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.

Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

“…41 Experimentally, several agents have shown potential to increase frataxin expression (recombinant erythropoietin, interferon-gamma, nicotinamide, and resveratrol); however, there has been limited success in their capacity to elevate frataxin levels when tested clinically. [42][43][44][45] Molecules coupled with frataxin deficiency were also elevated in response to treatment. Specifically, G-CSF and/or SCF increased expression of molecules associated with frataxin antioxidant functions, including Nrf2, SODs, catalase, and GPX1.…”

Clinical role of electrocochleography in children with auditory neuropathy spectrum disorder

“…The presence and morphology of these potentials depend strongly on the stimuli used. Most previous studies that focused on ANSD subjects have used clicks or high frequency tone-pips which contain limited energy to low frequencies [1, 28, 40, 41]. In CI recipients, however, ECochG responses are most reliably elicited by low frequency stimuli [25, 26, 31, 32].…”

Friedreich Ataxia: current status and future prospects

“…The effect of low and high doses of resveratrol were studied in an open-label, non-randomized trial. While frataxin levels in peripheral blood cells, patient-reported outcome measures and cardiac parameters did not change over 12 weeks, neurological symptoms were found to improve in the high dose group [106]. …”