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

Lodewijk A.W. Vijftigschild, Gitte Berkers, Johanna F. Dekkers, Domenique D. Zomer-Van Ommen, Elizabeth Matthes, Evelien Kruisselbrink, Annelotte Vonk, Chantal E. Hensen, Sabine Heida-Michel, Margot Geerdink, Hettie M. Janssens, Eduard A. Van De Graaf, Inez Bronsveld, Karin M. De Winter-De Groot, Christof J. Majoor, Harry G.M. Heijerman, Hugo R. De Jonge, John W. Hanrahan, Cornelis K. Van Der Ent, Jeffrey M. Beekman

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)768-779
Number of pages12
JournalEuropean Respiratory Journal
Issue number3
Publication statusPublished - 1 Sept 2016
Externally publishedYes


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