CSF-enhanced-aggregation biomarker for Huntingtons disease

描述（由申请人提供）：亨廷顿病（HD）是一种神经退行性疾病，由基因突变引起，导致亨廷顿（HTT）蛋白的突变形式表达，导致中枢神经系统不可阻挡地恶化，伴有脑组织损失、异常身体运动、认知障碍和精神症状。HD是一种致死性、进行性疾病，尚无已知的有效疾病缓解治疗。有效治疗HD的发展将大大加快验证的检测，可以灵敏地测量HD病理学的微小变化。生物标志物是与疾病相关的可测量因素，有效时可作为疾病诊断、严重程度和/或进展的替代指标。生物标志物可能比临床症状更敏感和反映疾病病理，这可能需要数年才能变得明显。例如，有用的生物标志物可以反映药物的靶向作用，并在临床症状发生任何变化之前很久就帮助建立剂量和给药频率要求。迄今为止，尚无此类敏感且经验证的生物标志物可用于HD。该提案将评估新生物标志物反映HD病理学的能力，预测其病程，并允许在临床试验中定量评估靶点参与。该生物标志物是CSF增强的聚集，其是在外部应用来自HD患者的CSF后HD细胞模型中Htt聚集的定量测量。Htt蛋白的异常聚集是HD病理学的关键特征。最近开发的CSF-增强-聚集测定，该提案将完善和验证，预计是敏感的HD进展的病理学。本提案将使用从基因阳性和基因阴性个体的PREDICT-HD自然主义研究中采集的受试者CSF样本。我们将建立这种CSF生物标志物的敏感性和特异性，以及它与诊断开始和监测能力的关系。 HD的发展。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a neurodegenerative disease caused by the genetic mutation resulting in expression of a mutant form of the Huntington (HTT) protein that causes inexorable central nervous system deterioration with loss of brain tissue, abnormal physical movements, cognitive impairment, and psychiatric symptoms. HD is a fatal, progressive disorder with no known effective disease-modifying treatment. The development of effective treatments for HD will be greatly accelerated by a validated assay that can sensitively measure small changes in pathology of HD. Biomarkers are measurable factors that are associated with the illness and when effective, can serve as surrogates for disease diagnosis, severity, and/or progression. Biomarkers can be more sensitive and reflective of disease pathology than clinical symptoms, which may take years to become apparent. For example, a useful biomarker can reflect the target engagement of a drug and help establish the dose and dosing frequency requirements long before any change in clinical symptoms occurs. To date, no such sensitive and validated biomarkers are available for HD. This proposal will evaluate the ability of a new biomarker to reflect HD pathology, predict its course and allow for quantitative assessment of target engagement in clinical trials. This biomarker is CSF-enhanced-aggregation, a quantitative measure of Htt aggregation in HD cell models following the external application of CSF from HD patients. Abnormal aggregation of Htt protein is a key feature of HD pathology. The recently developed CSF-enhanced-aggregation assay that this proposal will refine and validate is predicted to be sensitive to HD progression etiopathology. This proposal will utilize CSF samples collected from subjects in the PREDICT-HD naturalistic study of gene-positive and gene-negative individuals. We will establish the sensitivity and specificity of this CSF biomarker and its relationship to onset of diagnosis and ability to monitor the progression of HD.