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

Authors :
Vijftigschild LA
Berkers G
Dekkers JF
Zomer-van Ommen DD
Matthes E
Kruisselbrink E
Vonk A
Hensen CE
Heida-Michel S
Geerdink M
Janssens HM
van de Graaf EA
Bronsveld I
de Winter-de Groot KM
Majoor CJ
Heijerman HG
de Jonge HR
Hanrahan JW
van der Ent CK
Beekman JM
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.)

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