Peter van Mourik

141 Personalized treatment of CF using rectal organoids INTRODUCTION Functional drug testing on cells or tissue cultures of patients may represent a major step forward for selecting efficacious treatments in an individual setting. Our identification of Lgr5 as a marker of crypt stem cells and the development of technology to grow functional epithelial organoids from such stem cells allows the generation of disease- and patient-specific living biobanks 1–3 . These biobanks could serve as important resources for drug development and scientific studies, but examples demonstrating the validity of these tissue resources for the individual prediction of clinical drug efficacy are currently lacking. Cystic fibrosis (CF) is a genetic disease that is caused by mutations of the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which leads to impaired protein function 4 . Over 2000 CFTR mutations have been identified (www.genet.sickkids.on.ca ) and are associated with a variety of clinical phenotypes (www.cftr2.org ) 5,6 . Recently developed drugs for CF aim to restore CFTR protein function. Lumacaftor (VX-809) and Tezacaftor (VX-661) are corrector drugs, influencing trafficking of the CFTR protein to the apical membrane, while ivacaftor (VX-770) is a potentiator drug, improving the function of the CFTR protein that is present at the apical membrane. In previous work we showed that also the natural food components genistein and curcumin have potentiator activity in vitro , albeit at reduced efficacy and potency as compared to ivacaftor 7 . Currently three CFTR modulating drugs are registered for the treatment of CF patients with specific CFTR mutations; ivacaftor (VX770, Kalydeco®) for patients with different CFTR gating mutations and patients with an R117H mutation, and a combination of ivacaftor and the CFTR correctors lumacaftor or tezacaftor (resp VX770+VX809, Orkambi® and VX770+VX661, Symdeco/ Symkevi®) for patients homozygous for the F508del mutation and some mutations associated with residual function in the case of Symdeco/Symkevi treatment 8–13 . This CFTR genotype-based stratification for drug prescription presents a challenge for the inclusion of many people with rare CFTR mutations who are not included into clinical trials due to low prevalence of the mutation and lack of mechanistic insights. A recent label extension of ivacaftor by the US Food and Drug Administration (FDA) based on in vitro data of heterologous cell lines and mode-of-action, signals a paradigm shift of the regulatory pathway to faster drug access for people with rare CFTR mutations 14 . In previous work we showed that forskolin induced swelling (FIS) of rectal organoids can be used to quantify the function of the CFTR protein in response to CFTR modulating drugs. Forskolin raises intracellular cyclic AMP that 7