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）：亨廷顿氏病（HD）是由遗传突变引起的神经性疾病，导致表达亨廷顿（HTT）蛋白的突变体形式，导致中枢神经系统恶化，导致脑组织的丧失，异常运动，认知障碍，认知障碍和精神症状。 HD是一种致命的，进行性疾病，没有已知的有效疾病修饰治疗。通过有效的测定法可以敏感地衡量HD病理学的小变化，将大大加速HD的有效治疗方法。生物标志物是与疾病相关的可测量因素，并且在有效时可以作为疾病诊断，严重程度和/或进展的替代因素。生物标志物可以比临床症状更敏感和反映疾病病理学，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目标参与，并有助于在发生临床症状发生任何变化之前很早就确定剂量和给药频率要求。迄今为止，HD尚无这种敏感和经过验证的生物标志物。该提案将评估新生物标志物反映HD病理，预测其过程并允许对临床试验中目标参与的定量评估的能力。该生物标志物是CSF增强型聚集，这是HD细胞模型中HTT聚集的定量度量，此外，HD患者外部应用CSF。 HTT蛋白的异常聚集是HD病理的关键特征。最近开发的CSF增强种类分析测定法，该建议将改进并验证对HD进展病理学敏感。该建议将利用从基因阳性和基因阴性个体的预测HD自然研究中收集的CSF样本。我们将建立该CSF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 高清的进展。