Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression

Guido Veit, Radu G. Avramescu, Doranda Perdomo, Puay Wah Phuan, Miklos Bagdany, Pirjo M. Apaja, Florence Borot, Daniel Szollosi, Yu Sheng Wu, Walter E. Finkbeiner, Tamas Hegedus, Alan S. Verkman, Gergely L. Lukacs

Research output: Contribution to journalArticlepeer-review

257 Citations (Scopus)


Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.
Original languageEnglish
Article number246ra97
Number of pages14
JournalScience translational medicine
Issue number246
Publication statusPublished - 23 Jul 2014
Externally publishedYes


  • Prolonged exposure to VX-770
  • cellular expression
  • chloride conductance
  • primary respiratory epithelia
  • PM density
  • pulse-chase labeling


Dive into the research topics of 'Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression'. Together they form a unique fingerprint.

Cite this