RT Journal Article SR Electronic T1 β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 768 OP 779 DO 10.1183/13993003.01661-2015 VO 48 IS 3 A1 Lodewijk A.W. Vijftigschild A1 Gitte Berkers A1 Johanna F. Dekkers A1 Domenique D. Zomer-van Ommen A1 Elizabeth Matthes A1 Evelien Kruisselbrink A1 Annelotte Vonk A1 Chantal E. Hensen A1 Sabine Heida-Michel A1 Margot Geerdink A1 Hettie M. Janssens A1 Eduard A. van de Graaf A1 Inez Bronsveld A1 Karin M. de Winter-de Groot A1 Christof J. Majoor A1 Harry G.M. Heijerman A1 Hugo R. de Jonge A1 John W. Hanrahan A1 Cornelis K. van der Ent A1 Jeffrey M. Beekman YR 2016 UL http://erj.ersjournals.com/content/48/3/768.abstract AB 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 β2-adrenergic receptor agonists as the most potent inducers of CFTR function.β2-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 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 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.β2-Adrenergic receptor agonists as CFTR activating drugs in subjects with CFTR residual function http://ow.ly/Dm44300wjuw