Oligonucleotides for modulating ATXN2 expression
The present invention relates to antisense oligonucleotides that are capable of modulating expression of ATXN2 in a target cell. The oligonucleotides hybridize to ATXN2 mRNA. The present invention further relates to conjugates of the oligonucleotide and pharmaceutical compositions and methods for treatment of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), Alzheimer's frontotemporal dementia (FTD), parkinsonism and conditions with TDP-43 proteinopathies using the oligonucleotide.
1. An antisense oligonucleotide having the sequence:
ATTTtactttaaccTCC (SEQ ID NO: 7)
wherein capital letters are beta-D-oxy LNA nucleosides, lowercase letters are DNA nucleosides, all LNA C are 5-methyl cytosine, all internucleoside linkages are phosphorothioate internucleoside linkages.
2. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide is of formula
or a pharmaceutically acceptable salt thereof.
3. The antisense oligonucleotide according to claim 2 , wherein the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
4. The antisense oligonucleotide according to claim 2 , wherein the antisense oligonucleotide is in the form of a pharmaceutically acceptable sodium salt.
5. The antisense oligonucleotide according to claim 2 , wherein the antisense oligonucleotide is in the form of a pharmaceutically acceptable potassium salt.
6. The antisense oligonucleotide according to claim 1 , wherein the antisense oligonucleotide is in the form of a pharmaceutically acceptable salt.
7. The antisense oligonucleotide according to claim 1 , wherein the antisense oligonucleotide is in the form of a pharmaceutically acceptable sodium salt.
8. The antisense oligonucleotide according to claim 1 , wherein the antisense oligonucleotide is in the form of a pharmaceutically acceptable potassium salt.
9. A conjugate comprising the antisense oligonucleotide according to any one of claims 1 - 5 and at least one conjugate moiety covalently attached to the oligonucleotide.
10. A pharmaceutical composition comprising the conjugate of claim 9 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
11. The pharmaceutical composition according to claim 10 , wherein the composition comprises sterile phosphate buffered saline.
12. The pharmaceutical composition according to claim 10 , wherein the oligonucleotide is present at 1-100 mg/mL.
13. The pharmaceutical composition according to claim 10 , wherein the oligonucleotide is present at 2-30 mg/mL.
14. A pharmaceutical composition comprising the antisense oligonucleotide of any one of claims 1 - 5 and a pharmaceutically acceptable diluent, solvent, carrier, salt and/or adjuvant.
15. The pharmaceutical composition according to claim 14 , wherein the composition comprises sterile phosphate buffered saline.
16. The pharmaceutical composition according to claim 14 , wherein the oligonucleotide is present at 1-100 mg/mL.
17. The pharmaceutical composition according to claim 14 , wherein the oligonucleotide is present at 2-30 mg/mL.
18. A method for treating a neurodegenerative disease selected from the group consisting of spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), Alzheimer's, frontotemporal dementia (FTD), parkinsonism and conditions with TDP-43 proteinopathies, the method comprising administering the pharmaceutical composition of claim 14 to a subject in need thereof.
19. The method of claim 18 , wherein the neurodegenerative disease is spinocerebellar ataxia type 2 (SCA2).
20. The method of claim 18 , wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).
21. A method for treating a neurodegenerative disease selected from the group consisting of spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS), Alzheimer's, frontotemporal dementia (FTD), parkinsonism and conditions with TDP-43 proteinopathies, the method comprising administering the pharmaceutical composition of claim 10 to a subject in need thereof.
22. The method of claim 21 , wherein the neurodegenerative disease is spinocerebellar ataxia type 2 (SCA2).
23. The method of claim 21 , wherein the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).