Peter van Mourik

12 Chapter 1 subgroups (e.g. comparing average p.Ala455Glu/p.Phe508del, p.Asn1303Lys/p. F508del or class I/p.Phe508del responses), mutation-specific phenotypes with different therapeutic vulnerabilities can be deduced 19 . These theratyping efforts have no direct relation to the individual patient, but rely on the coupling of individual CFTR genotype to the cell-based data. Recent proof-of-concept in two patients with ultra-rare mutations showed clear in vitro- in vivo correlation in response to treatment with ivacaftor 7 . This study indicates that organoids could provide a functional readout, which might even integrate both the patient- specific CFTR mutations and additional genetic variation that modifies the response to treatment. If these results are validated in subsequent studies, this would suggest that a direct test on the patient organoid can be used to characterize the response to treatment, independent of any a priori knowledge on the CFTR genotype. Figure 1. Potential applications of intestinal organoids to study cystic fibrosis. Intestinal organoids can be generated from rectal biopsies. In organoids, robust cystic fibrosis transmembrane conductance regulator (CFTR) function measurements can be performed based on phenotypic differences between organoids and the observation that repair and activation of CFTR causes swelling of organoids. This model can be used in preclinical and clinical studies with the potential to obtain patient-specific information on disease severity and CFTR-modulator drug response.