Methods and compositions for the treatment of Huntington'S disease

• US 8,679,750 B2
• Filed: 05/08/2009
• Issued: 03/25/2014
• Est. Priority Date: 05/09/2008
• Status: Active Grant

• Current Assignee: University of British Columbia
• Original Assignee: University of British Columbia
• Inventors: Hayden, Michael, Carroll, Jeffrey, Warby, Simon
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US12/991,883
• Publication Number:
  US 20110213010A1
• Time in Patent Office: 1,782 Days
• Field of Search: None
• US Class Current: 435/6.1
• 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 15/111 General methods applicable to biologically active non-coding nucleic acids
• 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 2310/14 interfering N.A.
• CPC Class Codes: C12N 2320/34 Allele or polymorphism specific uses
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: G01N 2800/2835 Movement disorders, e.g. Parkinson, Huntington, Tourette
• CPC Class Codes: G01N 33/5023 on expression patterns

Abstract

Methods and compositions for reducing expression of a mutant huntingtin (mHTT) protein in a cell are provided. Such methods include contacting the cell with an effective amount of a nucleic acid silencing agent targeting a differentiating polymorphism in RNA encoding the mHTT.

Claims

1. A method of selecting a nucleic acid silencing agent targeting a differentiating polymorphism in RNA encoding an mHTT protein of a subject, comprising:

a. obtaining a nucleic acid sample from the subject;

b. identifying a differentiating polymorphism in the nucleic acid sample, the differentiating polymorphism is a single nucleotide polymorphism (SNP) identified by RefSNP number rs7685686; and

c. selecting a nucleic acid silencing agent comprising a sequence that preferentially targets the differentiating polymorphism in the RNA encoding an mHTT protein.

3. The method of claim 1 wherein the nucleic acid silencing agent is an oligonucleotide.

4. The method of claim 3 wherein the oligonucleotide comprises a nucleic acid sequence derived from SEQ ID NO:

61.

5. The method of claim 3 wherein the oligonucleotide comprises a nucleic acid sequence selected from the group consisting of a reverse complement of SEQ ID NO:

61, SEQ ID NOs;

128, 255 and 323, and SEQ ID NO;

128 comprising thymines (T) in place of uracils (U).

2. A method of screening for a nucleic acid silencing agent targeting a differentiating polymorphism in RNA encoding an mHTT protein in a subject, comprising:

a. providing a cell heterozygous for a differentiating polymorphism in a nucleic acid sequence encoding huntingtin (HTT), the differentiating polymorphism is a single nucleotide polymorphism (SNP) identified by RefSNP number rs7685686;

b. contacting the cell with one or more candidate nucleic acid silencing agents targeting the differentiating polymorphism;

c. assaying the cell for HTT and mHTT RNA, protein or RNA and protein expression; and

d. determining the one or more nucleic acid silencing agents from the candidate nucleic acid silencing agents.

6. The method of claim 2 wherein the nucleic acid silencing agent is an oligonucleotide.

7. The method of claim 6 wherein the oligonucleotide comprises a nucleic acid sequence derived from SEQ ID NO:

61.

8. The method of claim 6 wherein the oligonucleotide comprises a nucleic acid sequence selected from the group consisting of a reverse complement of SEQ ID NO:

61, SEQ ID NOs;

128, 255 and 323, and SEQ ID NO;

128 comprising thymines in place of uracils.