METHODS FOR REDUCING ATAXIN-2 EXPRESSION
Provided herein are methods for decreasing Ataxin-2 mRNA expression. Such methods are useful to ameliorate symptoms of Ataxin-2 associated diseases. Such Ataxin-2 associated diseases include amyotrophic lateral sclerosis (ALS). Such symptoms include loss of motor function, reduced compound muscle action potential (CMAP) amplitude, denervation, and loss of motor neurons. Specifically, the methods comprising administering to an animal having ALS an oligomenc compound comprising a modified oligonucleotide, wherein the modified oligonucleotide has a nucleobase sequence that is complementary to an Ataxin-2 nucleic acid.
1 . A method comprising administering to an animal having ALS an oligomeric compound comprising a modified oligonucleotide, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, and wherein the modified oligonucleotide has a nucleobase sequence that is complementary to an Ataxin-2 nucleic acid.
2 . A method comprising identifying an animal having ALS and administering to the animal having ALS an oligomeric compound comprising a modified oligonucleotide, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, and wherein the modified oligonucleotide has a nucleobase sequence that is complementary to the nucleobase sequence of an Ataxin-2 nucleic acid.
3 . The method of claim 1 or 2 , wherein the modified oligonucleotide has a nucleobase sequence that is at least 90% complementary to the Ataxin-2 nucleic acid.
4 . The method of claim 1 or 2 , wherein the modified oligonucleotide has a nucleobase sequence that is at least 95% complementary to the Ataxin-2 nucleic acid.
5 . The method of claim 1 or 2 , wherein the modified oligonucleotide has a nucleobase sequence that is 100% complementary to the Ataxin-2 nucleic acid.
6 . The method of any of claims 1 - 5 wherein the administering results in amelioration of at least one symptom of ALS.
7 . The method of any of claims 1 - 6 wherein the oligomeric compound is administered prior to the detection of the at least one symptom.
8 . The method of claim 6 or 7 , wherein the at least one symptom of ALS is loss of motor function, reduced CMAP amplitude, denervation, and loss of motor neurons.
9 . The method of any of claims 6 - 8 , wherein the amelioration is the slowing of progression of at least one symptom.
10 . The method of any of claims 6 - 9 , wherein the amelioration is the delay of onset of at least one symptom.
11 . The method of any of claims 6 - 10 , wherein the amelioration is the reduction of severity of at least one symptom.
12 . The method of any of claims 6 - 11 , wherein the amelioration is the reduction of frequency of at least one symptom.
13 . The method of any of claims 1 - 12 , wherein expression of Ataxin-2 mRNA is reduced in the animal.
14 . The method of any of claims 1 - 13 , wherein the amount of Ataxin-2 protein is reduced in the animal.
15 . The method of any of claims 1 - 14 , wherein the animal is a human.
16 . The method of any of claims 1 - 15 , wherein the nucleobase sequence of Ataxin-2 nucleic acid is SEQ ID NO: 3, the complement of SEQ ID NO: 4, or SEQ ID NO: 5.
17 . The method of any of claims 1 - 16 , wherein the oligomeric compound is single-stranded.
18 . The method of any of claim 1 - 17 , wherein the modified oligonucleotide comprises at least one modified nucleoside.
19 . The method of claim 18 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.
20 . The method of claim 19 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.
21 . The method of claim 20 , 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 —; —O—CH 2 —CH 2 ; and —O—CH(CH 3 )—.
22 . The method of any of claims 18 - 21 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified non-bicyclic sugar moiety.
23 . The method of claim 22 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic sugar moiety comprising a 2′-MOE or 2′-OMe.
24 . The method of any of claims 18 - 23 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.
25 . The method of claim 24 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate selected from a morpholino, a PNA, a F-HNA, a THP, or a modified THP.
26 . The method of any of claims 1 - 25 , wherein the modified oligonucleotide has a sugar motif comprising:
a 5′-region consisting of 1-5 linked 5′-nucleosides;
a central region consisting of 6-10 linked central region nucleosides; and
a 3′-region consisting of 1-5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety.
27 . The method of any of claims 1 - 26 , wherein the modified oligonucleotide comprises at least one modified intemucleoside linkage.
28 . The method of claim 27 , wherein each intemucleoside linkage of the modified oligonucleotide is a modified intemucleoside linkage.
29 . The method of claim 27 or 28 , wherein at least one intemucleoside linkage is a phosphorothioate intemucleoside linkage.
30 . The method of claim 27 or 29 , wherein the modified oligonucleotide comprises at least one unmodified phosphodiester intemucleoside linkage.
31 . The method of claim 27 , wherein each intemucleoside linkage is either an unmodified phosphodiester intemucleoside linkage or a phosphorothioate intemucleoside linkage.
32 . The method of any of claim 28 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
33 . The method of any of claims 1 - 32 , wherein the modified oligonucleotide comprises at least one modified nucleobase.
34 . The method of claim 33 , wherein the modified nucleobase is a 5-methylcytosine.
35 . The method of any of claims 1 - 34 , wherein each nucleobase of each nucleoside of the modified oligonucleotide is either an unmodified nucleobase or is a 5-methylcytosine.
36 . The method of any of claims 1 - 35 wherein the oligomeric compound comprises a conjugate group.
37 . The method of any of claims 1 - 16 or 18 - 36 , wherein the oligomeric compound is paired with a second oligomeric compound to form a duplex.