Peter van Mourik

188 Chapter 9 side-effects causing increased discontinuation 64,65 , these environmental factors could thereby impact on the correlations found between organoids and clinical effects. In conclusion, current evidence suggests that organoids are able to detect clinically significant differences in CFTR-function and drug response between individuals, but that variability in short-term clinical endpoints between patients with identical genotypes reduce in vitro-in vivo correlations, especially in compounds with a modest effect size. Moreover, the exact impact of environmental factors on clinical drug response needs to be further clarified and taken into account when determining the value of organoids. ORGANOIDS AS A TOOL FOR CLINICAL DECISION MAKING So how could we use organoid response to drugs for clinical purposes? Different possibilities exist, including (i) identifying groups or individuals who could be further evaluated in clinical trials, (ii) as part of the drug label, allowing direct access to drugs for patients with a ‘positive’ organoid response, and (iii) to titrate the best treatment combination per individual once different CFTR-modulating therapies are clinically available. Identifying novel populations for CFTR-modulating clinical trials We have previously shown that organoid response clustered by genotype correlates very well to mean clinical response on group level 66 . If mutations can be identified that seem amenable to a certain drug based on organoid response, clinical trials can be designed in groups of patients with these mutations. This approached has been pioneered in a Dutch population harboring the A455E mutation (ClinicalTrials. gov Identifier: NCT03061331), and a clinical trial will also be performed in a multi- centre, international settting for patients with the R334W mutation (ClinicalTrials. gov Identifier: NCT04254705), and the 3849+10kb C>T and D1152H mutations (Clinicaltrials.gov Identifier: NCT03068312). These types of group-based trials need sufficient numbers of patients, which is impossible for ultra-rare mutations. For those patients with ultra-rare mutations, the HIT-CF (Human Individualized Treatment for CF) Europe project has been developed (www.hitcf.org ). The first phase of HIT-CF is described in chapter 8 , and involves generating organoids from 500 subjects with ultra-rare CFTR mutations who are currently devoid of CFTR-modulator treatment, and screening different CFTR-modulators for efficacy in patient-specific organoids (HIT-CF Organoid Study, Clinical Trial Identifier NTR7520). The best in vitro responding subjects will subsequently be asked to participate in clinical trials to