Compounds and methods for reducing snca expression

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of SNCA mRNA in a cell or animal, and in certain instances reducing the amount of alpha-synuclein 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 of alpha-synuclein, neurodegeneration, cognitive decline and dementia. Such neurodegenerative diseases include Parkinson's disease, dementia with Lewy bodies, diffuse Lewy body disease, pure autonomic failure, multiple system atrophy, neuronopathic Gaucher's disease and Alzheimer's disease.

1 - 80 . (canceled) 
     
     
         81 . An oligomeric compound comprising a modified oligonucleotide consisting of 10-30 linked nucleosides and having a nucleobase sequence comprising at least 12 nucleobases of any of SEQ ID NOS: 28-2793. 
     
     
         82 . An oligomeric compound comprising a modified oligonucleotide consisting of 10-30 linked nucleosides and having a nucleobase sequence complementary to at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of:
 (i) an equal length portion of nucleobases 50915-50943 of SEQ ID NO: 2;   (ii) an equal length portion of nucleobases 19630-19656 of SEQ ID NO: 2;   (iii) an equal length portion of nucleobases 28451-28491 of SEQ ID NO: 2;   (iv) an equal length portion of nucleobases 48712-48760 of SEQ ID NO: 2;   (v) an equal length portion of nucleobases 23279-23315 of SEQ ID NO: 2;   (vi) an equal length portion of nucleobases 20964-21018 of SEQ ID NO: 2;   (vii) an equal length portion of nucleobases 22454-22477 of SEQ ID NO: 2;   (viii) an equal length portion of nucleobases 72294-72321 of SEQ ID NO: 2;   (ix) an equal length portion of nucleobases 20549-20581 of SEQ ID NO: 2; or   (x) an equal length portion of nucleobases 27412-27432 of SEQ ID NO: 2.   
     
     
         83 . The oligomeric compound of  claim 81 , wherein the modified oligonucleotide comprises at least one modified nucleobase. 
     
     
         84 . The oligomeric compound of  claim 83 , wherein the modified nucleobase is a 5-methyl cytosine. 
     
     
         85 . The oligomeric compound of  claim 81 , wherein the modified oligonucleotide consists of 17 or 20 linked nucleosides. 
     
     
         86 . The oligomeric compound of  claim 81 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety. 
     
     
         87 . The oligomeric compound of  claim 86 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety. 
     
     
         88 . The oligomeric compound of  claim 87 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety having a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH 2 — and —O—CH(CH 3 )—. 
     
     
         89 . The oligomeric compound of  claim 86 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety. 
     
     
         90 . The oligomeric compound of  claim 89 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety comprising a 2′-MOE modified sugar or a 2′-OMe modified sugar. 
     
     
         91 . The oligomeric compound of  claim 86 , wherein the modified oligonucleotide has a sugar motif comprising:
 a 5′-region consisting of 1-5 linked 5′-region nucleosides;   a central region consisting of 7-12 linked central region nucleosides; and   a 3′-region consisting of 1-5 linked 3′-region nucleosides;   wherein the 3′-most nucleoside of the 5′-region and the 5′-most nucleoside of the 3′-region comprise modified sugar moieties, and   each of the central region nucleosides is a 2′-β-D-deoxyribosyl sugar moiety.   
     
     
         92 . The oligomeric compound of  claim 91 , wherein
 the modified oligonucleotide consists of 17 linked nucleosides;   the central region of the modified oligonucleotide comprises at least 9 linked central region nucleosides;   the modified oligonucleotide comprises at least four bicyclic nucleosides;   each of the at least four bicyclic nucleosides comprises a bicyclic sugar moiety having a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH 2 — and —O—CH(CH 3 ).   
     
     
         93 . The oligomeric compound of  claim 81 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         94 . The oligomeric compound of  claim 93 , wherein each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         95 . The oligomeric compound of  claim 93  wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         96 . The oligomeric compound of  claim 94 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage. 
     
     
         97 . The oligomeric compound of  claim 92 , wherein each internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage. 
     
     
         98 . The oligomeric compound of  claim 81 , which consists of the modified oligonucleotide. 
     
     
         99 . The oligomeric compound of  claim 81 , wherein the oligomeric compound comprises a conjugate group comprising a conjugate moiety and a conjugate linker. 
     
     
         100 . The oligomeric compound of  claim 81  wherein the oligomeric compound is a single-stranded oligomeric compound. 
     
     
         101 . An oligomeric duplex comprising an oligomeric compound of  claim 81 . 
     
     
         102 . A population of oligomeric compounds of  claim 95 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom. 
     
     
         103 . A pharmaceutical composition comprising an oligomeric compound of  claim 81  and a pharmaceutically acceptable diluent. 
     
     
         104 . The pharmaceutical composition of  claim 103 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid. 
     
     
         105 . The pharmaceutical composition of  claim 104 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and PBS or artificial cerebrospinal fluid. 
     
     
         106 . A method comprising administering to an animal a pharmaceutical composition of  claim 103 . 
     
     
         107 . A method of treating a disease associated with SNCA comprising administering to an individual having or at risk for developing a disease associated with SNCA a therapeutically effective amount of a pharmaceutical composition of  claim 103  and thereby treating the disease associated with SNCA. 
     
     
         108 . The method of  claim 107 , wherein the disease associated with SNCA is a neurodegenerative disease. 
     
     
         109 . The method of  claim 108 , wherein the neurodegenerative disease is Parkinson's disease, dementia with Lewy bodies, diffuse Lewy body disease, pure autonomic failure, multiple system atrophy, neuronopathic Gaucher's disease, or Alzheimer's disease. 
     
     
         110 . The method of  claim 109 , wherein at least one symptom or hallmark of the neurodegenerative disease is ameliorated. 
     
     
         111 . The method of  claim 110 , wherein the symptom or hallmark is motor dysfunction, aggregation of alpha-synuclein, neurodegeneration, cognitive decline, and/or dementia.