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

Abstract

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 (P(o)) 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 approximately 10-fold, to approximately 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.

• Authors: Fredrick Van Goor, Sabine Hadida, Peter D J Grootenhuis, Bill Burton, Dong Cao, Tim Neuberger, Amanda Turnbull, Ashvani Singh, John Joubran, Anna Hazlewood, Jinglan Zhou, Jason McCartney, Vijayalaksmi Arumugam, Caroline Decker, Jennifer Yang, Chris Young, Eric R Olson, Jeffery J Wine, Raymond A Frizzell, Melissa Ashlock, Paul Negulescu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 44 Pg. 18825-30 (Nov 03 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19846789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminophenols
• Chlorides
• Epithelial Sodium Channels
• Quinolines
• Quinolones
• cystic fibrosis transmembrane conductance regulator delta F508
• Cystic Fibrosis Transmembrane Conductance Regulator
• ivacaftor
• Sodium

Topics

• Absorption (drug effects)
• Amino Acid Substitution (drug effects)
• Aminophenols (chemistry, pharmacology)
• Animals
• Bronchi (pathology)
• Cells, Cultured
• Chlorides (metabolism)
• Cilia (drug effects, metabolism)
• Cystic Fibrosis (physiopathology)
• Cystic Fibrosis Transmembrane Conductance Regulator (metabolism)
• Drug Synergism
• Epithelial Cells (drug effects, metabolism)
• Epithelial Sodium Channels (metabolism)
• Humans
• Ion Channel Gating (drug effects)
• Mice
• Mutation (genetics)
• NIH 3T3 Cells
• Quinolines (chemistry, pharmacology)
• Quinolones (chemistry, pharmacology)
• Sodium (metabolism)