Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations

Johanna F. Dekkers, Peter Van Mourik, Annelotte M. Vonk, Evelien Kruisselbrink, Gitte Berkers, Karin M. de Winter-de Groot, Hettie M. Janssens, Inez Bronsveld, Cornelis K. van der Ent, Hugo R. de Jonge, Jeffrey M. Beekman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

37 Citaten (Scopus)


The potentiator VX-770 (ivacaftor/KALYDECO™) 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. 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 indicated that all possible combinations of VX-770, genistein and curcumin synergistically repaired CFTR-dependent forskolin-induced swelling of organoids with CFTR-S1251N or CFTR-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. 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.

Originele taal-2Engels
Pagina's (van-tot)568-578
Aantal pagina's11
TijdschriftJournal of Cystic Fibrosis
Nummer van het tijdschrift5
StatusGepubliceerd - 1 sep. 2016
Extern gepubliceerdJa


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