Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

Abstract 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...

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Autores principales: Iwona M. Pranke, Aurélie Hatton, Juliette Simonin, Jean Philippe Jais, Françoise Le Pimpec-Barthes, Ania Carsin, Pierre Bonnette, Michael Fayon, Nathalie Stremler-Le Bel, Dominique Grenet, Matthieu Thumerel, Julie Mazenq, Valerie Urbach, Myriam Mesbahi, Emanuelle Girodon-Boulandet, Alexandre Hinzpeter, Aleksander Edelman, Isabelle Sermet-Gaudelus
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
Materias:
Medicine
R
Science
Q
Acceso en línea:https://doaj.org/article/71753db8957441c5881e8e0b86b29dbf
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Sumario:Abstract 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 (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc 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. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/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 FEV1 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.

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