title: Potentiator ivacaftor abrogates pharmacological correction of ΔF508 CFTR in cystic fibrosis.
abstract: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR). Newly developed "correctors" such as lumacaftor (VX-809) that improve CFTR maturation and trafficking and "potentiators" such as ivacaftor (VX-770) that enhance channel activity may provide important advances in CF therapy. Although VX-770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation (G551D) that affects only channel activity, a single compound is not sufficient to treat patients with the more common CFTR mutation, ΔF508. Thus, patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit. However, whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro, the impact of chronic therapy has not been established. In studies of human primary airway epithelial cells, we found that both acute and chronic treatment with VX-770 improved CFTR function in cells with the G551D mutation, consistent with clinical studies. In contrast, chronic VX-770 administration caused a dose-dependent reversal of VX-809-mediated CFTR correction in ΔF508 homozygous cultures. This result reflected the destabilization of corrected ΔF508 CFTR by VX-770, markedly increasing its turnover rate. Chronic VX-770 treatment also reduced mature wild-type CFTR levels and function. These findings demonstrate that chronic treatment with CFTR potentiators and correctors may have unexpected effects that cannot be predicted from short-term studies. Combining these drugs to maximize rescue of ΔF508 CFTR may require changes in dosing and/or development of new potentiator compounds that do not interfere with CFTR stability.
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Cholon
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Quinney
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: M Leslie
authors.initials: ML
authors.lastname: Fulcher
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Esther
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Jhuma
authors.initials: J
authors.lastname: Das
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
authors.affiliation: Marsico Lung Institute/Cystic Fibrosis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. gentzsch@med.unc.edu.
authors.forename: Martina
authors.initials: M
authors.lastname: Gentzsch
mesh_terms: D000627:Aminophenols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001980:Bronchi / Q000473:pathology; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000627:Aminophenols; D050505:Mutant Proteins; D015363:Quinolones; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor
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