ArticleAmerican journal of physiology. Lung cellular and molecular physiology2016
Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770.
Article in American journal of physiology. Lung cellular and molecular physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 35 citations in OpenAlex.
- Patient-derived cell models for personalized medicine approaches in cystic fibrosis.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2023Review
- A small-molecule inhibitor and degrader of the RNF5 ubiquitin ligase.Molecular biology of the cell · 2022Article
- Modulator Combination Improves In Vitro the Microrheological Properties of the Airway Surface Liquid of Cystic Fibrosis Airway Epithelia.International journal of molecular sciences · 2022Article
- Small-molecule eRF3a degraders rescue CFTR nonsense mutations by promoting premature termination codon readthrough.The Journal of clinical investigation · 2022Article
- Established and novel human translational models to advance cystic fibrosis research, drug discovery, and optimize CFTR-targeting therapeutics.Current opinion in pharmacology · 2022Review
- Review
- Enhanced delivery of peptide-morpholino oligonucleotides with a small molecule to correct splicing defects in the lung.Nucleic acids research · 2021Article
- DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy.Molecular biology of the cell · 2021Article
- A Peptide-Nucleic Acid Targeting miR-335-5p Enhances Expression of Cystic Fibrosis Transmembrane Conductance Regulator (Biomedicines · 2021Article
- Phenotypes of CF rabbits generated by CRISPR/Cas9-mediated disruption of the CFTR gene.JCI insight · 2021Article
- Cystic Fibrosis Transmembrane Conductance Regulator Folding Mutations Reveal Differences in Corrector Efficacy Linked to Increases in Immature Cystic Fibrosis Transmembrane Conductance Regulator Expression.Frontiers in physiology · 2021Article
- Airway Epithelial InflammationFrontiers in pharmacology · 2021Article
- Assessing Human Airway Epithelial Progenitor Cells for Cystic Fibrosis Cell Therapy.American journal of respiratory cell and molecular biology · 2020Article
- Accumulation and persistence of ivacaftor in airway epithelia with prolonged treatment.Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society · 2020Article
- Personalised medicine for non-classic cystic fibrosis resulting from rare CFTR mutations.The European respiratory journal · 2020Article
- Assistance for Folding of Disease-Causing Plasma Membrane Proteins.Biomolecules · 2020Review
- Functional Profiling of CFTR-Directed Therapeutics Using Pediatric Patient-Derived Nasal Epithelial Cell Models.Frontiers in pediatrics · 2020Article
- Bioactive Thymosin Alpha-1 Does Not Influence F508del-CFTR Maturation and Activity.Scientific reports · 2019Article
- Emerging Therapeutic Approaches for Cystic Fibrosis. From Gene Editing to Personalized Medicine.Frontiers in pharmacology · 2019Review
- The cystic fibrosis airway milieu enhances rescue of F508del in a pre-clinical model.The European respiratory journal · 2018Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
Cystic fibrosis (CF) is a lethal recessive genetic disease caused primarily by the F508del mutation in the CF transmembrane conductance regulator (CFTR). The potentiator VX-770 was the first CFTR modulator approved by the FDA for treatment of CF patients with the gating mutation G551D. Orkambi is a drug containing VX-770 and corrector VX809 and is approved for treatment of CF patients homozygous for F508del, which has folding and gating defects. At least 30% of CF patients are heterozygous for the F508del mutation with the other allele encoding for one of many different rare CFTR mutations. Treatment of heterozygous F508del patients with VX-809 and VX-770 has had limited success, so it is important to identify heterozygous patients that respond to CFTR modulator therapy. R117H is a more prevalent rare mutation found in over 2,000 CF patients. In this study we investigated the effectiveness of VX-809/VX-770 therapy on restoring CFTR function in human bronchial epithelial (HBE) cells from R117H/F508del CF patients. We found that VX-809 stimulated more CFTR activity in R117H/F508del HBEs than in F508del/F508del HBEs. R117H expressed exclusively in immortalized HBEs exhibited a folding defect, was retained in the ER, and degraded prematurely. VX-809 corrected the R117H folding defect and restored channel function. Because R117 is involved in ion conductance, VX-770 acted additively with VX-809 to restore CFTR function in chronically treated R117H/F508del cells. Although treatment of R117H patients with VX-770 has been approved, our studies indicate that Orkambi may be more beneficial for rescue of CFTR function in these patients.
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