Compositions and methods for modulating ataxin 3 expression

Abstract

Disclosed are methods for modulating splicing of Ataxin 3 mRNA in an animal with modified oligonucleotides. Such compounds and methods are useful to treat, prevent, or ameliorate spinocerebellar ataxia type 3 (SCA3) in an individual in need thereof.

1 .- 55 . (canceled) 
     
     
         56 . An oligomeric compound comprising a modified oligonucleotide consisting of 15-25 linked nucleosides, wherein the modified oligonucleotide has a nucleobase sequence comprising 15, 16, 17, or 18 contiguous nucleobases of SEQ ID NO: 6, wherein at least one nucleoside of the modified oligonucleotide comprises a 2′-O-methoxyethyl group. 
     
     
         57 . The oligomeric compound of  claim 56 , consisting of the modified oligonucleotide. 
     
     
         58 . The oligomeric compound of  claim 56 , wherein the modified oligonucleotide is single-stranded. 
     
     
         59 . The oligomeric compound of  claim 56 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         60 . The oligomeric compound of  claim 59 , wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         61 . The oligomeric compound of  claim 59 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         62 . The oligomeric compound of  claim 60 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage. 
     
     
         63 . The oligomeric compound of  claim 56 , wherein at least one nucleobase of the modified oligonucleotide is a modified nucleobase. 
     
     
         64 . The oligomeric compound of  claim 63 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         65 . The oligomeric compound of  claim 56 , wherein each nucleobase of each nucleoside of the modified oligonucleotide is either an unmodified nucleobase or is a 5-methylcytosine. 
     
     
         66 . The oligomeric compound of  claim 56 , wherein each nucleoside of the modified oligonucleotide comprises a 2′-O-methoxyethyl group. 
     
     
         67 . A pharmaceutical composition comprising the oligomeric compound of  claim 56  or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         68 . A method of modulating splicing of Ataxin-3 pre-mRNA in a cell comprising contacting the cell with the oligomeric compound of  claim 56 . 
     
     
         69 . The method of  claim 68 , wherein each nucleoside of the modified oligonucleotide comprises a 2′-O-methoxyethyl group. 
     
     
         70 . The method of  claim 68 , wherein the cell is in vitro. 
     
     
         71 . The method of  claim 68 , wherein the cell is in an animal. 
     
     
         72 . A method comprising administering to an animal having or at risk for developing spinocerebellar ataxia type 3 (SCA3) a therapeutically effective amount of the oligomeric compound of  claim 56 , wherein the administering reduces the number and/or volume of aggregates in brain tissue. 
     
     
         73 . The method of  claim 72 , wherein the brain tissue is selected from the group consisting of brainstem, cerebellum, and cortex. 
     
     
         74 . A pharmaceutical composition comprising:
 an oligomeric compound comprising:   a) a modified oligonucleotide consisting of 18, 19, 20, 21, or 22 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence comprising at least 18 contiguous nucleobases of any one of SEQ ID NO: 4 or 5, wherein at least one nucleoside of the modified oligonucleotide comprises a 2-O-methoxy-ethyl group;   b) a modified oligonucleotide consisting of 18, 19, 20, or 21 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence comprising at least 18 contiguous nucleobases of SEQ ID NO: 7, wherein at least one nucleoside of the modified oligonucleotide comprises a 2′-O-methoxyethyl group; or   c) a modified oligonucleotide consisting of 18, 19, or 20 linked nucleosides, wherein the oligonucleotide has a nucleobase sequence comprising at least 18 contiguous nucleobases of SEQ ID NO: 8, wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar; or   d) a salt thereof of a), b), or c); and   a pharmaceutically acceptable carrier or diluent.   
     
     
         75 . The pharmaceutical composition of  claim 74 , consisting of the modified oligonucleotide. 
     
     
         76 . The pharmaceutical composition of  claim 74 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         77 . The pharmaceutical composition of  claim 76 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         78 . The pharmaceutical composition of  claim 74 , wherein at least one nucleobase of the modified oligonucleotide is a modified nucleobase. 
     
     
         79 . The pharmaceutical composition of  claim 78 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         80 . A method of modulating splicing of Ataxin-3 pre-mRNA in a cell comprising contacting the cell with the oligomeric compound of  claim 74 . 
     
     
         81 . The method of  claim 80 , wherein the cell is in vitro. 
     
     
         82 . The method of  claim 80 , wherein the cell is in an animal. 
     
     
         83 . A method comprising administering to an animal having or at risk for developing SCA3 a therapeutically effective amount of an oligomeric compound of  claim 74 , wherein the administering reduces the number and/or volume of aggregates in brain tissue. 
     
     
         84 . The method of  claim 83 , wherein the brain tissue is selected from the group consisting of brainstem, cerebellum, and cortex.