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.
Highlights
Protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit
We provide the first evidence that correction of CFTR function in human nasal epithelial (HNE) cell cultures can predict respiratory improvement by CFTR
HNE cell cultures recapitulate the properties of Human bronchial epithelial (HBE) cell cultures
Summary
Protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. Improvement of the in vitro activity of F508del-CFTR requires the combination of lumacaftor (VX-809)-CFTR corrector[7] and ivacaftor CFTR potentiator[3] Such therapy is associated with variable clinical responsiveness. Different hypothesis have been proposed to explain the variable efficacy of Orkambi therapy, including destabilization of lumacaftor rescued F508del-CFTR by chronic ivacaftor treatment[9, 10], the rescue of a subpopulation of F508del-CFTR Cl− channels[11], and action of Orkambi on other factors than transepithelial ion transport such as mucociliary clearance[12] These observations highlight the importance of finding biomarkers that can predict the individual patients’ responses. These are easy to collect by simple nasal brushing and allow quantification of cyclic AMP (cAMP)-mediated Cl− transport as a surrogate marker of CFTR function
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