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.
Abstract
β2-Adrenergic receptor agonists as CFTR activating drugs in subjects with CFTR residual function http://ow.ly/Dm44300wjuw
Footnotes
This article has supplementary material available from erj.ersjournals.com
Support statement: E. Matthes and J.W. Hanrahan were supported by the Canadian Institutes of Health Research. This work was supported by grants from the Dutch Cystic Fibrosis Foundation (NCFS) as part of the HIT-CF programme, the Wilhelmina Children's Hospital (WKZ) Foundation and the Dutch health organisation ZonMW, The Netherlands. Funding information for this article has been deposited with FundRef.
Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com
- Received October 8, 2015.
- Accepted May 11, 2016.
- Copyright ©ERS 2016