Introduction: Variability in disease severity and CFTR modulator responses exists between patients with identical CFTR genotypes. Here, we characterized transcription, translation and function of R117H-CFTR using intestinal organoids and correlated them with in vitro responses to ivacaftor (VX-770). Methods: Organoids were generated from individuals possessing at least one R117H-CFTR allele. The forskolin-induced swelling (FIS) assay was used to measure CFTR function and response to VX-770 treatment. R117H-CFTR protein and mRNA expression levels were determined in parallel and Pearson's correlation coefficients were assessed. Results: Variability in R117H-CFTR FIS responses was observed and correlated significantly with mRNA and protein expression. Response to VX-770 treatment in organoids correlated with mRNA and protein expression as well. Conclusions: Our results indicate that gene expression, protein expression and CFTR function are strongly correlated in organoids from people with CFTR-R117H-7T/9T, which may suggest that CFTR gene expression may have consequences for CF diagnosis, prognosis and therapeutic benefit.

CFTR, mRNA, Organoids, R117H, VX-770,
Journal of Cystic Fibrosis
Department of Pediatrics

Van Mourik, P, van Haaren, P. (Paul), Kruisselbrink, E, Korkmaz, C. (Cemil), Janssens, H.M, De Winter-De Groot, K.M, … Beekman, J.M. (2020). R117H-CFTR function and response to VX-770 correlate with mRNA and protein expression in intestinal organoids. Journal of Cystic Fibrosis. doi:10.1016/j.jcf.2020.02.001