SENSITIVE DETECTION OF NEURODEGENERATIVE DISEASE FIBRILS

神经退行性疾病原纤维的灵敏检测

• 批准号: 6310909
• 负责人: CYNTHIA C. BAMDAD
• 金额: $ 43.59万
• 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/6310909
• 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.

我们已经开发了第一个实用的检测方法，直接测量β-淀粉样肽掺入聚集体。我们已经多路复用了该技术，使数十万种候选药物的筛选能够直接抑制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，因此其可容易地扩展至全细胞测定。分泌β-淀粉样蛋白的细胞可以用可能抑制上游元件如β-或γ-分泌酶的候选药物治疗。分泌的β-淀粉样蛋白的量将通过我们的专有方法进行定量。对阿尔茨海默病患者的CSF进行的初步实验表明，通过我们的技术检测的β-淀粉样蛋白聚集的程度与测得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。尽管我们已经优化了针对阿尔茨海默病的技术，但该检测方法是模块化的，并且很容易适用于以异常蛋白质聚集为特征的任何神经退行性疾病的特异性检测。其中包括老年痴呆症。帕金森氏症，亨廷顿氏症，克雅氏症，卢伽雷氏症和疯牛病。拟议的商业应用：我们已经开发出第一个特异性和敏感性高通量检测，检测异常蛋白质聚集特征的神经退行性疾病。该测定比现有技术更敏感和特异，并且已用于鉴定一类新的结构相关药物，其抑制早期β-淀粉样蛋白聚集，这是阿尔茨海默病的特征。这些结构决定因素可以被制药公司用来产生专注于早期AD的新的组合药物库。该测定是模块化的，因此它可以容易地适用于靶向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敏感的AD诊断方法。