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

测量人体中枢淀粉样蛋白β C 末端片段的代谢

• 批准号: 7746956
• 负责人: Tim West
• 金额: $ 13.31万
• 依托单位: C2N DIAGNOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746956
• 关键词: Affect; Age; Alzheimer' s Disease; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Behavior; Behavioral; Biological Assay; Biological Markers; Blood; Brain; C-terminal; Cell Culture System; Cell Culture Techniques; Cells; Cerebrospinal Fluid; Cleaved cell; Clinic; Clinical; Clinical Trials; Clinical assessments; Cognitive; Communities; Complex Mixtures; Confidential Information; Cost Sharing; Culture Media; Data; Development; Diagnostic; Diagnostic tests; Disease; Dose; Drug effect disorder; Enzyme-Linked Immunosorbent Assay; Evaluation; Feasibility Studies; Future; Government; Grant; Hand; Hour; Human; Immunoprecipitation; Individual; Infusion procedures; Kinetics; Label; Lead; Left; Legal patent; Leucine; Licensing; Measures; Metabolic Clearance Rate; Metabolism; Methodology; Methods; N-terminal; Neuraxis; Neurofibrillary Tangles; Noise; Pathogenesis; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Plasma; Play; Population; Positioning Attribute; Production; Protein Isoforms; Proteins; Proteolysis; Quality Control; Relative (related person); Reliance; Research Contracts; Role; Saints; Sampling; Schedule; Scientist; Senile Plaques; Services; Site; Small Business Innovation Research Grant; Specificity; Stable Isotope Labeling; Staging; Technology; Testing; Time; Universities; Upper arm; Validation; Variant; Washington; Work; abeta accumulation; base; beta secretase; clinical efficacy; commercialization; design; disorder control; drug candidate; drug development; experience; gamma secretase; human study; human subject; improved; in vivo; inhibitor/antagonist; instrument; interest; mass spectrometer; metabolic abnormality assessment; metabolomics; novel; point-of-care diagnostics; preclinical study; prevent; programs; public health relevance; research and development; research study; response; stable isotope; success; tau Proteins; therapy development; tissue/cell culture; tool; treatment trial

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.

描述（由申请人提供）：这项资助将寻求开发一种方法，使我们能够测试一种有希望的治疗阿尔茨海默病的新型药物是否在人脑中产生预期的效果。这种方法将使制药公司能够在知情的情况下决定将哪些药物推进到后期临床试验，并根据药效学反应优化剂量和给药计划。C2N诊断公司已经从华盛顿大学获得了该平台技术的许可，以进行该公司的稳定同位素标记动力学（SILK）测定。该试验用于测量大脑中蛋白质的产生和清除率。此前，该方法已被应用于测量大脑中总A2的产生和清除，以及评估临床开发中用于治疗阿尔茨海默氏症的某些化合物的生物活性。为了测量一类新兴化合物——γ分泌酶调节剂的生物活性，我们需要能够测量单个A2异构体的产生和清除，特别是A2 38、40和42。本拨款中提出的实验将在拨款的第一阶段发展这种方法。在II期，该方法将应用于一项小型患者研究。将该技术应用于概念验证的人体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。公共卫生相关性：阿尔茨海默病是一个日益严重的问题，目前在美国估计有500万人受到影响。目前还没有批准用于阿尔茨海默病的疾病修饰药物，部分原因是缺乏相关工具来测量这些类型药物的生物活性和临床疗效。拟议中的实验旨在让C2N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治疗方法推向临床。