TARGETING THE NEURONAL CALCIUM SENSOR 1 FOR TREATING WOLFRAM SYNDROME

• US 20190099502A1
• Filed: 03/23/2017
• Published: 04/04/2019
• 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: Institut National De La Sante Et De La Recherche Medicale (Inserm) (Allianz Global Investors GmbH), Universite De Montpellier I
• Inventors: DELPRAT, Benjamin, CRIBAILLET-DELETTRE, Cecile, ANGEBAULT, Claire
• Granted Patent: US 10,639,384 B2
• Time in Patent Office: Days
• 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. An agonist of NCS1 for use in the treatment of Wolfram Syndrome.

2. The agonist for use according to claim 1, wherein said agonist stimulates the expression of NCS1.

3. The agonist for use according to claim 2, wherein said agonist is a NCS1-encoding polynucleotide.

4. The agonist for use according to claim 1, wherein said agonist prevents the degradation of NCS1.

5. The agonist for use according to claim 4, wherein said agonist is an inhibitor of the proteasome.

6. The agonist for use according to claim 4, wherein said agonist is a calpain inhibitor.

7. A method for assessing the severity of Wolfram syndrome in a subject comprising the step of measuring the level of NCS1 in a biological sample obtained from said subject, wherein the level of NCS1 is negatively correlated with the severity of WS.

8. The method according to claim 7, wherein said biological sample is a fibroblast sample.