SENSITIVE DETECTION OF NEURODEGENERATIVE DISEASE FIBRILS

神经退行性疾病原纤维的灵敏检测

• 批准号: 6528656
• 负责人: CYNTHIA C. BAMDAD
• 金额: $ 45.85万
• 依托单位: MINERVA BIOTECHNOLOGIES CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528656
• 关键词: Alzheimer's disease; amyloid proteins; chemical aggregate; diagnosis design /evaluation; diagnostic tests; drug screening /evaluation; nervous system disorder diagnosis; neural degeneration; neuritic plaques; neurofilament; neuropharmacologic agent; protein protein interaction; technology /technique development

We have developed the first practical assay that directly measures the incorporation of beta-amyloid peptides into aggregates. We have multiplexed the technology to enable the screening of hundreds of thousands of drug candidates for their ability to directly inhibit beta- amyloid aggregation. Because the assay is rapid and does not use toxic substances, it can readily be extended to a whole cell assay. Cells that secrete beta-amyloid can be treated with drug candidates that might inhibit upstream elements such as beta- or gamma-secretase. The amount of secreted beta-amyloid would then be quantitated by our proprietary methods. Preliminary experiments performed on CSF from Alzheimer's patients show that the extent of beta-amyloid aggregation, detected by our technology, scaled with the measured degree of dementia and duration of disease, indicating that a clinical diagnostic assay based on this technology is feasible. The ability to quantitatively assess a patient's response to therapy would expedite clinical trials and FDA approval. Although we have optimized our technology for Alzheimer's disease, the assay is modular and is readily adapted to the specific detection of any neurodegenerative disease that is characterized by abnormal protein aggregation. These include, Alzheimer's. Parkinson's, Huntington's, Creutzfeldt Jakob, Lou Gehrig's and Mad Cow disease. PROPOSED COMMERCIAL APPLICATIONS: We have developed the first specific and sensitive high throughput assay that detects abnormal-protein aggregation characteristic of neurodegenerative diseases. The assay is orders of magnitude more sensitive and specific than the state of the art and has been used to identify a new class of structurally related drugs that inhibit early stage beta-amyloid aggregation, characteristic of Alzheimer's disease. These structural determinants can be used by pharmaceutical companies to generate new combinatorial drug libraries focused on early stage AD. The assay is modular so it can be readily adapted for use in assays that target other neurodegenerative diseases. We will use our technology to develop a more sensitive diagnostic for AD.

我们开发了第一个实用的检测方法，可以直接测量 β-淀粉样肽与聚集体的结合情况。我们采用了多重技术，能够筛选数十万种候选药物，以确定它们直接抑制 β-淀粉样蛋白聚集的能力。由于该测定快速且不使用有毒物质，因此可以轻松扩展到全细胞测定。分泌β-淀粉样蛋白的细胞可以用可能抑制上游元件（例如β-或γ-分泌酶）的候选药物进行治疗。然后通过我们的专有方法对分泌的β-淀粉样蛋白的量进行定量。对阿尔茨海默氏症患者脑脊液进行的初步实验表明，通过我们的技术检测到的β-淀粉样蛋白聚集程度与测量的痴呆程度和疾病持续时间成比例，表明基于该技术的临床诊断测定是可行的。定量评估患者对治疗的反应的能力将加快临床试验和 FDA 的批准。尽管我们针对阿尔茨海默病优化了技术，但该检测是模块化的，很容易适应任何以异常蛋白质聚集为特征的神经退行性疾病的特异性检测。这些包括阿尔茨海默氏症。帕金森病、亨廷顿病、克雅氏病、卢伽雷氏病和疯牛病。拟议的商业应用：我们开发了第一个特异性且灵敏的高通量测定法，可检测神经退行性疾病的异常蛋白质聚集特征。该测定比现有技术的灵敏度和特异性高几个数量级，并已用于鉴定一类新的结构相关药物，这些药物可抑制早期β-淀粉样蛋白聚集（阿尔茨海默病的特征）。制药公司可以使用这些结构决定因素来生成专注于早期 AD 的新组合药物库。该测定是模块化的，因此可以很容易地适用于针对其他神经退行性疾病的测定。我们将利用我们的技术开发更灵敏的 AD 诊断方法。