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

doi:10.1073/pnas.0904709106

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

^aVertex Pharmaceuticals Incorporated, 11010 Torreyana Road, San Diego, CA 92121;
^bVertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139;
^cDepartment of Psychology, Cystic Fibrosis Research Laboratory, Stanford University, Stanford, CA 94305-2130;
^dDepartment of Cell Biology and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, Pittsburgh, PA 15261; and
^eCystic Fibrosis Foundation Therapeutics, Inc., 6931 Arlington Road, Bethesda, MD 20814

Edited by Michael J. Welsh, University of Iowa, Iowa City, IA, and approved September 4, 2009 (received for review May 4, 2009)

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 ≈10-fold, 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.

Footnotes

¹To whom correspondence should be addressed. E-mail: fredrick_vangoor{at}sd.vrtx.com
Author contributions: F.V.G., S.H., P.D.J.G., J.W., R.A.F., and M.A. designed research; F.V.G., B.B., D.C., T.N., A.T., A.S., J.J., A.H., J.Z., J.M., V.A., C.D., J.Y., C.Y., and E.R.O. performed research; F.V.G. and B.B. analyzed data; and F.V.G. and P.N. wrote the paper.
Conflict of interest statement: F.V.G., S.H., P.D.J.G., B.B., D.C., T.N., A.T., A.S., J.J., A.H., J.Z., J.M., V.A., C.D., J.Y., C.Y., E.R.O., and P.N. are employees of Vertex Pharmaceuticals Incorporated, which is evaluating VX-770 as a potential treatment for cystic fibrosis.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0904709106/DCSupplemental.