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Sci Transl Med. 2014 Jul 23;6(246):246ra97. doi: 10.1126/scitranslmed.3008889.

Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.

Author information

1
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
2
Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, CA 94143-0521, USA.
3
MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, 1444 Budapest, Hungary. Department of Biophysics and Radiation Biology, Semmelweis University, 1444 Budapest P.O. Box 263, Hungary.
4
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143-0511, USA.
5
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada. Department of Biochemistry, McGill University, Montréal, Quebec H3G 1Y6, Canada. Groupe de Recherche Axé sur la Structure des Protéines (GRASP), McGill University, Montréal, Quebec H3G 1Y6, Canada. gergely.lukacs@mcgill.ca.

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.

PMID:
25101887
PMCID:
PMC4467693
DOI:
10.1126/scitranslmed.3008889
[Indexed for MEDLINE]
Free PMC Article

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