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β2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.
- Source :
-
The European respiratory journal [Eur Respir J] 2016 Sep; Vol. 48 (3), pp. 768-79. Date of Electronic Publication: 2016 Jul 28. - Publication Year :
- 2016
-
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.<br /> (Copyright ©ERS 2016.)
- Subjects :
- Administration, Oral
Albuterol administration & dosage
Biological Assay
Bronchi pathology
Cell Line
Cells, Cultured
Chlorides chemistry
Cystic Fibrosis genetics
Cystic Fibrosis Transmembrane Conductance Regulator genetics
Drug Evaluation, Preclinical
Epithelial Cells metabolism
Epithelium metabolism
Humans
Mutation
Nasal Mucosa drug effects
Nasal Mucosa metabolism
Organoids
Pilot Projects
Respiratory System metabolism
Signal Transduction
Adrenergic beta-2 Receptor Agonists pharmacology
Cystic Fibrosis drug therapy
Cystic Fibrosis metabolism
Cystic Fibrosis Transmembrane Conductance Regulator metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1399-3003
- Volume :
- 48
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The European respiratory journal
- Publication Type :
- Academic Journal
- Accession number :
- 27471203
- Full Text :
- https://doi.org/10.1183/13993003.01661-2015