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Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
Open accessAbstract
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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“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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Self-citation
Research works printed but not linked: 1
- ; Cystic Fibrosis Foundation US Cystic Fibrosis Patient Registry (Cystic Fibrosis Foundation, Bethesda, 2002).
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Metadata
- 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
- Publisher
- National Academy of Sciences
- Published
- 2011-10-05
- Volume
- 108
- Issue
- 46
- Pages
- 18843-18848
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3219147
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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