Peter van Mourik

185 General discussion plasma of patients on ivacaftor did result in organoid swelling 48 . Nevertheless, the study results imply that organoid swelling should not be the sole observation to drive clinical development, but ADME (absorption, distribution, metabolism and excretion) properties of drugs should also be taken into account so that experimental design of in vitro experiments are as predictive as possible. The potential of elexacaftor Elexacaftor is highly effective in combination with tezacaftor/ivacaftor 36,37 , but limited pre-clinical information on it’s mechanisms of action have been published 51 . Available literature suggests it works as a CFTR-corrector and improves folding and trafficking of F508del-CFTR to the plasma membrane. We are currently exploring the effects of elexacaftor on different CFTR alleles as monotherapy and in combination with tezacaftor and ivacaftor. Surprisingly, preliminary evidence suggests that elexacaftor acutely improves CFTR function in organoids with gating mutations in addition to its established F508del-CFTR correcting effects. Could elexacaftor thus be a dual corrector-potentiator, and could these characteristics explain the large improvements in in vivo CFTR function and lung function? Whether the potentiating effects of elexacaftor are additive or even synergistic to ivacaftor needs further study, but if this is the case, then the molecular target of elexacaftor might be different to ivacaftor. Further studies with e.g. patch-clamp recordings should elucidate the exact mechanisms of action of elexacaftor as a potentiator. The studies described here indicate the potential of organoids to tailor treatment (combinations) and can help to improve our understanding of available therapies. With organoid biobanks, upcoming research questions can be efficiently studied using available tissues, thereby avoiding repeated and burdensome biopsies in patients. But can we also use the biobank for the direct benefit of the donors? i.e., is it possible to extrapolate organoid measurements to potential clinical benefit of individuals? ORGANOID CFTR-FUNCTION MEASUREMENTS AS BIO- MARKER OF PATIENT-SPECIFIC OUTCOMES In the next section, I will discuss if and how organoids could be used for personalized or precision medicine approaches. If organoids are to be implemented for this purpose, the first step in ensuring results used for individual predictions are reproducible is standardizing and harmonizing organoid culturing and assay conditions across laboratories. For this purpose, we collaborated with Hubrecht Organoid Technology and the CF research laboratories of the KU Leuven and University of Lisboa, and 9