COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN

• US 20070299027A1
• Filed: 01/26/2007
• Published: 12/27/2007
• Est. Priority Date: 01/26/2006
• Status: Abandoned Application

• Current Assignee: CHDI Foundation, Inc., ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Original Assignee: ISIS Pharmaceuticals Incorporated (Ionis Pharmaceuticals, Inc.)
• Inventors: Hung, Gene, Leeds, Janet
• Application Number:
  US11/627,921
• Publication Number:
  US 20070299027A1
• Time in Patent Office: Days
• US Class Current: 514/44.00A
• 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. A method of treating an individual at risk of suffering from or currently suffering from Huntington'"'"'s Disease (HD) comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising an antisense compound 12 to 35 nucleobases in length having at least 90% complementarity to nucleotides 1650-1704, 1807-1874, 3183-3228, 4010-4087, 4265-4288, 4553-4608, 5781-5820, and 6793-6796 of SEQ ID NO:

4;

wherein said administration treats said individual.

2. The method of claim 1, wherein said administering comprises intrathecal delivery, intracerebroventricular delivery, or intraparenchymall delivery.

3. The method of claim 2, wherein the administering comprises administration into the cerebrospinal fluid of the individual by intrathecal infusion.

4. The method of claim 1, wherein said treatment comprises improvement in one or more indicators of HD.

5. The method of claim 1, wherein said treatment comprises increasing the survival time of the individual.

6. The method of claim 1, wherein said treatment comprises delaying the onset of HD.

7. The method of claim 1, wherein said antisense compound has at least at least 95% complementarity to nucleotides 1650-1704, 1807-1874, 3183-3228, 4010-4087, 4265-4288, 4553-4608, 5781-5820, and 6793-6796 of SEQ ID NO:

4.

8. The method of claim 1, wherein said antisense compound has 100% complementarity to nucleotides 1650-1704, 1807-1874, 3183-3228, 4010-4087, 4265-4288, 4553-4608, 5781-5820, and 6793-6796 of SEQ ID NO:

4.

9. The method of claim 1, wherein said antisense compound is an antisense oligonucleotide.

10. The method of claim 9, wherein said antisense oligonucleotide has at least one modified internucleoside linkage, sugar moiety, or nucleobase.

11. The method of claim 10, wherein said oligonucleotide comprises a chimeric oligonucleotide having a gap segment positioned between 5′

and 3′

wing segments.

12. The method of claim 10, wherein said gap segment of the chimeric oligonucleotide is comprised of 2′

-deoxynucleotides and the wing segments are comprised of nucleotides having modified sugar moieties.

13. The method of claim 12, wherein the modified sugar moiety is 2′

-OMe or a bicyclic nucleic acid.

14. The method of claim 13, wherein the gap segment of the chimeric oligonucleotide consists of ten 2′

-deoxynucleotides and each wing segment consists of five 2′

-O-methoxyethyl-modified nucleotides.

15. The method of claim 9, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

16. The method of claim 9, wherein each cytosine is a 5-methylcytosine.

17. The method of claim 1, comprising 17 to 25 nucleotides.

18. The method of claim 1, comprising 19 to 23 nucleotides.

19. The method of claim 1, comprising 20 nucleotides.

20. The method of claim 1, further comprising selecting an individual suffering from HD.

21. The method of claim 1, further comprising selecting an individual susceptible to HD.

22. A method of treating an individual at risk of suffering from or currently suffering from Huntington'"'"'s Disease (HD) comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising an antisense oligonucleotide 12 to 35 nucleotides in length comprising at least 12 consecutive nucleotides of a nucleotide sequence selected from the group consisting of SEQ ID NOs 46-357.

23. The method of claim 22, wherein said nucleotide sequence is selected from the group consisting of SEQ ID NOs:

50, 93, 100, 105, 110, 125, 137, 345, 346, and 353.