An open-label trial in Friedreich ataxia suggests clinical benefit with high-dose resveratrol, without effect on frataxin levels
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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.
KeywordsFriedreich ataxia Clinical trial Resveratrol Oxidative stress Mitochondrial disorder
This study was funded by the Kyle Bryant Translational Research Award, Friedreich Ataxia Research Alliance (USA). The authors gratefully acknowledge the participants of this study. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS.
Conflicts of interest
Dr. Yiu is supported by a National Health & Medical Research Council of Australia (NHMRC) Early Career Fellowship. Ms. Tai reports no disclosures. Dr. Peverill reports no disclosures. Dr. Lee reports no disclosures. Dr. Croft reports no disclosures. Dr. Mori reports no disclosures. Dr. Scheiber-Mojdehkar reports no disclosures. Dr. Sturm reports no disclosures. Ms. Praschberger reports no disclosures. Dr. Vogel is a former employee of CogState Ltd, a company that provides services to the pharmaceutical industry, and owns CogState stock. Dr. Vogel has received salary support from the NHMRC. Dr. Rance reports no disclosures. Ms. Stephenson reports no disclosures. Dr. Sarsero receives research support from the Friedreich’s Ataxia Research Alliance (USA), Muscular Dystrophy Association (USA) and National Ataxia Foundation (USA). Ms. Stockley reports no disclosures. Dr. Lee reports no disclosures. Dr. Churchyard reports no disclosures. Dr. Evans-Galea receives grant support and personal fees from the NHMRC. Dr. Ryan receives research support from NHMRC. Dr. Lockhart is supported by an NHMRC Career Development Fellowship. Dr. Corben is supported by an NHMRC Early Career Fellowship. Dr. Delatycki receives grant support from the Friedreich Ataxia Research Alliance and the NHMRC.
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