COMPOSITIONS AND THEIR USES DIRECTED TO HUNTINGTIN

• US 20130281684A1
• Filed: 03/07/2013
• Published: 10/24/2013
• Est. Priority Date: 01/26/2006
• Status: Active Grant

• Current Assignee: Ionis Pharmaceuticals, Inc.
• Original Assignee: ISIS Pharmaceuticals Incorporated
• Inventors: Freier, Susan M.
• Granted Patent: US 8,952,145 B2
• Time in Patent Office: Days
• US Class Current: 536/24.5
• 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 (HD) progression using an antisense compound targeted to huntingtin. Additionally provided are methods of delaying or preventing the onset of Huntington'"'"'s Disease (HD) in an individual susceptible to Huntington'"'"'s Disease (HD). Also provided are uses of disclosed compounds and compositions in the manufacture of a medicament for treatment of diseases and disorders.

Claims

1. 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.

2. The antisense oligonucleotide of claim 1, wherein said antisense oligonucleotide has at least at least 95% complementarity to SEQ ID NO:

4.

3. The antisense oligonucleotide of claim 1, wherein said antisense oligonucleotide has at least at least 100% complementarity to SEQ ID NO:

4.

4. The antisense oligonucleotide of claim 1 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.

5. The antisense oligonucleotide of claim 1 comprising a chimeric oligonucleotide having a gap segment positioned between 5′

and 3′

wing segments.

6. The antisense oligonucleotide of claim 5, wherein the gap segment of the chimeric oligonucleotide is comprised of 2′

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

7. The antisense oligonucleotide of claim 6, wherein the modified sugar moiety is 2′

-OMe or a bicyclic nucleic acid.

8. The antisense oligonucleotide of claim 5, 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.

9. The antisense oligonucleotide of claim 8, wherein said antisense oligonucleotide is 20 nucleotides in length.

10. The antisense oligonucleotide of claim 1, wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

11. The antisense oligonucleotide of claim 1, wherein the each cytosine is a 5-methylcytosine.

12. The antisense oligonucleotide of claim 1, wherein said oligonucleotide is 17 to 25 nucleotides in length.

13. The antisense oligonucleotide of claim 1, wherein said oligonucleotide is 19 to 23 nucleotides in length.

14. The antisense oligonucleotide of claim 1, wherein said oligonucleotide is 20 nucleotides in length.

15. A pharmaceutical composition comprising an antisense oligonucleotide of claim 1 and a pharmaceutically acceptable diluent.

16. The antisense oligonucleotide of claim 1, wherein said nucleotide sequence is selected from the group consisting of SEQ ID NOs:

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

17. The antisense oligonucleotide of claim 16, wherein said antisense oligonucleotide has at least at least 95% complementarity to SEQ ID NO:

4.

18. The antisense oligonucleotide of claim 16, wherein said antisense oligonucleotide has at least at least 100% complementarity to SEQ ID NO:

4.

19. The antisense oligonucleotide of claim 16 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.

20. The antisense oligonucleotide of claim 16 comprising a chimeric oligonucleotide having a gap segment positioned between 5′

and 3′

wing segments.