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

描述（由申请人提供）：对HD神经保护治疗干预措施的研究正在加速。体积MRI研究表明，基底神经节的神经退行性变在表现为HD之前10年或更早开始。治疗性神经保护试验旨在延迟显着HD的发病，可能对这种破坏性疾病有潜在的重大影响。辅酶Q10 （CoQ）已成为显着HD患者神经保护的主要治疗候选药物之一，在一项为期30个月的研究（CARE-HD）中，每天600毫克的辅酶Q10在几个结果测量中具有强烈的接近显著的疗效趋势。虽然有大量数据表明症状性HD患者每天服用600毫克CoQ的耐受性，但剂量范围研究表明，在更高剂量下，健康个体的耐受性可能会降低。我们建议研究CoQ在600毫克/天、1200毫克/天和2400毫克/天的剂量，以确定在扩展阳性预显参与者群体中，可耐受的最高剂量；长期目标是在该剂量下开展CoQ的预防性治疗试验。在Specific Aim 1中，我们将在一项随机双盲20周平行组试验中，在突变阳性的HD CAG重复扩增前人群中，确定CoQ在600mg /天、1200mg /天和2400 mg/天剂量下的安全性和耐受性。在Specific Aim 2中，我们将通过在同一试验中评估血清CoQ水平、8-羟基脱氧鸟苷（8OHdG）和8-羟基鸟苷（8OHrG）水平的变化来确定辅酶Q10具有生物活性。我们将评估血清CoQ水平、氧化应激生物标志物、DNA修复机制生物标志物（OGG1）和CoQ剂量水平之间的关系。这项拟议中的试验意义重大，因为它将是第一个在患有神经退行性疾病的风险为100%但尚未患病的人群中评估潜在治疗药物的研究。这将允许我们选择CoQ的剂量，用于未来明确的随机安慰剂对照试验，以延迟或预防显性HD的发作，并将为我们提供有关此类试验在显性参与者中的过程和可行性的宝贵信息。

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.