COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN

• US 20160053256A1
• Filed: 05/11/2015
• Published: 02/25/2016
• Est. Priority Date: 01/26/2006
• Status: Abandoned Application

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: CHDI Foundation, Inc., ISIS Pharmaceuticals Incorporated
• Inventors: Hung, Gene, Bennett, C. Frank, Freier, Susan M., Leeds, Janet M.
• Application Number:
  US14/708,511
• Publication Number:
  US 20160053256A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/111 spanning the whole gene, or a large part of it
• CPC Class Codes: C12N 2310/31 of the backbone
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/32 of the sugar
• CPC Class Codes: C12N 2310/321 2'-O-R Modification
• CPC Class Codes: C12N 2310/322 2'-R Modification
• CPC Class Codes: C12N 2310/323 modified ring structure
• CPC Class Codes: C12N 2310/3231 having an additional ring, e.g. LNA, ENA
• CPC Class Codes: C12N 2310/33 of the base
• CPC Class Codes: C12N 2310/3341 5-Methylcytosine
• CPC Class Codes: C12N 2310/335 Modified T or U
• CPC Class Codes: C12N 2310/341 Gapmers, i.e. of the type ===---===
• CPC Class Codes: C12N 2310/346 having a combination of backbone and sugar modifications
• CPC Class Codes: C12N 2310/3525 MOE, methoxyethoxy
• CPC Class Codes: C12N 2320/30 Special therapeutic applications

Abstract

Disclosed herein are compounds, compositions and methods for modulating the expression of huntingtin in a cell, tissue or animal. Further provided are methods of slowing or preventing Huntington'"'"'s disease progression using an antisense compound targeted to huntingtin. Additionally provided are methods of delaying or preventing the onset of Huntingtin'"'"'s disease in an individual susceptible to Huntingtin'"'"'s Disease. Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders.

Claims

1-25. -25. (canceled)

26. A compound comprising a single-stranded modified oligonucleotide consisting of 12 to 35 linked nucleosides, wherein at least 12 consecutive nucleobases of said modified oligonucleotide are at least 90% complementary within nucleobases 193-215 of SEQ ID NO.:

4.

27. The compound of claim 26, wherein the modified oligonucleotide is at least 95% complementary within nucleobases 193-215 of SEQ ID NO.:

4.

28. The compound of claim 26, wherein the modified oligonucleotide is 100% complementary within nucleobases 193-215 of SEQ ID NO.:

4.

29. The method of claim 26, wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage.

30. The method of claim 29, wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphorothioate internucleoside linkage.

31. The method of claim 26, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

32. The method of claim 26, wherein at least one nucleoside comprises a modified sugar.

33. The method of claim 32, wherein at least one modified sugar is a bicyclic sugar.

34. The method of claim 32, wherein at least one modified sugar comprises a 2′

-O-methoxyethyl moiety.

35. The method of claim 26, wherein at least one nucleoside comprises a modified nucleobase.

36. The method of claim 35, wherein the modified nucleobase is a 5-methylcytosine.

37. The method of claim 26, wherein the modified oligonucleotide comprises:

a gap segment consisting of linked deoxynucleosides;

a 5′

wing segment consisting of linked nucleosides;

a 3′

wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

38. The method of claim 37, wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked deoxynucleosides;

a 5′

wing segment consisting of five linked nucleosides;

a 3′

wing segment consisting of five linked nucleosides;

wherein the gap segment is positioned between the 5′

wing segment and the 3′

wing segment, wherein each nucleoside of each wing segment comprises a 2′

-O-methoxyethyl sugar; and

wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.

39. The method of claim 38, wherein the modified oligonucleotide consists of 20 linked nucleosides.

40. The method of claim 26, wherein said modified oligonucleotide consists of 17 to 25 linked nucleosides.

41. The method of claim 26, wherein said modified oligonucleotide consists of 19 to 23 linked nucleosides.

42. The compound of method of claim 26, wherein said modified oligonucleotide consists of 20 linked nucleosides.

43. The compound of claim 26, wherein the 5′

nucleotide of the modified oligonucleotide is T.

44. The compound of claim 26, wherein the 5′

nucleotide of the modified oligonucleotide is C.

45. A composition comprising a compound of claim 26 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.