Compounds and methods for modulating ATXN1

11542,504

17/751450

May 23, 2022

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN1 RNA in a cell or subject, and in certain instances reducing the amount of ATXN1 in a cell or subject. 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 gait and limb ataxia, cognitive impairments, difficulty with speaking and swallowing, atrophy of the cerebellum and brainstem in magnetic resonance imaging (MRI), neurochemical abnormalities in the cerebellum and brainstem detected via magnetic resonance spectroscopy (MRS), and death within 10-15 years of symptom onset. Such neurodegenerative diseases include Spinocerebellar ataxia type 1.

Ionis Pharmaceuticals, Inc. (Carlsbad, CA, US)

Ionis Pharmaceuticals, Inc. (Carlsbad, CA, US)

1. A modified oligonucleotide according to the following chemical structure: [chemical expression included] [chemical expression included] [chemical expression included] salt thereof.

2. The modified oligonucleotide of claim 1 , which is the sodium salt or the potassium salt.

3. A modified oligonucleotide according to the following chemical structure: [chemical expression included]

4. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: m Ces m Ceo m Ceo Geo Tes Ads Tds Tds m Cds m Cds Tds m Cds Tds Tds Ads m Ceo m Ceo Aes Tes m Ce (SEQ ID NO: 3590), 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.

5. A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

6. A population of modified oligonucleotides of claim 2 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

7. A population of modified oligonucleotides of claim 3 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

8. A population of oligomeric compounds of claim 4 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.

9. A pharmaceutical composition comprising the modified oligonucleotide of claim 1 , and a pharmaceutically acceptable diluent.

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.

11. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

12. The pharmaceutical composition of claim 10 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.

13. A pharmaceutical composition comprising the modified oligonucleotide of claim 2 , and a pharmaceutically acceptable diluent.

14. The pharmaceutical composition of claim 13 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.

15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

16. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.

17. A pharmaceutical composition comprising the modified oligonucleotide of claim 3 , and a pharmaceutically acceptable diluent.

18. The pharmaceutical composition of claim 17 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.

19. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.

20. The pharmaceutical composition of claim 18 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.

21. A pharmaceutical composition comprising the oligomeric compound of claim 4 , and a pharmaceutically acceptable diluent.

22. The pharmaceutical composition of claim 21 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.

23. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and artificial cerebrospinal fluid.

24. The pharmaceutical composition of claim 22 , wherein the pharmaceutical composition consists essentially of the oligomeric compound and PBS.

25. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 5 , and a pharmaceutically acceptable diluent.

26. The pharmaceutical composition of claim 25 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.

27. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 7 , and a pharmaceutically acceptable diluent.

28. The pharmaceutical composition of claim 27 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.

29. A pharmaceutical composition comprising the population of oligomeric compounds of claim 8 , and a pharmaceutically acceptable diluent.

30. The pharmaceutical composition of claim 29 , wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.

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