Peter van Mourik

13 General Introduction FURTHER DEVELOPMENT OF ORGANOIDS AS A TOOL IN CYSTIC FIBROSIS RESEARCH Since the use of intestinal organoids in Cystic Fibrosis is quite recent, standardized protocols have not been adopted and validity and reproducibility of the FIS assay in organoids has not been assessed. Studies exploring these aspects could further elucidate the qualities of organoids as biomarker in Cystic Fibrosis. Current studies with organoids support that additional classification of residual function may be possible. CFTR function is likely a biological continuum that is mostly dependent on CFTR genotype and further modified by individual genetic and environmental factors. The first clinical validation studies showed how relatively large differences in residual function (albeit all in the CF domain) correspond with clinical manifestations 15 . Whether more subtle differences in organoid swelling (e.g. between organoids from people with identical CF-causing mutations; or in conditions of borderline CF and CFTR-related disease) also associate with clinical phenotype and drug response should be investigated in clinical correlation studies. AIMS OF THIS THESIS The aim of this thesis is to assess intestinal organoids as a tool for CFTR-modulator development and precision medicine. More specifically, the following research questions are addressed: I. Can intestinal organoids improve our knowledge on the interaction between CFTR-modulators and CFTR-genotypes? II. Could intestinal organoids be internationally implemented for CF research and clinical care? III. How does CFTR-modulator efficacy in intestinal organoids relate to clinical response in individual patients? In part 1 of this thesis, we focus on the use of intestinal organoids to further characterize the interaction between CFTR-genotype and CFTR-modulators. Chapter 2 explores whether variability in CFTR-mRNA expression between donors might influence CFTR function and ivacaftor efficacy in organoids with the R117H- CFTR genotype, while Chapter 3 examines the responsiveness of several CFTR- genotypes to combinations of potentiators. 1