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

Eur Respir J. 2016 Sep;48(3):768-79. doi: 10.1183/13993003.01661-2015. Epub 2016 Jul 28.

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.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Albuterol / administration & dosage
  • Biological Assay
  • Bronchi / pathology
  • Cell Line
  • Cells, Cultured
  • Chlorides / chemistry
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • 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

Substances

  • Adrenergic beta-2 Receptor Agonists
  • CFTR protein, human
  • Chlorides
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Albuterol

Grants and funding