Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770.
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.
Vertex Pharmaceuticals Incorporated, 11010 Torreyana Road, San Diego, CA 92121, USA. fredrick_vangoor@sd.vrtx.com
Fredrick
F
Van Goor
Sabine
S
Hadida
Peter D J
PD
Grootenhuis
Bill
B
Burton
Dong
D
Cao
Tim
T
Neuberger
Amanda
A
Turnbull
Ashvani
A
Singh
John
J
Joubran
Anna
A
Hazlewood
Jinglan
J
Zhou
Jason
J
McCartney
Vijayalaksmi
V
Arumugam
Caroline
C
Decker
Jennifer
J
Yang
Chris
C
Young
Eric R
ER
Olson
Jeffery J
JJ
Wine
Raymond A
RA
Frizzell
Melissa
M
Ashlock
Paul
P
Negulescu
D000042:Absorption / Q000187:drug effects; D019943:Amino Acid Substitution / Q000187:drug effects; D000627:Aminophenols / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000473:pathology*; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D053503:Epithelial Sodium Channels / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism
D000627:Aminophenols; D002712:Chlorides; D053503:Epithelial Sodium Channels; D011804:Quinolines; D015363:Quinolones; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; D012964:Sodium