IP Library › Granted Patent US 12,188,020
Granted Patent B2
US 12,188,020 · App. 17/323,826 · Granted Jan 7, 2025

Methods for reducing Ataxin-2 expression

Inventor: Frank Rigo (Carlsbad, CA)
Assignee: Ionis Pharmaceuticals, Inc.
C12N15/1138A61K31/7088A61P25/28C12N5/0619C12N15/113A01K2227/105A01K2267/0318C12N2310/11C12N2310/315C12N2310/3233C12N2510/00
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Quick Facts
Patent No.
US 12,188,020
App. No.
17/323,826
Granted
Jan 7, 2025
Kind
B2
Abstract

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 CMAP amplitude, denervation, and loss of motor neurons.

Claims (51)

1. A method comprising administering to an animal having ALS an oligomeric compound comprising a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the nucleobase sequence of an Ataxin-2 nucleic acid, wherein the animal has ALS associated with a SOD1 or TDP43 mutation, and wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides; the animal does not have a polyglutamine (polyQ) expansion in the Ataxin-2 protein; and the administering results in amelioration of at least one symptom of ALS.

2. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an Ataxin-2 nucleic acid having the nucleobase sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

3. The method of claim 1 , wherein the oligomeric compound is administered prior to detection of the at least one symptom.

4. The method of claim 1 , wherein the at least one symptom of ALS is loss of motor function, reduced CMAP amplitude, denervation, or loss of motor neurons.

5. The method of claim 1 , wherein the amelioration of at least one symptom of ALS results in slowing of progression of at least one symptom, delaying onset of at least one symptom, or reducing severity or frequency of at least one symptom.

6. The method of claim 1 , wherein the amount of Ataxin-2 mRNA and/or Ataxin-2 protein is reduced in the animal following administration of the oligomeric compound.

7. The method of claim 1 , wherein the oligomeric compound is single-stranded.

8. The method of claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety, at least one modified nucleoside comprising a non-bicyclic sugar moiety, or at least one modified nucleoside comprising a sugar surrogate.

9. The method of claim 8 , wherein the bicyclic sugar moiety has 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 )—.

10. The method of claim 8 , wherein the non-bicyclic sugar moiety comprises a 2′-MOE or 2′-OMe.

11. The method of claim 8 , wherein the sugar surrogate is selected from a morpholino, a PNA, a F-HNA, a THP, or a modified THP.

12. The method of claim 1 , 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 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.

13. The method of claim 1 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

14. The method of claim 1 , wherein each internucleoside linkage is either an unmodified phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

15. The method of claim 1 , wherein the modified oligonucleotide comprises at least one 5-methylcytosine.

16. The method of claim 1 , wherein the oligomeric compound comprises a conjugate group.

17. The method of claim 1 , wherein the oligomeric compound is paired with a second oligomeric compound to form a duplex.

18. The method of claim 1 , wherein the administering is to the central nervous system.

19. The method of claim 18 , wherein the administering is intrathecal administration or intracerebroventricular administration.

20. The method of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% or is 100% complementary to an Ataxin-2 nucleic acid having the nucleobase sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

21. The method of claim 1 , wherein the animal does not have a CAG expansion in the ATXN2 gene of more than 22 repeats.

22. A method comprising identifying an animal having ALS and administering to the animal having ALS an oligomeric compound comprising a modified oligonucleotide, wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to the nucleobase sequence of an Ataxin-2 nucleic acid, wherein the animal has ALS associated with a SOD1 or TDP43 mutation, and wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides; the animal does not have a polyglutamine (polyQ) expansion in the Ataxin-2 protein; and the administering results in amelioration of at least one symptom of ALS.

23. The method of claim 22 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an Ataxin-2 nucleic acid having the nucleobase sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

24. The method of claim 22 , wherein the oligomeric compound is administered prior to detection of the at least one symptom.

25. The method of claim 22 , wherein the at least one symptom of ALS is loss of motor function, reduced CMAP amplitude, denervation, or loss of motor neurons.

26. The method of claim 22 , wherein the amelioration of at least one symptom of ALS results in slowing of progression of at least one symptom, delaying onset of at least one symptom, or reducing severity or frequency of at least one symptom.

27. The method of claim 22 , wherein the amount of Ataxin-2 mRNA and/or Ataxin-2 protein is reduced in the animal following administration of the oligomeric compound.

28. The method of claim 22 , wherein the oligomeric compound is single-stranded.

29. The method of claim 22 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety, at least one modified nucleoside comprising a non-bicyclic sugar moiety, or at least one modified nucleoside comprising a sugar surrogate.

30. The method of claim 29 , wherein the bicyclic sugar moiety has 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 )—.

31. The method of claim 29 , wherein the non-bicyclic sugar moiety comprises a 2′-MOE or 2′-OMe.

32. The method of claim 29 , wherein the sugar surrogate is selected from a morpholino, a PNA, a F-HNA, a THP, or a modified THP.

33. The method of claim 22 , 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 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.

34. The method of claim 22 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

35. The method of claim 22 , wherein each internucleoside linkage is either an unmodified phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage.

36. The method of claim 22 , wherein the modified oligonucleotide comprises at least one 5-methylcytosine.

37. The method of claim 22 , wherein the oligomeric compound comprises a conjugate group.

38. The method of claim 22 , wherein the oligomeric compound is paired with a second oligomeric compound to form a duplex.

39. The method of claim 22 , wherein the administering is to the central nervous system.

40. The method of claim 39 , wherein the administering is intrathecal administration or intracerebroventricular administration.

41. The method of claim 22 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% or is 100% complementary to an Ataxin-2 nucleic acid having the nucleobase sequence of SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

42. The method of claim 22 , wherein the animal does not have a CAG expansion in the ATXN2 gene of more than 22 repeats.

43. A method of reducing Ataxin 2 RNA in an animal, comprising administering to the animal an oligomeric compound wherein the oligomeric compound comprises a modified oligonucleotide, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides, and wherein the modified oligonucleotide has a nucleobase sequence comprising at least 12 contiguous nucleobases of any one of SEQ ID NOS: 14-45.

44. The method of claim 1 , wherein the animal is a human.

45. The method of claim 22 , wherein the animal is a human.

Continuity (3)
Continuation 16063852
Provisional Application 62273689 · Dec 31, 2015
Related Publication 20220162615A1 · May 26, 2022
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