Cited by 1,088Cystic Fibrosis Research AdvancesIon Transport and Channel RegulationInhalation and Respiratory Drug Delivery

Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809

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Van Goor, Fredrick, Hadida, Sabine, Grootenhuis, Peter D. J., Burton, Bill, Stack, Jeffrey H., Straley, Kimberly S., Decker, Caroline J., Miller, Mark +6 more·2011·Proceedings of the National Academy of Sciences

Abstract

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene that impair the function of CFTR, an epithelial chloride channel required for proper function of the lung, pancreas, and other organs. Most patients with CF carry the F508del CFTR mutation, which causes defective CFTR protein folding and processing in the endoplasmic reticulum, resulting in minimal amounts of CFTR at the cell surface. One strategy to treat these patients is to correct the processing of F508del-CFTR with small molecules. Here we describe the in vitro pharmacology of VX-809, a CFTR corrector that was advanced into clinical development for the treatment of CF. In cultured human bronchial epithelial cells isolated from patients with CF homozygous for F508del, VX-809 improved F508del-CFTR processing in the endoplasmic reticulum and enhanced chloride secretion to approximately 14% of non-CF human bronchial epithelial cells (EC 50 , 81 ± 19 nM), a level associated with mild CF in patients with less disruptive CFTR mutations. F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability. VX-809 was more efficacious and selective for CFTR than previously reported CFTR correctors. VX-809 represents a class of CFTR corrector that specifically addresses the underlying processing defect in F508del-CFTR.

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Crossref · 10.1073/pnas.1105787108

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  • CFTR mutations cause multi-organ dysfunctions affecting lungs, pancreas, liver, and intestine.

    “Mutations in CFTR cause multi-organ dysfunctions affecting lungs, pancreas, liver and intestine187.”

    From Organoids (2022) · cites this paper as [187]

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Authors
Van Goor, F., Hadida, S., Grootenhuis, P. D. J., Burton, B., Stack, J. H., Straley, K. S., Decker, C. J., Miller, M., McCartney, J., Olson, E. R., Wine, J. J., Frizzell, R. A., Ashlock, M., & Negulescu, P. A.
Affiliations
  • Vertex Pharmaceuticals, San Diego, CA 92121;
  • Vertex Pharmaceuticals (United States) (US)
  • Stanford University (US)
  • Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and
  • Cystic Fibrosis Foundation (US)
Corresponding author
Negulescu, Paul A.
Venue
Proceedings of the National Academy of Sciences
Published
2011-10-05
Volume
108
Issue
46
Pages
18843-18848
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2071407356
Cited by
1,088
References
44
Citations by year
2026: 24 · 2025: 48 · 2024: 48 · 2023: 57 · 2022: 64 · 2021: 83 · 2020: 98 · 2019: 95 · 2018: 101 · 2017: 103 · 2016: 77 · 2015: 85 · 2014: 84 · 2013: 61 · 2012: 58
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Cystic Fibrosis Foundation Therapeutics
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Inhalation and Respiratory Drug Delivery
Keywords
cystic fibrosis, F508del-CFTR, CFTR correctors, lumacaftor, endoplasmic reticulum retention, chloride secretion, bronchial epithelial cells, CFTR mutations
MeSH terms
Aminopyridines, Bronchi, Cell Line, Cells, Cultured, Chemistry, Pharmaceutical, Chlorides, Cystic Fibrosis, Drug Evaluation, Preclinical, Epithelial Cells, Homozygote, Humans, Lung, Models, Genetic, Mutation, Drug Design, Cystic Fibrosis Transmembrane Conductance Regulator, Benzodioxoles, In Vitro Techniques

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