β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis

Abstract

We hypothesized that people with cystic fibrosis (CF) who expressCFTR(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 β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-Agonist-induced organoid swelling correlated with theCFTRgenotype, 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. Thein vivoresponse to treatment with an oral or inhaled β2-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 effectivein vivo. Furthermore, plasma that was collected after oral salbutamol treatment induced CFTR activation when administeredex vivoto organoids.This proof-of-concept study suggests that organoids can be used to identify drugs that activate CFTR functionin vivoand to select route of administration.