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直接测量β -淀粉样肽与聚集体结合的实际试验。我们已经将这项技术用于筛选成千上万的候选药物，因为它们具有直接抑制-淀粉样蛋白聚集的能力。由于该检测快速且不使用有毒物质，因此可以很容易地扩展到全细胞检测。分泌β -淀粉样蛋白的细胞可以用候选药物治疗，这些药物可能抑制上游元素，如β -或γ -分泌酶。分泌的β -淀粉样蛋白的数量将通过我们的专有方法进行定量。对阿尔茨海默病患者脑脊液进行的初步实验表明，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检测是可行的。定量评估患者对治疗反应的能力将加快临床试验和FDA的批准。虽然我们已经针对阿尔茨海默病优化了我们的技术，但该检测是模块化的，并且很容易适应于任何以异常蛋白质聚集为特征的神经退行性疾病的特定检测。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。建议的商业应用：我们已经开发了第一个特异性和敏感的高通量检测神经退行性疾病异常蛋白聚集特征。该检测方法的灵敏度和特异性比现有技术高出几个数量级，并已被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，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新的组合药物文库，重点是早期AD。该分析是模块化的，因此它可以很容易地适应用于针对其他神经退行性疾病的分析。我们将利用我们的技术开发一种更灵敏的阿尔茨海默病诊断方法。