Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation
Berkers, Gitte; van der Meer, Renske; van Mourik, Peter; Vonk, Annelotte M; Kruisselbrink, Evelien; Suen, Sylvia Wf; Heijerman, Harry Gm; Majoor, Christof J; Koppelman, Gerard H; Roukema, Jolt; Janssens, Hettie M; de Rijke, Yolanda B; Kemper, E Marleen; Beekman, Jeffrey M; van der Ent, Cornelis K; de Jonge, Hugo R
(2020) Journal of Cystic Fibrosis, volume 19, issue 6, pp. 955 - 961
(Article)
Abstract
BACKGROUND: The natural food supplements curcumin and genistein, and the drug ivacaftor were found effective as CFTR potentiators in the organoids of individuals carrying a S1251N gating mutation, possibly in a synergistic fashion. Based on these in vitro findings, we evaluated the clinical efficacy of a treatment with curcumin, genistein
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and ivacaftor, in different combinations. METHODS: In three multi-center trials people with CF carrying the S1251N mutation were treated for 8 weeks with curcumin+genistein, ivacaftor and ivacaftor+genistein. We evaluated change in lung function, sweat chloride concentration, CFQ-r, BMI and fecal elastase to determine the clinical effect. We evaluated the pharmacokinetic properties of the compounds by evaluating the concentration in plasma collected after treatment and the effect of the same plasma on the intestinal organoids. RESULTS: A clear clinical effect of treatment with ivacaftor was observed, evidenced by a significant improvement in clinical parameters. In contrast we observed no clear clinical effect of curcumin and/or genistein, except for a small but significant reduction in sweat chloride and airway resistance. Plasma concentrations of the food supplements were low, as was the response of the organoids to this plasma. CONCLUSIONS: We observed a clear clinical effect of treatment with ivacaftor, which is in line with the high responsiveness of the intestinal organoids to this drug. No clear clinical effect was observed of the treatment with curcumin and/or genistein, the low plasma concentration of these compounds emphasizes that pharmacokinetic properties of a compound have to be considered when in vitro experiments are performed.
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Keywords: CFTR, Curcumin, Cystic fibrosis, Genistein, Ivacaftor, Organoids, Pediatrics, Perinatology, and Child Health, Pulmonary and Respiratory Medicine
ISSN: 1569-1993
Publisher: Elsevier
Note: Funding Information: J.M.B. and C.K.v.d.E are inventors on a patent application related to these findings. GHK reports research funding from the Lung Foundation of the Netherlands, GSK, Ubbo Emmius Foundation, Vertex, TEVA the Netherlands, TETRI Foundation, outside the submitted work and participation in advisory boards from GSK and PureIMS, outside the submitted work. Funding Information: We thank all patients who gave informed consent for participating in the clinical trials; all the members of the research teams that contributed to this work, especially E.M. Nieuwhof-Stoppelenburg, E.C. Kooij - van der Wiel (Department of Pediatric Pulmonology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, Netherlands), N. Adriaens and P.F.M. Mau Asam (department of Respiratory Medicine Amsterdam University Medical Centers, Amsterdam, Netherlands), M. Smink, and I. Paalvast-Schouten (Haga Teaching Hospital, The Hague, Netherlands), S. Heida-Michel, M. Geerdink, I. Janse-Seip, H. van Panhuis, M.C.J. Olling-de Kok (Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands), E. Wilms (Apotheek Haagse Ziekenhuizen, Haga Teaching Hospital, The Hague, Netherlands) E.M. van Maarseveen (Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands); and MCO health BV for donating ?AOV 811 curcuma longa? and ?AOV 805 genistein? Publisher Copyright: © 2020
(Peer reviewed)