ArticlePharmacology research & perspectives2015
Increased efficacy of VX-809 in different cellular systems results from an early stabilization effect of F508del-CFTR.
Article in Pharmacology research & perspectives, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 43 citations in OpenAlex.
- Progress of personalized medicine of cystic fibrosis in the times of efficient CFTR modulators.Molecular and cellular pediatrics · 2025Review
- Nasal cells as a bronchial cell surrogate for pre-clinical assessment of drug response in cystic fibrosis.Frontiers in pharmacology · 2025Article
- Cystic Fibrosis: A Journey through Time and Hope.International journal of molecular sciences · 2024Review
- Targeting ubiquitination machinery in cystic fibrosis: Where do we stand?Cellular and molecular life sciences : CMLS · 2024Review
- Phenotypic Alteration of an Established Human Airway Cell Line by Media Selection.International journal of molecular sciences · 2023Article
- Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis.Journal of personalized medicine · 2022Review
- A small molecule high throughput screening platform to profile conformational properties of nascent, ribosome-bound proteins.Scientific reports · 2022Article
- Article
- Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies.International journal of molecular sciences · 2021Article
- Organoids as a personalized medicine tool for ultra-rare mutations in cystic fibrosis: The case of S955P and 1717-2A>G.Biochimica et biophysica acta. Molecular basis of disease · 2020Article
- Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation.Scientific reports · 2020Article
- GRAF2, WDR44, and MICAL1 mediate Rab8/10/11-dependent export of E-cadherin, MMP14, and CFTR ΔF508.The Journal of cell biology · 2020Article
- Recent Strategic Advances in CFTR Drug Discovery: An Overview.International journal of molecular sciences · 2020Review
- Unravelling the Regions of Mutant F508del-CFTR More Susceptible to the Action of Four Cystic Fibrosis Correctors.International journal of molecular sciences · 2019Article
- Activity of lumacaftor is not conserved in zebrafish Cftr bearing the major cystic fibrosis-causing mutation.FASEB bioAdvances · 2019Article
- Clinically-approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia.The Journal of clinical investigation · 2019Article
- CFTR modulator theratyping: Current status, gaps and future directions.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2019Review
- Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine.Frontiers in pharmacology · 2019Review
- Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity.American journal of human genetics · 2018Article
- Peripheral Protein Quality Control as a Novel Drug Target for CFTR Stabilizer.Frontiers in pharmacology · 2018Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cystic fibrosis (CF), the most common recessive autosomal disease among Caucasians, is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. The most common mutation, F508del, leads to CFTR impaired plasma membrane trafficking. Therapies modulating CFTR basic defect are emerging, such as VX-809, a corrector of F508del-CFTR traffic which just succeeded in a Phase III clinical trial. We recently showed that VX-809 is additive to two other correctors (VRT-325 and compound 4a). Here, we aimed to determine whether the differential rescuing by these compounds results from cell-specific factors or rather from distinct effects at the early biogenesis and/or processing. The rescuing efficiencies of the above three correctors were first compared in different cellular models (primary respiratory cells, cystic fibrosis bronchial epithelial and baby hamster kidney [BHK] cell lines) by functional approaches: micro-Ussing chamber and iodide efflux. Next, biochemical methods (metabolic labeling, pulse-chase and immunoprecipitation) were used to determine their impact on CFTR biogenesis / processing. Functional analyses revealed that VX-809 has the greatest rescuing efficacy and that the relative efficiencies of the three compounds are essentially maintained in all three cellular models tested. Nevertheless, biochemical data show that VX-809 significantly stabilizes F508del-CFTR immature form, an effect that is not observed for C3 nor C4. VX-809 and C3 also significantly increase accumulation of immature CFTR. Our data suggest that VX-809 increases the stability of F508del-CFTR immature form at an early phase of its biogenesis, thus explaining its increased efficacy when inducing its rescue.
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