Methods and compositions for treating trinucleotide repeat disorders

• US 10,646,543 B2
• Filed: 03/09/2018
• Issued: 05/12/2020
• Est. Priority Date: 07/28/2009
• Status: Active Grant

• Current Assignee: Sangamo Therapeutics, Inc.
• Original Assignee: Sangamo Therapeutics, Inc.
• Inventors: Gregory, Philip D., Rebar, Edward J., Zhang, H. Steve
• Primary Examiner(s): Emch, Gregory S
• Application Number:
  US15/916,719
• Publication Number:
  US 20180200332A1
• Time in Patent Office: 795 Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/71 containing domain for transcriptional activaation, e.g. VP16
• CPC Class Codes: C07K 2319/81 containing a Zn-finger domain for DNA binding
• CPC Class Codes: C12N 15/907 in mammalian cells

Abstract

Disclosed herein are methods and compositions for treating trinucleotide repeat disorders.

Claims

1. A method of repressing Htt expression in a cell, the method comprising providing a non-naturally occurring transcription factor that represses expression of an Htt gene, wherein the transcription factor comprises a repression domain and a zinc finger DNA-binding domain that binds to a target site of at least 9 nucleotides of the target sites as set forth in any of SEQ ID NO:

20-23 and 36-39, wherein the zinc finger DNA-binding domain comprises a zinc finger protein that comprises 5 or 6 zinc finger recognition regions, ordered F1 to F5 or F1 to F6 from N-terminus to C-terminus, wherein the zinc finger protein comprises the recognition regions in the order shown in a single row of Table 1.

2. The method of claim 1, wherein the Htt gene is wild-type.

3. The method of claim 2, wherein the DNA-binding domain binds to a SNP associated with a wild-type allele.

4. The method of claim 1, wherein the Htt gene comprises one or more expanded trinucleotide repeats.

5. The method of claim 4, wherein the expanded trinucleotide repeat encodes poly-glutamine.

6. The method of claim 4, wherein the expanded trinucleotide repeat encodes poly-serine.

7. The method of claim 4, wherein the DNA-binding domain binds to a SNP associated with the expanded trinucleotide repeat.

8. The method of claim 1, comprising providing a multimer comprising at least two zinc finger proteins that preferentially binds to expanded trinucleotide tracts as compared to wild-type trinucleotide repeat tracts.

9. The method of claim 1, wherein the non-naturally occurring transcription factor is provided as a polynucleotide encoding the protein.

10. The method of claim 9, wherein the polynucleotide is a viral or non-viral vector.

11. A method of treating Huntington'"'"'s disease in a subject in need thereof, the method comprising repressing Htt expression in a cell of the subject according to the method of claim 1.