METHODS AND COMPOSITIONS FOR TREATING HUNTINGTON'S DISEASE

• US 20150335708A1
• Filed: 05/07/2015
• Published: 11/26/2015
• Est. Priority Date: 05/08/2014
• Status: Active Grant

• Current Assignee: CHDI Foundation, Inc., Sangamo Therapeutics, Inc.
• Original Assignee: CHDI Foundation, Inc., Sangamo Biosciences, Inc.
• Inventors: Froelich, Steven, Zhang, H. Steve, Kwak, Seung, Munoz-Sanjuan, Ignacio
• Granted Patent: US 11,110,154 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/465 acting on ester bonds (3.1), e.g. lipases, ribonucleases
• CPC Class Codes: A61K 38/54 Mixtures of enzymes or proenzymes covered by more than a single one of groups A61K38/44 - A61K38/46 or A61K38/51 - A61K38/53
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/001152 Transcription factors, e.g. SOX or c-MYC
• 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: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• 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: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/71 containing domain for transcriptional activaation, e.g. VP16
• CPC Class Codes: C07K 2319/80 containing a DNA binding domain, e.g. Lacl or Tet-repressor
• CPC Class Codes: C07K 2319/81 containing a Zn-finger domain for DNA binding
• CPC Class Codes: C12N 15/62 DNA sequences coding for fusion proteins
• CPC Class Codes: C12N 15/63 Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 15/8645 Adeno-associated virus
• CPC Class Codes: C12N 2750/14121 : Viruses as such, e.g. new isolates, mutants or their genomic sequences
• CPC Class Codes: C12N 2750/14171 : Demonstrated in vivo effect

Abstract

Disclosed herein are methods and compositions for treating or preventing Huntington'"'"'s Disease.

Claims

1. A method of modifying a neuron in a subject with Huntington'"'"'s Disease (HD), the method comprising administering a repressor of a mutant Htt (mHtt) allele to the subject such that the neuron is modified.

2. The method of claim 1, wherein the neuron is an HD neuron.

3. The method of claim 1, wherein the modification comprises reducing aggregation of Htt in the neuron;

increasing energy metabolism in the neuron;

reducing susceptibility to apoptosis in the neuron and combinations thereof.

4. The method of claim 3, wherein intracellular ATP levels are increased.

5. A method of preventing or reducing the formation of Htt aggregates in an HD neuron, the method comprising modifying the HD neuron according to the method of claim 2.

6. A method of increasing cellular activity in an HD neuron, the method comprising modifying the HD neuron according to the method of claim 3.

7. A method of reducing apoptosis in an HD neuron, the method comprising modifying the HD neuron according to the method of claim 3.

8. A method for reducing motor deficits in an HD subject in need thereof, the method comprising modifying an HD neuron in the subject according to the method of claim 2.

9. The method of claim 8, wherein the motor deficit comprises clasping.

10. The method of claim 1, further comprising detecting mHtt levels in the subject.

11. The method of claim 10, wherein the mHtt levels are detected in cerebrospinal fluid (CSF).

12. The method of claim 1, wherein the repressor comprises a zinc finger protein transcription factor (ZF)-TF), a TAL-effector domain transcription factor (TALE-TF), a CRISPR/Cas-transcription factor, a zinc finger nuclease (ZFN), TAL-effector domain nuclease (TALEN) or a CRISPR/Cas nuclease system.

13. The method of claim 1, wherein the repressor is delivered to the neuron as a protein or as polynucleotide.

14. The method of claim 13, wherein the polynucleotide comprises mRNA or an expression construct selected from the group consisting of a plasmid and a viral vector.

15. The method of claim 1, wherein the repressor reduces mHtt expression by at least 85%.

16. A kit comprising an Htt repressor and reagents for detecting and/or quantifying mHtt protein levels.