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Appel à projets transnational pour la recherche sur les maladies rares dans le cadre de l’ERA-NET E-Rare-2 (E-Rare) 2014
Projet RescueCFTRpreclinic

Cysteamine for the treatment of cystic fibrosis: a translational research project

The proposed approach focuses on a bottom-up, cost-effective strategy of drug discovery in
CF in which drugs, already approved for other human diseases or natural compounds with
well known safety profile, are combined to reverse the alterations of proteostasis resulting
from the loss-of-function mutation of CFTR.
We aim at setting up a translational proof-of-concept for a rationale-based combination of
proteostasis modifiers in the therapy of CF patients, as well as at validating a prediction test
of the responsiveness of each individual patient to candidate drugs for CF therapy. We will
use a multifaceted pre-clinical approach implicating animal models of CF, as well as primary
nasal epithelial cells from CF patients harbouring different CFTR mutants. We have
demonstrated that cystamine restores mismanaged proteostasis and deficient autophagy
resulting from defective CFTR function and that cystamine can rescue and stabilize F508del
at the cell membrane, an effect that can persist for days after drug withdrawal. Herein, we
will test how long the effects of cysteamine, the reduced form of cystamine, a FDA-approved
drug for therapy of cystinosis, might persist after washout and how these effects may be
prolonged. We also aim at deciphering the mechanisms through which small molecules with
known safety profile might extend the action of cysteamine. We will select small molecules
capable to inhibit the Casein-kinase 2, a major culprit of CFTR fragmentation and poor
stability. Altogether, this strategy should delineate novel therapeutic options for the
treatment of CF.

Partenaires

Hadassah-Hebrew University Medical Center Department of Pediatrics

INSERM INSERM UMRS 1138 Centre de Recherche des Cordeliers

Ospedale San Raffaele European Institute for Research in Cystic Fibrosis

Aide de l'ANR 339 360 euros
Début et durée du projet scientifique février 2015 - 36 mois

 

Programme ANR : Appel à projets transnational pour la recherche sur les maladies rares dans le cadre de l’ERA-NET E-Rare-2 (E-Rare) 2014

Référence projet : ANR-14-RARE-0007

Coordinateur du projet :
Luigi Maiuri (European Institute for Research in Cystic Fibrosis)

 

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L'auteur de ce résumé est le coordinateur du projet, qui est responsable du contenu de ce résumé. L'ANR décline par conséquent toute responsabilité quant à son contenu.