Compounds and Methods for Reducing ATXN3 Expression

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN3 RNA in a cell or animal, and in certain embodiments reducing the amount of ATXN3 protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include motor dysfunction, aggregation formation, and neuron death. Such neurodegenerative diseases include spinocerebellar ataxia type 3 (SCA3).

1 .- 77 . (canceled) 
     
     
         78 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         79 . The modified oligonucleotide of  claim 78 , which is the sodium salt or the potassium salt. 
     
     
         80 . A modified oligonucleotide according to the following chemical structure: 
       
         
           
           
               
               
           
         
       
     
     
         81 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation (5′ to 3′): Ges  m Ceo Aeo  m Ceo  m Ces Ads Tds Ads Tds Ads Tds Ads Tds  m Cds Tds  m Ceo Aeo Ges Aes Ae (SEQ ID NO: 1226), wherein,
 A=an adenine nucleobase, 
   m C=a 5-methylcytosine nucleobase, 
 G=a guanine nucleobase, 
 T=a thymine nucleobase, 
 e=a 2′-MOE sugar moiety, 
 d=a 2′-β-D deoxyribosyl sugar moiety, 
 s=a phosphorothioate internucleoside linkage, and 
 o=a phosphodiester internucleoside linkage. 
 
     
     
         82 . A population of modified oligonucleotides of  claim 78 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         83 . A population of modified oligonucleotides of  claim 79 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         84 . A population of modified oligonucleotides of  claim 80 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         85 . A population of oligomeric compounds of  claim 81 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         86 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 78  and a pharmaceutically acceptable diluent. 
     
     
         87 . The pharmaceutical composition of  claim 86 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid. 
     
     
         88 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid. 
     
     
         89 . The pharmaceutical composition of  claim 87 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS. 
     
     
         90 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 79  and a pharmaceutically acceptable diluent. 
     
     
         91 . The pharmaceutical composition of  claim 90 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid. 
     
     
         92 . The pharmaceutical composition of  claim 91 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid. 
     
     
         93 . The pharmaceutical composition of  claim 91 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS. 
     
     
         94 . A pharmaceutical composition comprising the modified oligonucleotide of  claim 80  and a pharmaceutically acceptable diluent. 
     
     
         95 . The pharmaceutical composition of  claim 94 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid. 
     
     
         96 . The pharmaceutical composition of  claim 95 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid. 
     
     
         97 . The pharmaceutical composition of  claim 95 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS. 
     
     
         98 . A pharmaceutical composition comprising the oligomeric compound of  claim 81  and a pharmaceutically acceptable diluent. 
     
     
         99 . The pharmaceutical composition of  claim 98 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid. 
     
     
         100 . The pharmaceutical composition of  claim 99 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and artificial cerebrospinal fluid. 
     
     
         101 . The pharmaceutical composition of  claim 99 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and PBS. 
     
     
         102 . A pharmaceutical composition comprising the population of modified oligonucleotides of  claim 82  and a pharmaceutically acceptable diluent. 
     
     
         103 . A pharmaceutical composition comprising the population of modified oligonucleotides of  claim 83  and a pharmaceutically acceptable diluent. 
     
     
         104 . A pharmaceutical composition comprising the population of modified oligonucleotides of  claim 84  and a pharmaceutically acceptable diluent. 
     
     
         105 . A pharmaceutical composition comprising the population of oligomeric compounds of  claim 85  and a pharmaceutically acceptable diluent. 
     
     
         106 . A method comprising administering to a subject a pharmaceutical composition of  claim 86 . 
     
     
         107 . The method of  claim 106 , wherein the subject has or is at risk for developing a disease associated with ATXN3. 
     
     
         108 . A method of treating a disease associated with ATXN3, comprising administering to a subject having or at risk for developing a disease associated with ATXN3 a therapeutically effective amount of a pharmaceutical composition according to  claim 86  and thereby treating the disease associated with ATXN3. 
     
     
         109 . The method of  claim 108 , wherein the disease associated with ATXN3 is a neurodegenerative disease. 
     
     
         110 . The method of  claim 109 , wherein the neurodegenerative disease is SCA3. 
     
     
         111 . The method of  claim 109 , wherein at least one symptom or hallmark of the neurodegenerative disease is ameliorated. 
     
     
         112 . The method of  claim 111 , wherein the symptom or hallmark is any of ataxia, neuropathy, and aggregate formation. 
     
     
         113 . The method of  claim 108 , wherein the subject is human. 
     
     
         114 . A method of reducing expression of ATXN3 in a cell comprising contacting the cell with a modified oligonucleotide of  claim 78 . 
     
     
         115 . The method of  claim 114 , wherein the cell is a human cell.