Precision medicine for Cystic Fibrosis using intestinal organoids

Abstract

In this thesis, the use of intestinal organoids for the development and tailoring of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-modulating treatments is described. Available data indicate that intestinal organoids can be a very helpful tool to preclinically assess novel CFTR-modulating treatments and can serve as a useful model for developing new approaches such as gene editing. Moreover, currently available CFTR-modulator treatment can be repurposed and optimized through testing in intestinal organoids, while pilot studies indicate that we can predict clinical treatment effect in individual subjects using their intestinal organoids as a surrogate. Although drug screening on organoids is currently possible in 384 wells format, this approach is time-consuming and expertise in organoid culturing is necessary. Moreover, data analysis has not been fully automated, limiting widespread implementation. In the future, screening platforms utilizing robots to culture organoids and artificial intelligence to analyse the data could increase the throughput and effectiveness of drug screening in organoids. In addition, studies directly comparing intestinal organoids with other pre-clinical models such as human bronchial epithelial cells and human nasal epithelial cells should further elucidate how CFTR-function in intestinal organoids relates to respiratory disease severity. Future clinical studies should elucidate thresholds of organoid swelling that can predict whether a patient will or will not respond to a specific drug (combination), and whether these thresholds are identical for drugs with different modes-of-action, or whether drug-specific thresholds are necessary. Moreover, concerted efforts should ensure that widely available organoid biobanks are created that enable access to a diverse range of (intestinal) tissues to further expand our knowledge of CF and CFTR-directed therapeutics.