title: Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770.
abstract: 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.
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina; Department of Cell Biology and Physiology. University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Martina
authors.initials: M
authors.lastname: Gentzsch
authors.affiliation: Department of Cell Biology and Physiology. University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Hong Y
authors.initials: HY
authors.lastname: Ren
authors.affiliation: Department of Cell Biology and Physiology. University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Houck
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Quinney
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina;
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Cholon
authors.affiliation: Department of Cell Biology and Physiology. University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Pattarawut
authors.initials: P
authors.lastname: Sopha
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina; Department of Cell Biology and Physiology. University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Imron G
authors.initials: IG
authors.lastname: Chaudhry
authors.affiliation: Department of Biochemistry, School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Jhuma
authors.initials: J
authors.lastname: Das
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina; Department of Biochemistry, School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina; Department of Cell Biology and Physiology. University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina, Chapel Hill, North Carolina; Department of Cell Biology and Physiology. University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Cyr
mesh_terms: D000627:Aminophenols / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020125:Mutation, Missense; D017510:Protein Folding / Q000187:drug effects; D015363:Quinolones / Q000494:pharmacology*; D017384:Sequence Deletion
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; C569105:lumacaftor
keywords: Orkambi; R117H; VX-770; VX-809; W1282X; cystic fibrosis; heterozygote; rare mutation