2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis

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Abstract

We hypothesized that people with cystic fibrosis (CF) who express CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations associated with residual function may benefit from G-protein coupled receptor (GPCR)-targeting drugs that can activate and enhance CFTR function. We used intestinal organoids to screen a GPCR-modulating compound library and identified ?2-adrenergic receptor agonists as the most potent inducers of CFTR function. ?2-Agonist-induced organoid swelling correlated with the CFTR genotype, and could be induced in homozygous CFTR-F508del organoids and highly differentiated primary CF airway epithelial cells after rescue of CFTR trafficking by small molecules. The in vivo response to treatment with an oral or inhaled ?2-agonist (salbutamol) in CF patients with residual CFTR function was evaluated in a pilot study. 10 subjects with a R117H or A455E mutation were included and showed changes in the nasal potential difference measurement after treatment with oral salbutamol, including a significant improvement of the baseline potential difference of the nasal mucosa (+6.35 mV, p<0.05), suggesting that this treatment might be effective in vivo. Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administered ex vivo to organoids. This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR function in vivo and to select route of administration.

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Vijftigschild, L. A. W., Berkers, G., Dekkers, J. F., Zomer-Van Ommen, D. D., Matthes, E., Kruisselbrink, E., … Beekman, J. M. (2016). 2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis. European Respiratory Journal, 48(3), 768–779. https://doi.org/10.1183/13993003.01661-2015

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