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

有亨廷顿病风险的受试者纹状体-小脑回路的生长和发育

• 批准号: 10248458
• 负责人: PEGGY C NOPOULOS
• 金额: $ 390.15万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10248458
• 关键词: Age; Age-Years; Antisense Oligonucleotide Therapy; Behavioral; Biological Markers; Blood; Brain; CAG repeat; California; Cerebellum; Child; Childhood; Cognition; Cognitive; Corpus striatum structure; DNA; Data; Degenerative Disorder; Development; Diffusion Magnetic Resonance Imaging; Disadvantaged; Disease; Funding; Genes; Genotype; Globus Pallidus; Grant; Growth and Development function; Human; Huntington Disease; Huntington gene; Hypertrophy; Iowa; Length; Light; Magnetic Resonance Imaging; Measures; Modeling; Motor; Neurodegenerative Disorders; Neuronal Dysfunction; Parents; Participant; Pathology; Patients; Pediatric Hospitals; Pennsylvania; Phase; Philadelphia; Preventive therapy; Process; Puberty; Research Support; Rest; Risk; Sample Size; Sampling; Shapes; Signal Transduction; Site; Structure; Study Subject; Symptoms; Texas; Trinucleotide Repeats; Universities; brain abnormalities; cognitive development; design; early childhood; frontal lobe function; grandparent; knock-down; longitudinal design; mutant; neurofilament; novel; phase 3 study; prevent; programs; putamen

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.

项目概要 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 有亨廷顿病（HD）风险的儿童纹状体-小脑回路的发育。标准 假设 HD 是一种纹状体退行性疾病。然而，研究支持支持 HD 病理学的一个重要组成部分是大脑发育异常。这笔补助金是 最初于 2009 年资助，被称为 Kids-HD 项目，旨在研究这一假设 对有亨廷顿舞蹈症风险的儿童（父母或祖父母患有亨廷顿舞蹈症的儿童）进行的研究。有风险的参与者是 基因分型和基因扩展 (GE) 的患者与基因未扩展的患者进行比较 （GNE）。 基因敲除疗法——反义寡核苷酸或ASO——目前正在进入III期研究， 有望为疾病早期阶段的患者提供治疗（通过防止病情进一步恶化）。如果 ASO 满足 这一承诺，下一步将是预防性治疗——尽早给予 ASO（可能是儿童） 预防症状的发生。了解纹状体的生长和发育至关重要，因为这是 疾病病理学的主要部位。然而，敲除对这些发育至关重要的基因 必须非常谨慎地接近结构。人的大脑发育时间较长， 纹状体的成熟变化发生在 30 岁之前。因此，持续存在的歧视 疾病退化阶段的发展/成熟可能是了解何时给药的关键 和阿索。我们的初步数据表明，一种新型血液生物标志物——神经丝光 (NfL) 在体内升高 大约 20 年发病，但在此之前是正常的，表明它在发育过程中不存在，但在 退化的最初阶段。 更新和扩展的理由（美国 5 个站点）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，并且 2）对大脑的整个时期进行建模 发育（一直到 30 岁，而不是仅仅到 18 岁）； 3) 评估神经血液生物标志物的效用 功能障碍、神经丝光 (NFl) 可能有助于描绘退化的最早阶段。