Growth and development of Striatal-Cerebellum circuitry in subjects at risk for Huntington’s Disease

项目摘要 该提案是一项独特研究的竞争性更新，该研究测量了体积，功能和 亨廷顿病（HD）高危儿童纹状体-小脑环路的发展。标准 假设HD是纹状体的退行性疾病。然而，研究支持了 HD的病理学的一个重要组成部分是异常的大脑发育。补助金 最初于2009年获得资助，被称为Kids-HD计划，旨在调查这一假设， 研究有HD风险的儿童（父母或祖父母患有HD的儿童）。风险参与者包括 将基因分型的人和基因扩增（GE）的人与基因未扩增的人进行比较 （GNE）。 基因敲除疗法-反义寡核苷酸或ASO-目前正进入III期研究， 为治疗疾病早期阶段的患者（通过防止进一步下降）提供了希望。如果ASO满足 这一承诺，下一步将是预防性治疗-给予阿索足够早（可能是儿童）， 防止症状发生。纹状体的生长和发育对于理解至关重要，因为这是 疾病病理的主要部位。然而，敲除一个对这些细胞发育至关重要的基因， 必须非常小心地接近建筑物。人类大脑的发育是延长的， 纹状体的成熟变化发生在30岁之前。因此，歧视正在进行， 疾病退行性阶段的发育/成熟可能是了解何时给予 和阿索。我们的初步数据表明，一种新的血液生物标志物-神经丝光（NfL）在 大约20年的发病，但在此之前是正常的，这表明它不存在于发展中，但在 退化的最初阶段 更新和扩展（美国5个研究中心）的理由包括：1）增加样本量，以复制 原始发现具有足够的能力来检测CAG特异性效应，2）模拟整个大脑周期 发展（最多30岁，而不是仅最多18岁）; 3）评估神经系统疾病的血液生物标志物的效用 功能障碍，神经丝光（NF 1），可以帮助描绘退化的最早阶段。

PROJECT SUMMARY This proposal is a competitive renewal for a unique study that measures the volume, function, and development of striatal-cerebellar circuity in children at risk for Huntington's Disease (HD). The standard assumption is that HD is a degenerative disease of the striatum. However, research supports supported the notion that a crucial component of the pathoetiology of HD is abnormal brain development. The grant was originally funded in 2009 and dubbed the Kids-HD program, designed to investigate this hypothesis by the study of children at risk for HD (those with a parent or grandparent with HD). The at-risk participants are genotyped and those who are gene-expanded (GE) are compared to those who are gene non-expanded (GNE). Gene knock-down therapy – Antisense Oligonucleotides or ASOs – are currently entering Phase III studies and hold promise for treatment of patients in early stages of disease (by preventing further decline). If ASOs fulfill that promise, the next step will be preventive therapy – giving the ASO early enough (potentially to children) to prevent symptoms from occurring. The growth and development of the striatum is vital to understand as this is the primary site of disease pathology. Yet, knocking down a gene that is vital to development of these structures must be approached with an abundance of caution. Human brain development is prolonged, with striatal maturational changes occurring up through 30 years of age. Therefore, discriminating ongoing development/maturation with the degenerative phase of the disease may be key in knowing when to administer and ASO. Our preliminary data suggest that a novel blood biomarker – Neurofilament light (NfL) rises within roughly 20 years of onset but is normal prior to that, suggesting it is not present in development, but is seen at the very beginning phases of degeneration. Rationale for renewal and expansion (5 sites across the US) include: 1) increase sample size for replication of original findings with sufficient power to detect CAG-specific effects and 2) model the entire period of brain development (up to age 30 rather than only up to age 18); 3) evaluate the utility of a blood biomarker of neural dysfunction, Neurofilament light (NFl) that may help delineate the earliest phases of degeneration.