Peter van Mourik

40 Chapter 3 ABSTRACT Introduction: The potentiator VX-770 (ivacaftor / KALYDECO TM ) targets defective gating of CFTR and has been approved for treatment of cystic fibrosis (CF) subjects carrying G551D, S1251N or one of 8 other mutations. Still, the current potentiator treatment does not normalize CFTR-dependent biomarkers, indicating the need for development of more effective potentiator strategies. Methods: We have recently pioneered a functional CFTR assay in primary rectal organoids and used this model to characterize interactions between VX-770, genistein and curcumin, the latter 2 being natural food components with established CFTR potentiation capacities. Results: Results indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR- dependent forskolin-induced swelling of organoids with CFTR-S1251N or -G551D, even under suboptimal CFTR activation and compounds concentrations, conditions that may predominate in vivo . Genistein and curcumin also enhanced forskolin-induced swelling of F508del homozygous organoids that were treated with VX-770 and the prototypical CFTR corrector VX- 809. Discussion: These results indicate that VX-770, genistein and curcumin in double or triple combinations can synergize in restoring CFTR-dependent fluid secretion in primary CF cells, and support the use of multiple potentiators for treatment of CF. .