Peter van Mourik

25 R117H function and VX-770 response in organoids Figure 3. Correlation analyses between FIS, mRNA and protein expression in R117H-CFTR organoids. Correlation analyses was performed for (A) normalized R117H-CFTR mRNA expression and organoid swelling after stimulation with 0.128 µM forskolin, (B) normalized CFTR protein expression and organoid swelling after stimulation with 0.128 µM forskolin, (C) normalized R117H-CFTR mRNA expression and organoid swelling in the presence of 3 µM VX-770 and 0.05 µM forskolin stimulation, and (D) normalized CFTR mRNA expression and vehicle-corrected organoid swelling in the presence of 3 µM VX-770 and 0.05 µM forskolin stimulation. DISCUSSION Recent studies using airway epithelial cells and intestinal organoids found strong correlations between residual CFTR function and response to CFTR modulators across different genotypes 10,12 . Our current study adds to these findings that within one genotype, i.e. one R117H-CFTR allele, the CFTR modulator response (VX-770) seems to be primarily influenced by differences in mRNA expression. These observations warrant exploration of the relationship between CFTR mRNA expression and CFTR modulator responsiveness within individual genotypes in more detail. We observed variability in FIS responses, which cannot be attributed to in vitro exposure differences as all organoid cultures were cultured simultaneously under identical conditions and processed in parallel. Clinical heterogeneity between patients harbouring R117H-7T has been reported 13,14 but in vitro studies into possible non-environmental contributors are lacking. The strong correlation between mRNA expression and CFTR function in our study suggests that (epi)genetic factors 2