RescueCFTRpreclinic

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 persists 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.