Measuring metabolism of C-terminal fragments of amyloid beta in the human central

描述(由申请人提供)：这笔赠款将寻求开发一种方法，使我们能够测试一种有前途的治疗阿尔茨海默病的新药是否在人脑中产生预期的效果。这一方法将使制药公司能够就哪些药物进入后期临床试验做出明智的决定，并根据药效反应优化剂量和给药时间表。C2N诊断公司已经从华盛顿大学获得了平台技术的许可，以进行该公司的稳定同位素标记动力学(丝)分析。这种分析方法用来测量大脑中蛋白质的产量和清除率。以前，这种方法已经被应用于测量大脑中总A2的产生和清除，以及在治疗阿尔茨海默病的临床开发中评估某些化合物的生物活性。要测量一类新兴的化合物--伽玛分泌酶调节剂的生物活性，我们需要能够测量单个A2亚型的产生和清除，特别是A2 38、40和42。这笔赠款中提议的实验将在这笔赠款的第一阶段发展这一方法。在第二阶段，该方法将应用于一项小型患者研究。将这项技术应用于概念验证人类研究将极大地促进该技术的商业化。此外，这项技术将极大地增强我们对AD代谢如何在疾病发病机制中发挥作用的理解。与公共卫生相关：阿尔茨海默病是一个日益严重的问题，目前美国估计有500万人受到影响。目前还没有被批准用于AD的疾病修饰药物，部分原因是缺乏衡量这些类型药物的生物活性和临床疗效的相关工具。拟议的实验旨在使C2N能够帮助制药公司优化其药物开发工作的质量，并加快将有希望的疾病修改疗法带到临床。

DESCRIPTION (provided by applicant): This grant will seek to develop a methodology that will allow us to test whether a promising new class of drugs for Alzheimer's disease is having the desired effect in the human brain. This methodology will allow pharmaceutical companies to make informed decisions about which drugs to advance into late stage clinical trials, and to optimize dosing and administration schedules based on pharmacodynamic response. C2N Diagnostics has licensed the platform technology from Washington University to carry out the company's stable isotope labeling kinetic (SILK) assay. This assay is used to measure production and clearance rates of proteins in the brain. Previously, this methodology has been applied to measuring production and clearance of total A2 from the brain, and evaluating the biologic activity of certain compounds in clinical development for the treatment of Alzheimer's. To measure the biologic activity of an emerging class of compounds, gamma-secretase modulators, we need to be able to measure the production and clearance of the individual A2 isoforms, specifically A2 38, 40 and 42. The experiments proposed in this grant will develop this methodology in Phase I of this grant. In Phase II, the methodology will be applied to a small patient study. Applying the technology to a proof of concept human study will greatly facilitate commercialization of the technology. Further, this technology will greatly enhance our understanding of how AD metabolism plays a role in the pathogenesis of the disease. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a growing problem with an estimated 5 million people currently affected in the US. There are currently no disease modifying drugs approved for AD, in part due to a paucity of relevant tools to measure biologic activity and clinical efficacy for these types of drugs. The proposed experiments are intended to allow C2N to help pharmaceutical companies optimize the quality of their drug development efforts and to expedite bringing promising disease modifying treatments to the clinic.