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Potentiating Trouble

Cystic fibrosis is a genetic disease caused by mutations of the CFTR ion channel, resulting in pulmonary and other complications. Ivacaftor is the only targeted drug approved for cystic fibrosis, but it is not effective enough to treat the severest and most common form of this disease. Ivacaftor is a “potentiator,” which means that it improves the activity of mutant CFTR, but cannot work if there is no CFTR on the cell surface. Other drugs, called “correctors,” help bring mutant CFTR to the cell surface, but two manuscripts by Cholon and Veit and co-authors now show that combining the two types of drugs does not work effectively because potentiators make CFTR less stable, accelerating the removal of this channel from the cell membrane.

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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Supplementary Material

Summary

Materials and Methods
Fig. S1. Comparison between 3HA- and HRP-tagged ΔF508-CFTR.
Fig. S2. Acute VX-770 potentiation in CFBE and the effect of extended VX-770 exposure on the PM density of rΔF508-CFTR in other epithelial cell models.
Fig. S3. Structure and effect of CFFT potentiator panel on the rΔF508-CFTR function and PM density.
Fig. S4. The effect of prolonged exposure to VX-770 on the biogenesis and stability of CFTR variants.
Fig. S5. The effect of VX-770 on the PM density of CFTR variants.
Fig. S6. Representative records of ΔF508-R1S and ΔF508-E1371S activities in artificial phospholipid bilayer.
Fig. S7. In silico modeling of VX-770 and P5 binding to wild-type and ΔF508-CFTR cytosolic regions.
Fig. S8. The effect of prolonged VX-770 exposure on the CF-causing mutants R347H-, R170G-, and P67L-CFTR.
Table S1. Effect of 24 hours of potentiator treatment on Isc measurements in primary CFTRWT/WT HBE.
Table S2. CFTR mutants used in this study.
Table S3. Data and derived P values used in composite graphs (provided as an Excel file).
References (6770)

Resources

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Science Translational Medicine
Volume 6Issue 24623 July 2014
Pages: 246ra97

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Received: 24 February 2014
Accepted: 30 June 2014

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Guido Veit
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
Radu G. Avramescu
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
Doranda Perdomo
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
Puay-Wah Phuan
Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, CA 94143–0521, USA.
Miklos Bagdany
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
Pirjo M. Apaja
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
Florence Borot
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
Daniel Szollosi
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.
Yu-Sheng Wu
Department of Physiology, McGill University, Montréal, Quebec H3G 1Y6, Canada.
Walter E. Finkbeiner
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143–0511, USA.
Tamas Hegedus
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.
Alan S. Verkman
Departments of Medicine and Physiology, University of California, San Francisco, San Francisco, CA 94143–0521, USA.
Gergely L. Lukacs* [email protected]
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.

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*Corresponding author. E-mail: [email protected]

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Science Translational Medicine
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