Treatment of Polarized Cystic Fibrosis Airway Cells With HGF Prevents VX-661-Rescued F508del-CFTR Destabilization Caused by Prolonged Co-exposure to VX-770

• DOI: 10.3389/fmolb.2021.812101
• Publication Date: 2021-12-22T07:53:42Z
• Authors: Ana M. Matos; Peter Jordan; Paulo Matos
• Keywords: Potentiator; Ivacaftor

Cystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations CFTR, frequent of which F508del. F508del causes ER retention and degradation mutant CFTR protein, but also defective channel gating decreased half-life at plasma membrane. Despite recent successes with small-molecule modulator drugs, folding-corrector/gating-potentiator drug combinations approved for CF individuals carrying F508del-CFTR have sometimes produced severe side effects. Previously, we showed that a prolonged, 15-days treatment polarized bronchial epithelial monolayers VX-809+VX-770 combination resulted dedifferentiation effects found were specifically VX-809. Moreover, prolonged VX-770 exposure led to destabilization VX-809-rescued F508del-CFTR. Notably, co-treatment physiological factor HGF prevented VX-809-mediated differentiation reverted destabilizing effect on CFTR. Here, show VX-661, second-generation corrector developed based VX-809 structure, does not perturb integrity monolayers. Yet, its efficacy still affected co-exposure VX-770, potentiator present all VX-661-containing therapies United States Europe carriers. Importantly, ameliorated impact functional rescue without increasing cell proliferation (Ki-67) or altering overall expression markers (ZO-1, E-cadherin, CK8, CK18). Our findings highlight importance evaluating cellular modulators suggest benefits adding current should be further investigated.