Selective antisense compounds and uses thereof

Abstract

The present disclosure provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell. In certain embodiments, certain oligomeric compounds selectively reduce the expression of a target nucleic acid transcript relative to a non-target nucleic acid transcript.

1 .- 168 . (canceled) 
     
     
         169 . A oligomeric compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides, wherein the modified oligonucleotide has a modification motif comprising: a 5′-region consisting of 1-9 linked 5′-region nucleosides, each independently selected from among a modified nucleoside and an unmodified deoxynucleoside, provided that at least one 5′-region nucleoside is a modified nucleoside and wherein the 3′-most 5′-region nucleoside is a modified nucleoside;
 a 3′-region consisting of 2-10 linked 3′-region nucleosides, wherein each 3′-region nucleoside comprises a modified nucleoside; and 
 a central region between the 5′-region and the 3′-region consisting of 6-10 linked central region nucleosides, each independently selected from among: a modified nucleoside and an unmodified deoxynucleoside, wherein the 5′-most central region nucleoside is an unmodified deoxynucleoside and the 3′-most central region nucleoside is an unmodified deoxynucleoside; and wherein the modified oligonucleotide has a nucleobase sequence complementary to the nucleobase sequence of a target region of a nucleic acid associated with a huntingtin transcript; 
 wherein the nucleobase sequence of the target region of the target nucleic acid differs from the nucleobase sequence of at least one non-target nucleic acid by a single differentiating nucleobase; and wherein the single differentiating nucleobase is a single-nucleotide polymorphism selected from among rs6446723 and rs363064. 
 
     
     
         170 . The oligomeric compound of  claim 169 , wherein the single-nucleotide polymorphism is rs6446723. 
     
     
         171 . The oligomeric compound of  claim 169 , wherein the single-nucleotide polymorphism is rs363064. 
     
     
         172 . The oligomeric compound of  claim 169 , wherein the modified oligonucleotide has a modification motif selected from:
 eeekk-d7-kkeee,   eekk-d8-kkeee, and   ekek-d8-kekee,   wherein each “e” is a 2′MOE modified nucleoside, each “k” is a cEt modified nucleoside, and each d is an unmodified deoxynucleoside.   
     
     
         173 . The oligomeric compound of  claim 172 , wherein the modified oligonucleotide has a eeekk-d7-kkeee modification motif, wherein each “e” is a 2′MOE modified nucleoside, each “k” is a cEt modified nucleoside, and each d is an unmodified deoxynucleoside. 
     
     
         174 . The oligomeric compound of  claim 172 , wherein the modified oligonucleotide has a eekk-d8-kkeee modification motif, wherein each “e” is a 2′MOE modified nucleoside, each “k” is a cEt modified nucleoside, and each d is an unmodified deoxynucleoside. 
     
     
         175 . The oligomeric compound of  claim 172 , wherein the modified oligonucleotide has a ekek-d8-kekee modification motif, wherein each “e” is a 2′MOE modified nucleoside, each “k” is a cEt modified nucleoside, and each d is an unmodified deoxynucleoside. 
     
     
         176 . The oligomeric compound of  claim 169 , comprising at least one modified internucleoside linkage. 
     
     
         177 . The oligomeric compound of  claim 176 , wherein each internucleoside linkage is a modified internucleoside linkage. 
     
     
         178 . The oligomeric compound of  claim 169 , comprising at least one phosphorothioate internucleoside linkage. 
     
     
         179 . The oligomeric compound of  claim 177 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         180 . The oligomeric compound of  claim 176 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage or a phosphodiester internucleoside linkage. 
     
     
         181 . The oligomeric compound of  claim 180 , wherein the 5′-most internucleoside linkage of the 5′-region is a phosphorothioate internucleoside linkage, wherein the 3′-most internucleoside linkage of the 3′-region is a phosphorothioate internucleoside linkage, and wherein each internucleoside linkage of the central region is a phosphorothioate internucleoside linkage. 
     
     
         182 . The oligomeric compound of  claim 180 , wherein the 5′-most internucleoside linkage of the 5′-region is a phosphorothioate internucleoside linkage, wherein the 3′-most internucleoside linkage of the 3′-region is a phosphorothioate internucleoside linkage, wherein each internucleoside linkage of the central region is a phosphorothioate internucleoside linkage, and wherein each remaining internucleoside linkage is a phosphodiester internucleoside linkage. 
     
     
         183 . The oligomeric compound of  claim 180 , wherein the oligomeric compound contains 2 phosphodiester internucleoside linkages. 
     
     
         184 . The oligomeric compound of  claim 180 , wherein the oligomeric compound contains 3 phosphodiester internucleoside linkages.