CSF-enhanced-aggregation biomarker for Huntingtons disease

亨廷顿病的脑脊液增强聚集生物标志物

• 批准号: 8915257
• 负责人: STEVEN G POTKIN
• 金额: $ 29.5万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915257
• 关键词: Activities of Daily Living; Age; Alzheimer' s Disease; Antibodies; Biological Assay; Biological Factors; Biological Markers; Blood; Brain; Brain imaging; CAG repeat; Cell model; Cells; Clinical; Clinical Pathology; Clinical Trials; Cognitive; DNA Sequence Alteration; Data; Deterioration; Development; Diagnosis; Disease; Disease Progression; Dose; Epitopes; Frequencies; Genes; Genetic; Goals; Health; Huntington Disease; Huntington protein; Image; Immunoassay; Immunotherapeutic agent; Impaired cognition; Individual; Life; Measurable; Measures; Molecular Conformation; Monitor; Motor; Movement; Neuraxis; Neurodegenerative Disorders; Onset of illness; Pathogenesis; Pathologic Processes; Pathology; Patients; Pharmaceutical Preparations; Sampling; Seeds; Sensitivity and Specificity; Severities; Specificity; Standardization; Symptoms; Time; Trinucleotide Repeats; Urine; base; brain tissue; clinical phenotype; cognitive performance; cohort; disease diagnosis; disorder control; effective therapy; extracellular; human Huntingtin protein; mild cognitive impairment; motor impairment; mutant; novel; polyglutamine; pre-clinical

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.

描述（由申请人提供）：亨廷顿舞蹈病（HD）是一种神经退行性疾病，由基因突变导致亨廷顿舞蹈病（HTT）蛋白突变形式的表达引起中枢神经系统不可避免的恶化，伴有脑组织丧失、身体运动异常、认知障碍和精神症状。HD是一种致命的进行性疾病，目前尚无有效的治疗方法。一种有效的检测方法可以灵敏地测量HD病理的微小变化，这将大大加快HD有效治疗方法的开发。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。生物标志物可能比临床症状更敏感，更能反映疾病病理，而临床症状可能需要数年才能显现出来。例如，一种有用的生物标志物可以反映药物的靶标作用，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给药频率要求。到目前为止，还没有这样敏感和有效的生物标志物可用于HD。该提案将评估一种新的生物标志物反映HD病理的能力，预测其病程，并允许在临床试验中对靶标参与进行定量评估。该生物标志物是CSF增强聚集，这是HD细胞模型外用HD患者CSF后Htt聚集的定量测量。Htt蛋白的异常聚集是HD病理的一个关键特征。最近开发的csf增强聚集试验，该提案将改进和验证，预计对HD进展病因病理学敏感。本研究将利用PREDICT-HD基因阳性和基因阴性个体自然研究中收集的脑脊液样本。我们将建立这种脑脊液生物标志物的敏感性和特异性及其与诊断和监测能力的关系