Peter van Mourik

11 General Introduction FIS in organoids was related to increased pulmonary and pancreatic disease parameters at the age of 1 year 15 . Interestingly, in cases where SCC and ICM disagreed, FIS appeared to correctly align with the clinical indicators 15 . This study suggests that the full CFTR dependency of FIS and the 48 datapoints we typically gather (by titrating forskolin and repeating measurements) to type individual CFTR residual function may provide a higher accuracy and precision as compared to other biomarkers of CFTR function. The precise measurement of CFTR function also suggests that a further refinement of residual function classification is possible. Since these early studies are small, it is of yet unclear how well the model predicts long-term clinical risk. Follow-up studies in larger cohorts are needed to validate the use of organoids for predicting disease phenotype in individuals with rare mutations, and predicting phenotypic variability between individuals with identical CF-causing mutations. Organoids for studying drug efficacy Preclinically, organoids are being used to identify and develop CFTR modulating drugs and explore mechanisms associated with differences in CFTR function. Pharmaceutical companies use intestinal organoids in their drug development pipeline 17,18 . During initial high-throughput-screening, many different chemical structures are discovered that could work as CFTR-modulating drugs. Organoids can be a useful tool to efficiently validate lead compounds, because of their medium-high throughput, sensitivity to drug effects in combination with the fact that they express endogenous CFTR. Organoids are used to test the potency of single drugs, but also to compare the efficacy of different combination treatments 17,18 . Moreover, studies by Dekkers et al. in organoids indicated that both the CFTR mutations and additional patient-specific genetic differences modify response to CFTR modulators 7,10,19 . By studying the effects of a range of drugs on different genotypes, the optimal CFTR modulating drug and their potency for each genotype can be identified for further clinical studies 19,20 . Several studies have highlighted the translational potential of organoids. Genotype- specific effects of ivacaftor and lumacaftor/ivacaftor in organoids correlate with clinical trial data at group level 7 . The failure of a phase III clinical trial with Ataluren in subjects with stop-codon mutations was preceded by a report on the absence of drug activity in the organoid model 21,22 . These group-based observations indicate that organoids can help to characterize the response of mutations to particular treatments. Such an approach would complement current CFTR ‘theratyping’ efforts that mostly rely on cell line expression systems in which CFTR mutations are introduced. Based on quantitative and qualitative differences in therapy response between organoid 1