1. Restoration of R117H CFTR folding and function in human airway cells through combination treatment with VX-809 and VX-770
- Author
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Martina Gentzsch, Nancy L. Quinney, Imron G. Chaudhry, Deborah M. Cholon, Scott A. Houck, Scott H. Randell, Hong Yu Ren, Pattarawut Sopha, Jhuma Das, Douglas M. Cyr, and Nikolay V. Dokholyan
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Protein Folding ,medicine.medical_specialty ,Cystic Fibrosis ,Physiology ,Drug Evaluation, Preclinical ,Mutation, Missense ,Aminopyridines ,Cystic Fibrosis Transmembrane Conductance Regulator ,Gating ,Quinolones ,Biology ,Aminophenols ,medicine.disease_cause ,Cystic fibrosis ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Benzodioxoles ,Allele ,Sequence Deletion ,Mutation ,Heterozygote advantage ,Cell Biology ,Potentiator ,medicine.disease ,Cystic fibrosis transmembrane conductance regulator ,030104 developmental biology ,Endocrinology ,030228 respiratory system ,Cell culture ,Call for Papers ,Cancer research ,biology.protein - 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.
- Published
- 2016