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Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators
Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547155/ https://www.ncbi.nlm.nih.gov/pubmed/28785019 http://dx.doi.org/10.1038/s41598-017-07504-1 |
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author | Pranke, Iwona M. Hatton, Aurélie Simonin, Juliette Jais, Jean Philippe Le Pimpec-Barthes, Françoise Carsin, Ania Bonnette, Pierre Fayon, Michael Stremler-Le Bel, Nathalie Grenet, Dominique Thumerel, Matthieu Mazenq, Julie Urbach, Valerie Mesbahi, Myriam Girodon-Boulandet, Emanuelle Hinzpeter, Alexandre Edelman, Aleksander Sermet-Gaudelus, Isabelle |
author_facet | Pranke, Iwona M. Hatton, Aurélie Simonin, Juliette Jais, Jean Philippe Le Pimpec-Barthes, Françoise Carsin, Ania Bonnette, Pierre Fayon, Michael Stremler-Le Bel, Nathalie Grenet, Dominique Thumerel, Matthieu Mazenq, Julie Urbach, Valerie Mesbahi, Myriam Girodon-Boulandet, Emanuelle Hinzpeter, Alexandre Edelman, Aleksander Sermet-Gaudelus, Isabelle |
author_sort | Pranke, Iwona M. |
collection | PubMed |
description | Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆I(scF/I+V)) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. I(sc) measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆I(scF/I+V) correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆I(scF/I+V) response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV(1) change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators. |
format | Online Article Text |
id | pubmed-5547155 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-55471552017-08-09 Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators Pranke, Iwona M. Hatton, Aurélie Simonin, Juliette Jais, Jean Philippe Le Pimpec-Barthes, Françoise Carsin, Ania Bonnette, Pierre Fayon, Michael Stremler-Le Bel, Nathalie Grenet, Dominique Thumerel, Matthieu Mazenq, Julie Urbach, Valerie Mesbahi, Myriam Girodon-Boulandet, Emanuelle Hinzpeter, Alexandre Edelman, Aleksander Sermet-Gaudelus, Isabelle Sci Rep Article Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆I(scF/I+V)) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. I(sc) measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆I(scF/I+V) correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆I(scF/I+V) response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV(1) change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators. Nature Publishing Group UK 2017-08-07 /pmc/articles/PMC5547155/ /pubmed/28785019 http://dx.doi.org/10.1038/s41598-017-07504-1 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Pranke, Iwona M. Hatton, Aurélie Simonin, Juliette Jais, Jean Philippe Le Pimpec-Barthes, Françoise Carsin, Ania Bonnette, Pierre Fayon, Michael Stremler-Le Bel, Nathalie Grenet, Dominique Thumerel, Matthieu Mazenq, Julie Urbach, Valerie Mesbahi, Myriam Girodon-Boulandet, Emanuelle Hinzpeter, Alexandre Edelman, Aleksander Sermet-Gaudelus, Isabelle Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators |
title | Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators |
title_full | Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators |
title_fullStr | Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators |
title_full_unstemmed | Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators |
title_short | Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators |
title_sort | correction of cftr function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by cftr modulators |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5547155/ https://www.ncbi.nlm.nih.gov/pubmed/28785019 http://dx.doi.org/10.1038/s41598-017-07504-1 |
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