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Managing the Underlying Cause of Cystic Fibrosis: A Future Role for Potentiators and Correctors

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Abstract

Cystic fibrosis (CF), a severe genetic disease, is caused by mutations that alter the structure and function of CFTR, a plasma membrane channel permeable to chloride and bicarbonate. Defective anion transport in CF irreversibly damages the lungs, pancreas, liver, and other organs. CF mutations cause loss of CFTR function in multiple ways. In particular, class 3 mutations such as p.Gly551Asp strongly decrease the time spent by CFTR in the open state (gating defect). Instead, class 2 mutations impair the maturation of CFTR protein and its transport from the endoplasmic reticulum to the plasma membrane (trafficking defect). The deletion of phenylalanine 508 (p.Phe508del), the most frequent mutation among CF patients (70–90 %), destabilizes the CFTR protein, thus causing both a trafficking and a gating defect. These two defects can be overcome with drug-like molecules generically called correctors and potentiators, respectively. The potentiator Kalydeco™ (also known as Ivacaftor or VX-770), developed by Vertex Pharmaceuticals, has been recently approved by the US FDA and the European Medicines Agency (EMA) for the treatment of CF patients carrying at least one CFTR allele with the p.Gly551Asp mutation (2–5 % of all patients). In contrast, the corrector VX-809, which significantly improves p.Phe508del-CFTR trafficking in vitro, is still under study in clinical trials. Because of multiple defects caused by the p.Phe508del mutation, it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action. This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect.

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Acknowledgments

No sources of funding were used to assist in the preparation of this review. Luis Galietta has no conflicts of interest that are directly relevant to the content of this report. Thanks to Dr. Anna Capurro for critically reading the manuscript.

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  1. Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147, Genova, Italy

    Luis J. V. Galietta

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Galietta, L.J.V. Managing the Underlying Cause of Cystic Fibrosis: A Future Role for Potentiators and Correctors. Pediatr Drugs 15, 393–402 (2013). https://doi.org/10.1007/s40272-013-0035-3

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