GAMMA SECRETASE ASSAYS FOR DRUG DISCOVERY IN ALZHEIMER'S

阿尔茨海默病(AD)是一种严重的认知障碍，是一种衰弱的精神障碍。超过1000万人患有阿尔茨海默病，导致医疗费用高达3500亿美元。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。阿尔茨海默病的神经病理机制涉及淀粉样前体蛋白(APP)的蛋白分解过程产生神经毒性β-肽(BetaP)。βP沉积在AD脑内的淀粉样斑块中，介导神经细胞死亡，提示βP在AD的发生发展中起关键作用。多种形式的β-P是由被称为“伽马分泌酶”的酶产生的，它能将淀粉样前体蛋白(APP)转化为更小的、具有神经毒性的β-P。据认为，伽玛分泌酶抑制剂将阻断β-P的产生，延缓AD神经退行性变的进程。然而，这种抑制剂还没有被发现，因为真正的伽马分泌酶还不清楚。ActiveSite Biotech已经确定了产生BetaP的真正的伽马分泌酶。我们建议在这项第一阶段研究中使用我们的专利技术来开发和优化高灵敏度的伽马分泌酶分析，这将允许筛选伽马蛋白产生的抑制剂。第一阶段将评估伽马分泌酶活性分析的可行性，以监测商业上可获得的蛋白酶抑制剂的抑制作用；这项第一阶段研究还将确定是否可以分离出不同的γ-分泌酶，以进行更具选择性的药物筛选。第一阶段的结果将被用作未来第二阶段研究的基础，以筛选伽马分泌酶活性和β-P产生的抑制剂的小分子组合文库。这些已确定的化合物将由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伽马分泌酶分析是Viian Hook教授拥有的一项专利申请的主题，她正在授权Activesite Biotech。在这项专利发布后，Activesite Biotech将能够独家销售、许可和合作伽马分泌酶分析。Activesite Biotech将使用这种测试来识别和开发治疗阿尔茨海默病(AD)的新的、有效的治疗方法。有效治疗阿尔茨海默病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.