Targeting the neuronal calcium sensor 1 for treating wolfram syndrome

• US 10,639,384 B2
• Filed: 03/23/2017
• Issued: 05/05/2020
• Est. Priority Date: 03/23/2016
• Status: Active Grant

• Current Assignee: Inserm (institut national de la sant et de la recherche mdicale, Universite De Montpellier I
• Original Assignee: Inserm (institut national de la sant et de la recherche mdicale
• Inventors: Delprat, Benjamin, Cribaillet-Delettre, Cecile, Angebault, Claire
• Primary Examiner(s): Babic, Christopher M
• Assistant Examiner(s): Aron, Kimberly A.
• Application Number:
  US16/086,861
• Publication Number:
  US 20190099502A1
• Time in Patent Office: 1,139 Days
• Field of Search: None
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/06 Tripeptides
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/55 Protease inhibitors
• CPC Class Codes: A61K 48/0066 Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
• CPC Class Codes: A61K 9/51 Nanocapsules; Nanoparticles; nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00
• CPC Class Codes: A61P 27/00 Drugs for disorders of the senses
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 7/12 Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: G01N 2333/4727 Calcium binding proteins, e.g. calmodulin
• CPC Class Codes: G01N 2800/042 Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

The present invention relates to novel therapeutic ways for treating Wolfram Syndrome (WS) by targeting the neuronal calcium sensor 1 (NCS1). The present inventors have demonstrated that WFS1, which loss of function is responsible of the Wolfram Syndrome, forms a complex with the neuronal calcium sensor 1 (NCS1). The inventors have further demonstrated that WFS1 associates with NCS1 to prevent its degradation by the proteasome and that NCS1 regulates VDAC expression and mitochondrial respiratory chain. Thus, present invention provides an agonist of NCS1 for use in the treatment of WS. Such an agonist is e.g. a NCS1-encoding polynucleotide, an inhibitor of the proteasome or of calpains. The inventors have further shown that overexpression of NCS1 in WS cells allows increasing complex II driven respiration. The present invention further relates to a method for predicting the severity of WS by measuring the NCS1 level in a sample obtained from a patient.

Claims

1. A method for the treatment of Wolfram Syndrome (WS), comprising administering, to a patient in need thereof, a therapeutically effective amount of an agonist of the neuronal calcium sensor 1 (NCS1), wherein said agonist is an NCS1-encoding polynucleotide.