CSF-enhanced-aggregation biomarker for Huntingtons disease

描述(申请人提供)：亨廷顿病(HD)是一种神经退行性疾病，由基因突变导致亨廷顿(HTT)蛋白突变表达，导致中枢神经系统不可阻挡地恶化，伴有脑组织丧失、身体异常运动、认知障碍和精神症状。HD是一种致命的进行性疾病，目前尚无有效的疾病修正治疗方法。一种可以灵敏地测量HD病理微小变化的有效方法将极大地加速HD有效治疗的发展。生物标志物是与疾病相关的可测量因素，当有效时，可以作为疾病诊断、严重程度和/或进展的替代指标。生物标记物可能比临床症状更敏感和反映疾病病理，而临床症状可能需要数年时间才能显现。例如，一个有用的生物标记物可以反映药物的靶向结合，并有助于在临床症状发生任何变化之前很久就确定剂量和剂量频率要求。到目前为止，还没有这种敏感和有效的生物标志物可用于HD。这项建议将评估一种新的生物标记物反映HD病理、预测其进程的能力，并允许在临床试验中对靶点参与进行定量评估。这种生物标记物是脑脊液增强聚集，这是HD患者外用脑脊液后HD细胞模型中Htt聚集的定量测量。Htt蛋白异常聚集是HD病理的一个重要特征。最近开发的脑脊液增强聚集分析，这项建议将完善和验证，预计是敏感的HD进展的病因。这项建议将利用在对基因阳性和基因阴性个体进行的预测-HD自然主义研究中从受试者那里收集的脑脊液样本。我们将建立脑脊液生物标记物的敏感性和特异性，以及它与诊断和监测能力的关系。 高清的进步。

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.