GAMMA SECRETASE ASSAYS FOR DRUG DISCOVERY IN ALZHEIMER'S

阿尔茨海默氏病（AD）是一种涉及严重认知障碍的使人衰弱的精神障碍。超过1000万人患有AD，导致3500亿美元的医疗费用。据估计，一种可以延缓AD发病和发展的药物价值超过500亿美元。然而，目前还没有有效的治疗AD的方法。AD的神经病理学机制涉及通过淀粉样前体蛋白（APP）的蛋白水解加工产生神经毒性β-肽（β P）。β P沉积在AD脑的淀粉样斑块中并介导神经元细胞死亡，表明β P是AD发展的关键因素。多种形式的β-P是由称为“γ-分泌酶”的蛋白酶产生的，该酶将淀粉样前体蛋白（APP）转化为较小的神经毒性β-P。据信，γ-分泌酶的抑制剂将阻断β P产生并延迟AD中神经变性的进展。然而，这种抑制剂尚未被发现，因为真正的γ-分泌酶一直是未知的。ActiveSite Biotech已经鉴定出产生β P的真正的γ分泌酶。我们建议使用我们的专有技术，以开发和优化高灵敏度的γ-分泌酶测定在这个阶段I的研究，将允许筛选抑制剂的γ P生产。 I期将评估γ-分泌酶活性测定的可行性，以监测市售蛋白酶抑制剂的抑制作用;该I期研究还将确定是否可以分离不同的γ-分泌酶，以进行更具选择性的药物筛选。第一阶段的结果将作为未来第二阶段研究的基础，以筛选γ-分泌酶活性和β-P生产抑制剂的小分子组合文库。这些已鉴定的化合物将由ActiveSite Biotech开发，作为治疗阿尔茨海默病的药物。拟议的商业应用：在这个项目中开发的γ-分泌酶测定是Vivian Hook教授拥有的专利申请的主题，她将其授权给Activesite Biotech。在本专利发布后，Activesite Biotech将能够独家销售，许可和合作伙伴的γ-分泌酶测定。Activesite Biotech将使用该检测方法来识别和开发阿尔茨海默病（AD）的新型有效治疗方法。有效治疗AD的估计市场价值估计为500亿美元。

Alzheimer's disease (AD) is a debilitating mental disorder involving severe cognitive impairment. Over 10 million people are afflicted with AD, resulting in healthcare costs of $350 billion. A drug that could delay the onset and development of AD has been estimated to be worth over $50 billion. However, there is presently no effective treatment for AD. The neuropathological mechanisms of AD involves production of the neurotoxic beta-peptide (betaP) by proteolytic processing of the amyloid precursor protein (APP). The betaP becomes deposited in amyloid plaques of AD brains and mediates neuronal cell death, indicating the betaP to be a key factor in the development of AD. Multiple forms of betaP are produced by proteases known as 'gamma-secretases' that convert the amyloid precursor protein (APP) into the smaller, neurotoxic betaP. It is believed that inhibitors of gamma-secretases will block betaP production and delay the progression of neurodegeneration in AD. However, such inhibitors have not been discovered because the authentic gamma-secretases have been unknown. ActiveSite Biotech has identified the authentic gamma-secretases that produce betaP. We propose to use our proprietary technology to develop and optimize highly sensitive gamma-secretase assays in this Phase I study that will allow screening of inhibitors of gammaP production. Phase I will assess the feasibility of gamma-secretase activity assays to monitor inhibition by commercially available protease inhibitors; this Phase I study will also determine whether distinct y-secretases can be separated for more selective drug screening. Results from Phase I will be used as the basis for future Phase II investigations to screen small molecule combinatorial libraries for inhibitors of gamma-secretase activity and betaP production. These identified compounds will be developed by ActiveSite Biotech as drugs for the therapeutic treatment of Alzheimer's disease. PROPOSED COMMERCIAL APPLICATIONS: The gamma-secretase assays developed in this project are the subject of a patent application owned by Professor Vivian Hook, which she is licensing to Activesite Biotech. Upon issuance of this patent, Activesite Biotech will be in a position to exclusively sell, license, and partner the gamma-secretase assays. Activesite Biotech will use the assay to identify and develop novel, effective treatments for Alzheimer's disease (AD). The estimated market value for an effective treatment of AD is estimated to be $50 billion.