Compounds and Methods for Reducing ATXN3 Expression
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.