tocopherylquinone and Friedreich-Ataxia

This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit.

Topics: Adolescent; Adult; Animals; Antioxidants; Biomarkers; Double-Blind Method; Female; Fibroblasts; Frataxin; Friedreich Ataxia; Glucose; Glucose Tolerance Test; Humans; Iron-Binding Proteins; Lymphocytes; Male; Mice; Middle Aged; Mitochondria; Point Mutation; Sample Size; Treatment Outcome; Vitamin E; Young Adult

We report on the synthesis, biological and pharmacological activity of the tocoquinone natural product, α-tocopherol quinone (ATQ); an oxidative metabolite of α-tocopherol. ATQ is a potent cellular protectant against oxidative stress, whose biological activity is dependent upon its ability to undergo reversible two-electron redox cycling. ATQ is orally bioavailable, with a favorable pharmacokinetic profile and has demonstrated a beneficial clinical response in patients with Friedreich's ataxia. ATQ is a member of a broader class of vitamin E derived quinone metabolites which may be ascribable in whole or in part to the activity of vitamin E.

Topics: alpha-Tocopherol; Animals; CHO Cells; Cricetinae; Dogs; Dose-Response Relationship, Drug; Drug Design; Fibroblasts; Friedreich Ataxia; Humans; Hydrolases; Mice; Micronucleus Tests; Models, Chemical; NAD(P)H Dehydrogenase (Quinone); Nutritional Sciences; Oxidation-Reduction; Oxidative Stress; Quinones; Rats; Vitamin E