Peter van Mourik

193 General discussion INTESTINAL ORGANOIDS IN PERSPECTIVE: COMPARI- SON TO OTHER MODELS How do organoids compare to other ex vivo or in vitro cell models? Cell-based approaches have mostly been used to type the average therapeutic response of a mutation or genotype. The Fisher Rat Thyroid (FRT) cell line in which CFTR mutations are introduced in a standardized manner using defined cDNAs can be used for high-throughput drug screening, and has helped to extend ivacaftor treatment to new CFTR mutations 75 . The strength of this model is its definition of standardized test components, and that patients do not have to undergo additional procedures. However, FRT cells are non-human, which influences CFTR- protein folding 76 and pharmacological treatment responsiveness 77,78 . Moreover, heterozygosity might influence CFTR-function, and these effects cannot be fully captured in this model. To complement this mutation-oriented approach, several models have been developed using patient-derived cells. Only a few studies directly compare drug outcomes in ex vivo or in vitro cultured cells and in vivo parameters of treatment. Intestinal Current Measurement (ICM) on ex vivo rectal biopsies is validated for measuring residual CFTR function 79,80 , and sensitively detects CFTR-modulator treatment effects after in vivo drug treatment 26,81 . In chapter 6, we found that both ICM on rectal biopsies and FIS in intestinal organoids could sensitively detect treatment effects of lumacaftor/ivacaftor on the F508del genotype, but the magnitude of response of the two biomarkers was not correlated. Thus, more research is needed to determine the role of and relationship between these biomarkers. The major downside of ICM is that only one therapy can be tested per biopsy, making personalized drug assessment burdensome, especially in an era with different treatment options. CFTR function in Human Bronchial Epithelial (HBE) and Nasal Epithelial (HNE) cells is assessed using electrophysiological studies on air-liquid interface cultures, which mimics the airway environment 82 . High-throughput screening is not feasible due to cell senescence after a limited number of passages, and repeatedly obtaining HBE cells from living donors is an invasive process. HNE cells can be obtained by nasal brushing, and initial studies show that electrophysiological measurements in brushed HNE cells correlate with in vivo CFTR function and might be predictive of individual treatment response 83,84 . Compared to the abovementioned models, intestinal organoids have caveats. Because healthy organoids are pre-swollen, FIS cannot compare CF to healthy 9