VX-809/661 Correction of F508del-CFTR Rescue Nrf2 Dysfunction In CF Airway Epithelia

Cystic Fibrosis (CF) is a multi-organ progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel, including in airway epithelia. Previously, we identified a significant dysfunction in CF cells of the transcription factor nuclear-factor-E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report the discovery of an interaction and colocalization of Nrf2 and CFTR in non-CF human primary bronchial epithelia by Proximity Ligation Assay, immunoprecipitation, and immunofluorescence, which is diminished in CF human primary bronchial epithelia, and rescued with VX-809 or VX-661 treatment for 48-72 hr. In primary CF cells, F508del-CFTR correctors induce Nrf2 nuclear localization, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Diminished Nrf2 activity and colocalization with F508del-CFTR is also exhibited in mutant mice. Correction of Nrf2 by VX-809/VX-661 is dependent on sufficient correction of F508del and is blocked by inhibition of corrected channel function, or high-level shRNA knockdown of F508del-CFTR. Finally, partial CFTR knockdown, insufficient to decrease channel function, does not inhibit Nrf2 activity, further establishing the importance of CFTR function. Our findings demonstrate, for the first time, that CFTR and Nrf2 interact, and that VX-809/VX-661 correction of CFTR can correct Nrf2 dysfunction in CF.