Therapeutic Potential for CFTR Correctors in Autosomal Recessive Polycystic Kidney Disease.

Background & aims ARPKD is caused by mutations in PKHD1, encoding FPC [1-4]. Severe disease occurs in perinates[5]. Those who survive the neonatal period face a myriad of comorbidities, including systemic and portal hypertension, liver fibrosis, and hepatosplenomegaly. The goal here is to uncover therapeutic strategies for ARPKD. Methods We used wild-type and an FPC-mutant cholangiocyte cell line in 3-dimenional cysts and in confluent monolayers to evaluate protein expression using western blotting and protein trafficking using confocal microscopy. Results We found that the protein level of the cystic fibrosis transmembrane conductance regulator, CFTR, was down-regulated. The levels of heat shock proteins were altered in the FPC-mutant cholangiocytes, with HSP27 being downregulated and HSP90, and HSP70 upregulated. FPC-mutant cholangiocytes formed cysts, but normal cells did not. Cyst growth could be reduced by increasing HSP27 protein levels, by HSP90 and HSP70 inhibitor treatments, by silencing HSP90 through mRNA inhibition or by the novel approach of treating the cysts with the CFTR corrector VX-809. In wild-type cholangiocytes, CFTR is present in both apical and basolateral membranes. FPC malfunction resulted in altered colocalization of CFTR with both apical and basolateral membranes. Whereas, treatment with VX-809, increasing Hsp27 or inhibiting HSP70 or 90 restored CFTR localization toward normal values. Conclusions FPC malfunction induces the formation of cysts, which are fueled by alterations in heat shock proteins and in CFTR protein levels and miss-localization. We suggest that CFTR correctors, already in clinical use to treat cystic fibrosis, could also be used as a treatment for ARPKD.