title: Potentiator synergy in rectal organoids carrying S1251N, G551D, or F508del CFTR mutations.
abstract: 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.
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands; Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands; Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Mourik
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands; Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Annelotte M
authors.initials: AM
authors.lastname: Vonk
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands; Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Evelien
authors.initials: E
authors.lastname: Kruisselbrink
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Gitte
authors.initials: G
authors.lastname: Berkers
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Karin M
authors.initials: KM
authors.lastname: de Winter-de Groot
authors.affiliation: Department of Pediatric Pulmonology, Erasmus University Medical Centre/Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Hettie M
authors.initials: HM
authors.lastname: Janssens
authors.affiliation: Department of Pulmonology, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Inez
authors.initials: I
authors.lastname: Bronsveld
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Cornelis K
authors.initials: CK
authors.lastname: van der Ent
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: de Jonge
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands; Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
mesh_terms: D000627:Aminophenols / Q000494:pharmacology*; D065101:Chloride Channel Agonists / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology*; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D008962:Models, Theoretical; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D009940:Organoids / Q000187:drug effects / Q000473:pathology; D015363:Quinolones / Q000494:pharmacology*; D012007:Rectum / Q000473:pathology
chemical_list: D000627:Aminophenols; D065101:Chloride Channel Agonists; D004791:Enzyme Inhibitors; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; D019833:Genistein; D003474:Curcumin
keywords: Curcumin; Cystic fibrosis; Genistein; Intestinal current measurements (ICM); Intestinal organoids; VX-770