Methods and products for increasing frataxin levels and uses thereof

Patent metadata

Field	Value
Publication number	US-9708414-B2
Application number	US-201214358156-A
Country	US
Kind code	B2
Filing date	Nov 16, 2012
Priority date	Nov 18, 2011
Publication date	Jul 18, 2017
Grant date	Jul 18, 2017

Abstract

Methods and products (e.g., recombinant proteins) are described for increasing frataxin expression/levels in a cell, as well as uses of such methods and products, for example for the treatment of Friedreich ataxia in a subject suffering therefrom.

First claim

The invention claimed is:

1. A transcription activator-like (TAL) effector-based recombinant protein comprising:
i) a TAL effector domain comprising a repeat variable domain (RVD) comprising at least 10 tandem repeat monomers, each monomer consisting of an HD, NG, NN or NI module, wherein said RVD comprises the following configuration of said HD, NG, NN and NI modules:
a) NI-NN-NG-NN-HD-NG-NI-NI-NN-HD-NG-NN;
b) NN-NN-NN-NI-NI-NN-NG-NG-HD-NG-NG-HD-HD; or
c) HD-HD-NG-NN-NI-NN-NN-NG-HD-NG-NI-NI,
wherein said HD module consists of 34 contiguous amino acids of the amino acid sequence of SEQ ID NO: 61; said NG module consists of 34 contiguous amino acids of the amino acid sequence of SEQ ID NO: 59, said NI module consists of 34 contiguous amino acids of the amino acid sequence of SEQ ID NO: 57, and said NN module consists of 34 contiguous amino acids of the amino acid sequence of SEQ ID NO: 63; and
wherein said configuration of modules binds to a sequence within nucleotides 81-116 of SEQ ID NO: 88 of the promoter sequence of a mammalian frataxin gene;

ii) a nuclear localization signal; and
iii) a transcription activation domain.

2. The recombinant protein of claim 1 , wherein said transcription activation domain is a VP64 synthetic transcription activation domain.

3. The recombinant protein of claim 1 , wherein said nuclear localization signal is a mammalian nuclear localization signal derived from the simian virus 40 large T antigen.

4. A composition comprising the recombinant protein of claim 1 and a pharmaceutically acceptable carrier.

5. An isolated nucleic acid encoding the recombinant protein of claim 1 .

6. A vector comprising the isolated nucleic acid of claim 5 .

7. A host cell comprising the isolated nucleic acid of claim 5 .

8. A method for increasing frataxin expression in a cell comprising transducing said cell with the recombinant protein of claim 1 .

Assignees

• Univ Laval
• UNIVERSITé LAVAL

Inventors

• Tremblay Jacques P
• Rousseau Joel
• Chapdelaine Pierre
• Coulombe Zoe

Classifications

• A61P25/28

  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 title

• A61K38/00

  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 title

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · CPC title

• C07K2319/71

  containing domain for transcriptional activaation, e.g. VP16 · CPC title

• C07K19/00 Primary

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title