Peter van Mourik

164 Chapter 8 ABSTRACT Background: Cystic fibrosis is a rare recessive monogenic disease caused by loss- of-function mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Recently developed CFTR-modulators (i.e. drugs that rescue CFTR- function) have improved the prognosis of the disease, but are only available for certain, relatively common mutations. More than 2000 genetic variants in CFTR have been described, many of which are uncharacterized, while efficacy of CFTR- modulators can differ depending on genotype. Personalized models that can predict drug efficacy in patients with rare mutations could help to provide access to effective CFTR-modulator treatment. The forskolin induced swelling (FIS) assay in rectal organoids can robustly measure CFTR-function and CFTR-modulator efficacy, and pilot studies indicate that FIS accurately predicts treatment efficacy in individual patients. In the HIT-CF Organoid Study, rectal organoids from patients with rare CFTR-mutations are screened for CFTR-modulator efficacy to identify patients that could clinically benefit from these drugs. Methods: In this EU-H2020 funded multi-centre study, rectal biopsies are obtained from approximately 500 subjects with rare CFTR-mutations from 17 different EU countries and sent to central laboratories. Organoids are generated, on which several novel CFTR-modulating drugs are screened for efficacy. In the process, a biobank is generated which could be used for future research. Subjects whose organoids show a response to treatment will be asked to participate in subsequent clinical trials evaluating the clinical efficacy of tested drugs. Discussion: The HIT-CF Organoid Study applies the intestinal organoid model for personalized medicine in patients with rare variant cystic fibrosis, who are currently excluded from classical CFTR-modulator trials. Together with the subsequent clinical trials in high responders, this study aims to create a new pathway for access to CFTR-modulating drugs for patients with ultra-rare CFTR variants.