Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770

Am J Physiol Lung Cell Mol Physiol. 2016 Sep 1;311(3):L550-9. doi: 10.1152/ajplung.00186.2016. Epub 2016 Jul 8.


Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.

Keywords: Orkambi; R117H; VX-770; VX-809; W1282X; cystic fibrosis; heterozygote; rare mutation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / pharmacology*
  • Aminopyridines / pharmacology*
  • Benzodioxoles / pharmacology*
  • Cell Line
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Drug Evaluation, Preclinical
  • Humans
  • Mutation, Missense
  • Protein Folding / drug effects
  • Quinolones / pharmacology*
  • Sequence Deletion


  • Aminophenols
  • Aminopyridines
  • Benzodioxoles
  • CFTR protein, human
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor
  • lumacaftor