoxy (4′-CH 2 —O-2′) bicyclic nucleoside or ethyleneoxy (4′-CH 2 CH 2 —O-2′) bicyclic nucleoside. 
     
     
         8 .- 11 . (canceled) 
     
     
         12 . The oligomeric compound of  claim 1 , wherein the wing regions are between about 1 to about 7 nucleosides in length. 
     
     
         13 . The oligomeric compound of  claim 2 , wherein the wing regions are between about 1 to about 7 nucleosides in length. 
     
     
         14 . The oligomeric compound of  claim 1 , wherein the deoxy gap region is between about 6 to about 18 nucleotides in length. 
     
     
         15 . The oligomeric compound of  claim 2 , wherein the deoxy gap region is between about 6 to about 18 nucleosides in length. 
     
     
         16 .- 18 . (canceled) 
     
     
         19 . The oligomeric compound of  claim 2 , wherein the 4′ to 2′ bicyclic nucleoside is a methyleneoxy (4′-CH 2 —O-2′) bicyclic nucleoside or ethyleneoxy (4′-CH 2 CH 2 —O-2′) bicyclic nucleoside. 
     
     
         20 . (canceled) 
     
     
         21 . The oligomeric compound of  claim 1 , wherein the substitution of the 2′ position is 2′-OCH 2 C(O)—NR 1 R 2 , wherein R 1  and R 2  are independently hydrogen or substituted or unsubstituted alkyl or, in the alternative, are taken together to make a heterocyclic moiety. 
     
     
         22 .- 25 . (canceled) 
     
     
         26 . The oligomeric compound of  claim 2 , wherein the substitution of the 2′ position is 2′-OCH 3  or 2′-O(CH 2 ) 2 OCH 3 . 
     
     
         27 .- 29 . (canceled) 
     
     
         30 . A method of reducing the expression of a target RNA in an animal comprising administering to said animal a gapmer antisense oligonucleotide of  claim 1 , wherein the sequence of said antisense oligonucleotide is complementary to said target RNA. 
     
     
         31 .- 58 . (canceled) 
     
     
         59 . A method of reducing the expression of a target RNA in an animal comprising administering to said animal a gapmer antisense oligonucleotide of  claim 2 , wherein the sequence of said antisense oligonucleotide is complementary to said target RNA.