Peter van Mourik

180 Chapter 9 GENERAL DISCUSSION Therapies that improve CFTR-function can drastically alter the quality of life and life expectancy of people suffering from Cystic Fibrosis 1 . Nevertheless, currently available CFTR-modulators incur very high costs per patient and for the society as a whole 2,3 while treatment effects are highly heterogeneous. Therefore, it is essential to further optimize and personalize CFTR-modulator treatment. The current therapeutic landscape comprises a limited variety of CFTR-modulator therapies, which are all marketed by the same company. To increase cost-effectiveness of treatment these therapies need to be tailored to the individual, while generating alternative treatment options could decrease drug prices. This chapter discusses how organoids can (i) accelerate the preclinical development of drugs, (ii) optimize the use of currently available CFTR-modulators, (iii) increase access to CFTR-modulating therapy through personalized prediction of drug efficacy, and (iv) expand our knowledge of Cystic Fibrosis. USING ORGANOIDS TO ACCELERATE PRE-CLINICAL DE- VELOPMENT OF NEW CFTR-THERAPIES The recent clinical success of CFTR-modulators has fortified the belief that drug development targeting dysfunctional CFTR is achievable, and the current pipeline of therapeutics in the pre-clinical and clinical phase contains more than 20 possible candidates with different modes-of-action (https://www.cff.org/Trials/Pipeline ). Here, I highlight the current and potential use of organoids in accelerating the development of these therapies. Rewriting the script- targeting the CFTR gene and CFTR-mRNA Advances in genetic medicines have opened up new therapeutic avenues for CF, which is seen as a model monogenetic disease due to the well-defined disease pathophysiology. In addition, the phenotypic assessment of CFTR function (restoration) makes organoids a very useful model to test the feasibility of gene editing approaches. Techniques such as Crispr-CAS were successfully used to correct several CFTR-mutations in intestinal organoids 4,5 , and these techniques have subsequently created helpful animal models that can accelerate compound testing in the late-preclinical phase 6,7 . Moreover, the large diversity of samples in our biobank has been used to study a recent addition to gene editing, namely adenine base editing. We showed that a significant fraction of biobanked organoids harbouring Premature Termination