Compositions and methods for modulation of ikbkap splicing

Abstract

The present disclosure provides compounds comprising oligonucleotides complementary to a portion of the IKBKAP gene. Certain such compounds are useful for hybridizing to a portion of the IKBKAP gene, including but not limited to a portion of the IKBKAP gene in a cell. In certain embodiments, such hybridization results in modulation of splicing of the IKBKAP gene. In certain embodiments, the IKBKAP gene includes a mutation that results in defective splicing and a truncated IKAP protein. In certain embodiments, hybridization of oligonucleotides complementary to a portion of the IKBKAP gene results in a decrease in the amount of defective splicing and truncated IKAP protein. In certain embodiments, hybridization of oligonucleotides complementary to a portion of the IKBKAP gene results in an increase in the amount of normal splicing and functional, full-length IKAP protein. In certain embodiments, oligonucleotides are used to treat Familial Dysautonomia.

We claim: 
     
         1 . A compound comprising a modified oligonucleotide consisting of 8 to 30 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases complementary to a target region of equal length of an IKBKAP transcript. 
     
     
         2 . The compound of  claim 1 , wherein nucleobase sequence comprises at least 8 contiguous nucleobases complementary to intron 19, intron 20, or exon 20 of an IKBKAP transcript. 
     
     
         3 . The compound  claim 1 , wherein the modified oligonucleotide is 12 to 20 nucleosides in length. 
     
     
         4 . The compound  claim 3 , wherein the modified oligonucleotide is 15 nucleosides in length. 
     
     
         5 . The compound of  claim 4  having a nucleobase sequence comprising at least 9 contiguous nucleobases complementary to a target region of equal length of an IKBKAP transcript. 
     
     
         6 . The compound of  claim 5 , wherein the modified oligonucleotide comprises at least one modified nucleoside. 
     
     
         7 . The compound of  claim 6 , wherein at least one modified nucleoside comprises a modified sugar moiety. 
     
     
         8 . The compound of  claim 7 , wherein at least one modified sugar moiety is a 2′-substituted sugar moiety. 
     
     
         9 . The compound of  claim 8 , wherein the 2′-substitutent of at least one 2′-substituted sugar moiety is selected from the group consisting of 2′-OMe, 2′-F, and 2′-MOE. 
     
     
         10 . The compound of  claim 9 , wherein the 2′-substiuent of at least one 2′-substituted sugar moiety is a 2′-MOE. 
     
     
         11 . The compound of  claim 7 , wherein at least one modified sugar moiety is a bicyclic sugar moiety. 
     
     
         12 . The compound of  claim 11 , wherein at least one bicyclic sugar moiety is LNA or cEt. 
     
     
         13 . The compound of  claim 11 , wherein at least one bicyclic sugar moiety is cEt. 
     
     
         14 . The compound of  claim 11 , wherein at least one bicyclic sugar moiety is LNA. 
     
     
         15 . The compound of  claim 7 , wherein at least one sugar moiety is a sugar surrogate. 
     
     
         16 . The compound of  claim 15 , wherein at least one sugar surrogate is a morpholino. 
     
     
         17 . The compound of  claim 15 , wherein at least one sugar surrogate is a modified morpholino. 
     
     
         18 . The compound of  claim 6 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         19 . The compound of  claim 18 , wherein each internucleoside linkage is a modified internucleoside linkage. 
     
     
         20 . The compound of  claim 19 , wherein the modified internucleoside linkage is phosphorothioate.