title: An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels.
abstract: Friedreich ataxia (FRDA) is due to a triplet repeat expansion in FXN, resulting in deficiency of the mitochondrial protein frataxin. Resveratrol is a naturally occurring polyphenol, identified to increase frataxin expression in cellular and mouse models of FRDA and has anti-oxidant properties. This open-label, non-randomized trial evaluated the effect of two different doses of resveratrol on peripheral blood mononuclear cell (PBMC) frataxin levels over a 12-week period in individuals with FRDA. Secondary outcome measures included PMBC FXN mRNA, oxidative stress markers, and clinical measures of disease severity. Safety and tolerability were studied. Twenty-four participants completed the study; 12 received low-dose resveratrol (1 g daily) and 12 high-dose resveratrol (5 g daily). PBMC frataxin levels did not change in either dosage group [low-dose group change: 0.08 pg/μg protein (95% CI -0.05, 0.21, p = 0.21); high-dose group change: 0.03 pg/μg protein (95% CI -0.10, 0.15, p = 0.62)]. Improvement in neurologic function was evident in the high-dose group [change in Friedreich Ataxia Rating Scale -3.4 points, 95% CI (-6.6, -0.3), p = 0.036], but not the low-dose group. Significant improvements in audiologic and speech measures, and in the oxidative stress marker plasma F2-isoprostane were demonstrated in the high-dose group only. There were no improvements in cardiac measures or patient-reported outcome measures. No serious adverse events were recorded. Gastrointestinal side-effects were a common, dose-related adverse event. This open-label study shows no effect of resveratrol on frataxin levels in FRDA, but suggests that independent positive clinical and biologic effects of high-dose resveratrol may exist. Further assessment of efficacy is warranted in a randomized placebo-controlled trial.
authors.affiliation: Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, VIC, Australia.
authors.forename: Eppie M
authors.initials: EM
authors.lastname: Yiu
authors.forename: Geneieve
authors.initials: G
authors.lastname: Tai
authors.forename: Roger E
authors.initials: RE
authors.lastname: Peverill
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Lee
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Mori
authors.forename: Barbara
authors.initials: B
authors.lastname: Scheiber-Mojdehkar
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sturm
authors.forename: Monika
authors.initials: M
authors.lastname: Praschberger
authors.forename: Adam P
authors.initials: AP
authors.lastname: Vogel
authors.forename: Gary
authors.initials: G
authors.lastname: Rance
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Stephenson
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Sarsero
authors.forename: Creina
authors.initials: C
authors.lastname: Stockley
authors.forename: Chung-Yung J
authors.initials: CY
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: Churchyard
authors.forename: Marguerite V
authors.initials: MV
authors.lastname: Evans-Galea
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lockhart
authors.forename: Louise A
authors.initials: LA
authors.lastname: Corben
authors.forename: Martin B
authors.initials: MB
authors.lastname: Delatycki
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D000975:Antioxidants / Q000627:therapeutic use*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D028441:F2-Isoprostanes / Q000097:blood; D005260:Female; D005583:Fourier Analysis; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult; D000096923:Frataxin
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000975:Antioxidants; D003849:Deoxyguanosine; D028441:F2-Isoprostanes; D033862:Iron-Binding Proteins; D012333:RNA, Messenger; D000077185:Resveratrol; D013267:Stilbenes; D000096923:Frataxin
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