8-hydroxy-2--deoxyguanosine and Friedreich-Ataxia

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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antioxidants; Deoxyguanosine; F2-Isoprostanes; Female; Fourier Analysis; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Leukocytes, Mononuclear; Male; Middle Aged; Resveratrol; RNA, Messenger; Stilbenes; Treatment Outcome; Young Adult

To determine the exercise capacity of children and adolescents with Friedreich's Ataxia (FA) and to evaluate the effects of 6 months of idebenone treatment on exercise capacity.. Exploratory endpoint in a randomized double-blind, placebo-controlled, phase II clinical trial designed to investigate the effects of idebenone on a biomarker of oxidative stress.. Exercise physiology laboratory in a single clinical research center.. Ambulatory subjects (N=48; age range, 9-17 y) with genetically confirmed FA.. Idebenone administered orally 3 times a day for a total daily dose of approximately 5, 15, and 45 mg/kg or matching placebo for 6 months.. Peak oxygen consumption per unit time (peak VO(2)) and peak work rate (WR) were measured during incremental exercise testing at baseline and after treatment. Echocardiography and neurologic assessments were also completed before and after treatment.. Baseline mean peak VO(2) +/- SD was 746+/-246 mL/min (16.2+/-5.8 mL/kg/min), and WR was 40+/-23 W for all subjects. Peak VO(2) and WR were correlated with short guanine-adenine-adenine allele length and neurologic function. Relative left ventricular wall thickness was increased but left ventricular ejection fraction was normal in most subjects; there was no relationship between any exercise and echocardiographic measures. There were no significant changes in mean peak VO(2) or WR after idebenone treatment at any dose level relative to placebo.. Exercise capacity in children and adolescents with FA was significantly impaired. The basis for the impairment appears to be multifactorial and correlated to the degree of neurologic impairment. Although idebenone has previously been shown potentially to improve features of FA, idebenone treatment did not increase exercise capacity relative to placebo.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Antioxidants; Child; Deoxyguanosine; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Female; Friedreich Ataxia; Humans; Male; Oxidative Stress; Oxygen Consumption; Ubiquinone

In a "proof-of-concept" study, we demonstrated that recombinant human erythropoietin (rhuEPO) increases frataxin levels in Friedreich's ataxia (FRDA) patients. We now report a 6-month open-label clinical pilot study of safety and efficacy of rhuEPO treatment in FRDA. Eight adult FRDA patients received 2.000 IU rhuEPO thrice a week subcutaneously. Clinical outcome measures included Ataxia Rating Scales. Frataxin levels and indicators for oxidative stress were assessed. Hematological parameters were monitored biweekly. Scores in Ataxia Rating Scales such as FARS (P = 0.0063) and SARA (P = 0.0045) improved significantly. Frataxin levels increased (P = 0.017) while indicators of oxidative stress such as urine 8-OHdG (P = 0.012) and peroxide levels decreased (P = 0.028). Increases in hematocrit requiring phlebotomies occurred in 4 of 8 patients. In this explorative open-label clinical pilot study, we found an evidence for clinical improvement together with a persistent increase of frataxin levels and a reduction of oxidative stress parameters in patients with FRDA receiving chronic treatment with rhuEPO. Safety monitoring with regular blood cell counts and parameters of iron metabolism is a potential limitation of this approach.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Deoxyguanosine; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Follow-Up Studies; Frataxin; Friedreich Ataxia; Humans; Iron-Binding Proteins; Lymphocytes; Male; Middle Aged; Pilot Projects; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Friedreich's ataxia (FA) is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown.. 48 genetically confirmed FA patients, aged 9-17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone (approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632.. Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2'dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, FARS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0.03) and suggested a dose-related response in ICARS, FARS, and ADL scores.. Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Activities of Daily Living; Adolescent; Antioxidants; Benzoquinones; Child; Deoxyguanosine; DNA Damage; Dose-Response Relationship, Drug; Female; Friedreich Ataxia; Humans; Male; Nervous System; Neutropenia; Severity of Illness Index; Ubiquinone

Increased generation of reactive oxygen species may underlie the pathophysiology of Friedreich ataxia (FRDA). The authors measured concentrations of 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage, in urine and of dihydroxybenzoic acid (DHBA), a marker of hydroxyl radical attack, in plasma of 33 patients with FRDA. They found a 2.6-fold increase in normalized urinary 8OH2'dG but no change in plasma DHBA as compared with controls. Oral treatment with 5 mg/kg/day of the antioxidant idebenone for 8 weeks significantly decreased urinary 8OH2'dG concentrations, indicating that 8OH2'dG may be useful in monitoring therapeutic interventions in patients with FRDA.-1721

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Deoxyguanosine; Friedreich Ataxia; Humans; Oxidative Stress