PREQUEL Study In PRE-manifest HD of CoQ10/UbiquinonE Leading to Preventive Trials

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DESCRIPTION (provided by applicant): The search for neuroprotective therapeutic interventions for HD is accelerating. Volumetric MRI studies indicate that neurodegeneration in the basal ganglia begins ten years or more prior to manifest HD. Therapeutic neuroprotective trials in the pre- manifest population aimed at delaying the onset of manifest HD could potentially have a significant impact on this devastating disorder. CoEnzyme Q10 (CoQ) has emerged as one of the leading therapeutic candidates for neuroprotection in manifest HD, with strong near-significant trends for efficacy in several outcome measures in a 30 month study (CARE-HD) of 600 mg per day. While there are substantial data on the tolerability of CoQ at 600 mg/day in symptomatic HD, dose ranging studies suggest the possibility of decreased tolerability in otherwise healthy individuals at higher dosages. We propose to study CoQ at dosages of 600 mg/day, 1200 mg/day and 2400 mg/day to determine, in a population of expansion positive pre-manifest participants, the highest dosage that is tolerable; with the long term objective of developing future preventive therapeutic trials of CoQ at that dosage. In Specific Aim 1, we will establish the safety and tolerability of CoQ at dosages of 600 mg/day, 1200 mg/day and 2400 mg/day in a mutation positive pre-manifest population with the HD CAG repeat expansion, in the context of a randomized double-blind 20 week parallel-group trial. In Specific Aim 2, we will establish that Coenzyme Q10 is biologically active by assessing changes in serum CoQ levels, and 8-Hydroxydeoxyguanosine (8OHdG) and 8-Hydroxyguanosine (8OHrG) levels in the same trial. We will assess the relationships between serum levels of CoQ, biomarkers of oxidative stress, biomarkers of DNA repair mechanisms (OGG1) and dosage levels of CoQ. The proposed trial is significant in that it will be the first study to evaluate a potential therapeutic agent in a population of individuals at 100% risk for developing a neurodegenerative illness, but who are not yet ill. It will allow us to select a dosage of CoQ for future definitive randomized placebo controlled trials in pre-manifest HD to delay or prevent onset of manifest HD, and will give us valuable information about the process and feasibility of such trials in pre-manifest participants.