ß2-Adrenergic receptor agonists activate CFTR in intestinal organoids and subjects with cystic fibrosis.
Eur Respir J
; 48(3): 768-79, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-27471203
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 ß2-adrenergic receptor agonists as the most potent inducers of CFTR function.ß2-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 ß2-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 (+6.35â
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.
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Base de dados:
MEDLINE
Assunto principal:
Regulador de Condutância Transmembrana em Fibrose Cística
/
Fibrose Cística
/
Agonistas de Receptores Adrenérgicos beta 2
Tipo de estudo:
Clinical_trials
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article