ArticleScience translational medicine2014
Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.
Article in Science translational medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 185 papers.
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Who cites it
185 citing papers in PubMed, 284 citations in OpenAlex.
- Sweat rate analysis of ivacaftor potentiation of CFTR in non-CF adults.Scientific reports · 2018Trial
- In vivo and in vitro ivacaftor response in cystic fibrosis patients with residual CFTR function: N-of-1 studies.Pediatric pulmonology · 2017Trial
- A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.Cell death and differentiation · 2016Trial
- Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR.The New England journal of medicine · 2015Trial
- Combining Gene Therapy with Current Modulator Treatments for Cystic Fibrosis: A Promising Area of Research.Pharmaceutics · 2026Review
- Chronic and acute modulator treatment restore wild-type-like activity and stability to the primary cystic fibrosis-causingProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Barriers to the Pharmacologic Rescue of W1282X CFTR.Biochemistry · 2026Article
- Personalized Medicine in Cystic Fibrosis: Characterization of Eight Rare CFTR Variants in Intestinal Organoids and Cellular Models.Molecular diagnosis & therapy · 2026Article
- Article
- Photoaffinity Ligand of Cystic Fibrosis Corrector VX-445 Identifies SCCPDH as an Off-Target.ACS chemical biology · 2025Article
- Unifying perspectives on the activity and genotypic targeting of pharmacological chaperones.The Journal of biological chemistry · 2025Review
- Lumacaftor inhibits channel activity of rescued F508del cystic fibrosis transmembrane conductance regulator.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- The potentiator ivacaftor is essential for pharmacological restoration of F508del-CFTR function and mucociliary clearance in cystic fibrosis.JCI insight · 2025Article
- Review
- Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators.iScience · 2025Article
- Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.Nature communications · 2024Article
- HERC3 facilitates ERAD of select membrane proteins by recognizing membrane-spanning domains.The Journal of cell biology · 2024Article
- Targeting ubiquitination machinery in cystic fibrosis: Where do we stand?Cellular and molecular life sciences : CMLS · 2024Review
- In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets.JCI insight · 2024Article
- Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.Molecules (Basel, Switzerland) · 2024Review
125 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.