Clinical effects of the three CFTR potentiator treatments curcumin, genistein and ivacaftor in patients with the CFTR-S1251N gating mutation.

Gitte Berkers, Renske van der Meer, Peter van Mourik, Annelotte M Vonk, Evelien Kruisselbrink, Sylvia Wf Suen, Harry Gm Heijerman, Christof J Majoor, Gerard H Koppelman, Jolt Roukema, Hettie M Janssens, Yolanda B de Rijke, E Marleen Kemper, Jeffrey M Beekman, Cornelis K van der Ent, Hugo R de Jonge

Journal: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 2021;19(6):955-961

PMID: 32499204

Free Full Text on Elsevier Science View on PubMed

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 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.

Address: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Department of Pulmonology, Haga Teaching Hospital, The Hague, the Netherlands.; Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.; Department of Pulmonology, University Medical Center Utrecht, Utrecht, the Netherlands.; Department of Respiratory Medicine, Amsterdam University Medical Centers, Amsterdam, the Netherlands.; Department of Pediatric Pulmonology and Pediatric Allergology and GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands.; Department of Pediatric Pulmonology, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.; Department of Pediatrics, division of Respiratory Medicine and Allergology, Erasmus Medical Center/Sophia Children's Hospital, University Hospital Rotterdam, the Netherlands.; Department of Clinical Chemistry, Erasmus Medical Center, University Hospital Rotterdam, the Netherlands.; Department of Pharmacy, Amsterdam University Medical Centers, Amsterdam, the Netherlands.; Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address: [email protected].; Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Hospital Rotterdam, the Netherlands.

DOI: 10.1016/j.jcf.2020.04.014

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MeSH Terms: Adolescent, Adult, Aminophenols, Child, Chloride Channel Agonists, Curcumin, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Female, Genistein, Humans, Male, Organoids, Quinolones