Peter van Mourik

190 Chapter 9 Figure 2. Different pathways for tailoring CFTR-modulating treatment using intestinal organoids A plethora of companies are developing (combination) treatments that aim to enhance CFTR function. Due to the lack of effective therapy so far, clinical trials have been placebo-controlled. However, once CFTR-modulators are considered usual care, placebo-controlled trials are not ethical and new drugs should be compared against available options. These types of comparative or non-inferiority trials typically need large numbers of subjects to detect statistically significant differences, which is difficult in a rare disease such as Cystic Fibrosis with large heterogeneity in genotype. Moreover, certain mutations might be more amenable to specific modulators. So, how can we match the optimal treatment to each individual patient? Treating patients with different cocktails of drugs might be possible, but exposes patients to side effects of drugs, while the observed clinical differences might be insufficient to determine which treatment is superior. Here, organoids could potentially play an important role. We have previously shown that organoids can be used to compare effects of different CFTR-correctors and potentiators 54,66 . This approach could also be used to compare clinically available treatments in individual subjects, and could result in choosing the optimal treatment from a range of options based on organoid response.