Trikafta, a groundbreaking combination therapy involving two correctors (VX-445/VX-661) and one potentiator (VX770), has revolutionized the treatment for people with cystic fibrosis (CF) carrying the F508del mutation.  The possibility to extend its use to other CFTR mutations is still under investigation. However, the improvement of Trikafta therapy is both necessary and achievable.
This study aims to investigate the role of the Heat Shock Protein (HSP) machinery in the functional recovery of F508del-CFTR induced by correctors. The chaperone machinery exerts an opposite effect on protein biogenesis: facilitate the folding of other proteins and if not succeed they target to demolition the unfolded protein.
Researchers hypothesize that an active chaperone machinery can facilitate the action of correctors.
Preliminary findings indicate that four small molecule activators of the chaperone machinery enhance the rescue of F508del-CFTR in CF human bronchial epithelial cells (CFBE) induced by the combination of the correctors VX-445 and VX-661. CFBE expressing F508delCFTR will be treated with HSPs activators in presence or absence of VX445/VX661 and the functional rescue of the channel will be quantified.
Experiments on primary cells will be conducted in collaboration with FFC Ricerca CFaCore and Servizio Colture Primarie.
The project will characterize the molecular mechanism by which HSP exert functional rescue of F5088del-CFTR in CFBE cells, identifying potential synergistic or additive actions with the correctors.