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

项目总结 这项建议是对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-小脑环路的发育。标准 假设HD是一种纹状体退行性疾病。然而，研究支持了 HD病因学的一个重要组成部分是大脑发育异常。这笔赠款是 最初资助于2009年，被称为Kids-HD计划，旨在由 对患HD风险儿童(父母或祖父母患有HD的儿童)的研究。有风险的参与者包括 将基因分型和基因扩张者(GE)与基因非扩张者进行比较 (GNE)。 基因敲除疗法-反义寡核苷酸或ASO-目前正在进入第三阶段研究和 对疾病早期患者的治疗抱有希望(通过防止进一步下降)。如果ASOS履行 这一承诺，下一步将是预防性治疗-及早给予ASO(可能给儿童) 防止症状的发生。纹状体的生长和发育是理解这一点的关键 疾病病理的主要部位。然而，击倒一种对这些疾病的发育至关重要的基因 处理结构时必须格外小心。人脑发育时间延长， 纹状体成熟变化发生在30岁以下。因此，歧视正在进行 随着疾病退化期的发展/成熟，可能是知道何时给药的关键 和ASO。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 发病大约20年，但在此之前是正常的，这表明它不存在于发育中，但见于 退化的最开始阶段。 续订和扩展(全美5个站点)的理由包括：1)增加复制的样本大小 有足够能力检测CAG特异性效应的原创性发现，以及2)对整个大脑时期进行建模 发展(30岁以下，而不仅仅是18岁以下)；3)评估神经血液生物标记物的效用 功能障碍，神经丝光(NFL)，可能有助于描绘退变的最早阶段。

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.