title: β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.
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 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.
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work.
authors.forename: Lodewijk A W
authors.initials: LA
authors.lastname: Vijftigschild
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work.
authors.forename: Gitte
authors.initials: G
authors.lastname: Berkers
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work.
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands These two authors contributed equally to this work.
authors.forename: Domenique D
authors.initials: DD
authors.lastname: Zomer-van Ommen
authors.affiliation: CF Translational Research Centre, Dept of Physiology, McGill University, Montréal, QC, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matthes
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Evelien
authors.initials: E
authors.lastname: Kruisselbrink
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Laboratory of Translational Immunology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Annelotte
authors.initials: A
authors.lastname: Vonk
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Chantal E
authors.initials: CE
authors.lastname: Hensen
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Heida-Michel
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Margot
authors.initials: M
authors.lastname: Geerdink
authors.affiliation: Dept of Pediatric Pulmonology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Hettie M
authors.initials: HM
authors.lastname: Janssens
authors.affiliation: Dept of Pulmonology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Eduard A
authors.initials: EA
authors.lastname: van de Graaf
authors.affiliation: Dept of Pulmonology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Inez
authors.initials: I
authors.lastname: Bronsveld
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Karin M
authors.initials: KM
authors.lastname: de Winter-de Groot
authors.affiliation: Dept of Respiratory Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Christof J
authors.initials: CJ
authors.lastname: Majoor
authors.affiliation: Dept of Pulmonology and Cystic Fibrosis, Haga Teaching Hospital, The Hague, The Netherlands.
authors.forename: Harry G M
authors.initials: HG
authors.lastname: Heijerman
authors.affiliation: Dept of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: de Jonge
authors.affiliation: CF Translational Research Centre, Dept of Physiology, McGill University, Montréal, QC, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Hanrahan
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands.
authors.forename: Cornelis K
authors.initials: CK
authors.lastname: van der Ent
authors.affiliation: Dept of Pediatric Pulmonology, University Medical Center, Utrecht, The Netherlands Regenerative Medicine Center Utrecht, University Medical Center, Utrecht, The Netherlands jbeekman@umcutrecht.nl.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
mesh_terms: D000284:Administration, Oral; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage; D001681:Biological Assay; D001980:Bronchi / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D002712:Chlorides / Q000737:chemistry; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D009940:Organoids; D010865:Pilot Projects; D012137:Respiratory System / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C505032:CFTR protein, human; D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000420:Albuterol