Journal Article

Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Young, Chris, Negulescu, Paul, Hadida, Sabine, Frizzell, Raymond A, Van Goor, Fredrick, Neuberger, Tim, Wine, Jeffery J, McCartney, Jason, Cao, Dong, Hazlewood, Anna, Singh, Ashvani, Zhou, Jinglan, Decker, Caroline, Olson, Eric R, Turnbull, Amanda, Joubran, John, Arumugam, Vijayalaksmi, Yang, Jennifer, Ashlock, Melissa, Grootenhuis, Peter D.J, Burton, Bill

2009

Overview

Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (Po) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl⁻ secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by [almost equal to]10-fold, to [almost equal to]50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na⁺ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 3T3 cells / absorption / Absorption - drug effects / alleles / Amino Acid Substitution - drug effects / Aminophenols - chemistry / Aminophenols - pharmacology / Animals / Biological Sciences / Bronchi / Bronchi - pathology / cAMP-dependent protein kinase / Cell culture / Cells, Cultured / chlorides / Chlorides - metabolism / Cilia / Cilia - drug effects / Cilia - metabolism / Cystic fibrosis / Cystic Fibrosis - physiopathology / Cystic Fibrosis Transmembrane Conductance Regulator - metabolism / Dehydration / Drug Synergism / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Epithelial Sodium Channels - metabolism / epithelium / Gene expression / Genetic mutation / Humans / Ion Channel Gating - drug effects / Kinases / Lung diseases / Lungs / Membranes / Mice / Mutation / Mutation - genetics / NIH 3T3 Cells / Pharmacology / probability / Proteins / Quinolines - chemistry / Quinolines - pharmacology / Quinolones - chemistry / Quinolones - pharmacology / Secretion / sodium / Sodium - metabolism