Prolonged co-treatment with HGF sustains epithelial integrity and improves pharmacological rescue of Phe508del-CFTR

Scientific Reports
Ana M MatosPaulo Matos

Abstract

Cystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations in the CFTR chloride channel, the most frequent of which is Phe508del. Phe508del causes not only intracellular retention and premature degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life when experimentally rescued to the plasma membrane (PM). Despite recent successes in the functional rescue of several CFTR mutations with small-molecule drugs, the folding-corrector/gating-potentiator drug combinations approved for Phe508del-CFTR homozygous patients have shown only modest benefit. Several factors have been shown to contribute to this outcome, including an unexpected intensification of corrector-rescued Phe508del-CFTR PM instability after persistent co-treatment with potentiator drugs. We have previously shown that acute co-treatment with hepatocyte growth factor (HGF) can significantly enhance the chemical correction of Phe508del-CFTR. HGF coaxes the anchoring of rescued channels to the actin cytoskeleton via induction of RAC1 GTPase signalling. Here, we demonstrate that a prolonged, 15-day HGF treatment also significantly improves the functional rescue of Phe508del-CFTR by the VX-809 corre...Continue Reading

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Citations

Jan 26, 2020·Scientific Reports·C MooneyC M Greene
Mar 11, 2020·Frontiers in Pharmacology·Miquéias Lopes-Pacheco
Jun 25, 2019·Frontiers in Pharmacology·Cláudia Almeida LoureiroFrancisco R Pinto
Dec 11, 2020·Stem Cell Research & Therapy·Janine ObendorfMandy Laube
Nov 17, 2020·European Journal of Medicinal Chemistry·Margarida D Amaral
Jul 31, 2021·Journal of Experimental Pharmacology·Madalena C PintoMiquéias Lopes-Pacheco

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Methods Mentioned

BETA
GTPase
Fluorescence
confocal microscopy
biopsies
transfection

Software Mentioned

ImageJ
Adobe Photoshop

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