Tau Oligomer Platform Validation Using Lead Series Candidate in htau Mice

使用先导系列候选物在 htau 小鼠中进行 Tau 寡聚物平台验证

• 批准号: 9141080
• 负责人: JAMES G. MOE
• 金额: $ 74.98万
• 依托单位: OLIGOMERIX, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141080
• 关键词: Age-Months; Alzheimer' s Disease; Amyloid; Biochemical; Biomedical Technology; Brain; Chemicals; Clinical; Clinical Research; Clinical Trials; Collaborations; Contrast Media; Development; Direct Costs; Disease; Doctor of Philosophy; Dose; Economic Burden; Ensure; Failure; Flowcharts; Foxes; Goals; Grant; Lead; Libraries; Marketing; Mediation; Memory impairment; Metabolism; Methods; Mus; Oral; Oral Administration; Pathology; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Prevalence; Property; Qualifying; Research; Research Personnel; Route; Sales; Series; Shipping; Ships; Small Business Innovation Research Grant; Staging; Structure-Activity Relationship; Testing; Therapeutic; Validation; Vendor; Work; acute toxicity; advanced disease; aging population; base; commercial application; commercialization; drug discovery; experience; feeding; hTau Mice; high throughput screening; improved; in vivo; lead series; meetings; mouse model; neuron loss; novel strategies; prevent; programs; public health relevance; sarkosyl; scale up; screening; small molecule; success; tau Proteins; tau aggregation; technology development

 DESCRIPTION (provided by applicant): The prevalence of Alzheimer's disease (AD) is increasing worldwide due to demographic shifts resulting from an aging population. It is the most costly disease in the US with a financial burden of over $226 billion annually in direct costs that are estimated to increase to $1 trillion by 2050. Disease-modifying drugs that change the clinical course and delay symptomatic progression could reduce the economic burden by multiples of tens of billions of dollars per year if the onset of AD is delayed even a few years. To-date, all completed phase 3 clinical studies based on the amyloid hypothesis have failed to meet their clinical endpoints underscoring the critical need for alternative approaches for the development of AD therapeutics. The Company is developing disease-modifying small molecule drugs for AD that target the initial step in tau aggregation leading to the formation of tau oligomers, the toxic tau aggregates responsible for neuronal loss and impairment of memory formation. Competing programs use methods to select compounds inhibiting the formation of tau fibrils or large aggregates, previously thought to be the most toxic tau species. We hypothesized that by targeting the first step in tau self-association all forms of tau aggregates should be reduced. The long-term goal of the project is to advance disease-modifying drugs for AD to clinical studies and the market. The objective of this proposal is to validate our small molecule discovery platform targeting tau oligomer formation. The top candidate from our lead series of compounds will be used to demonstrate target engagement in the htau mouse model. The program aims are to 1) Select a compound from our lead series for the in vivo study 2) Produce and formulate the selected compound for the in vivo study 3) Demonstrate target engagement in the htau mouse model. Histological and biochemical analyses will be used to assess efficacy of compound for the in vivo reduction of tau pathology. Estimates show U.S only sales for a disease modifying therapeutic in the first year of launch of greater than $0.5 billion and surpassing $10 billion within 10 years post launch. The commercialization strategy is to form a strategic partnership with a large pharmaceutical company to accelerate to clinical studies and to the market. Significantly, the Company is now negotiating a collaboration with three different large pharma companies. This program will collaborate with Dr. Peter Davies, a major thought leader and world renowned expert in the study of tau pathology in Alzheimer's disease and in whose lab the htau mouse model was developed.

 描述（由申请人提供）：由于人口老龄化导致的人口变化，阿尔茨海默病（AD）的患病率在全球范围内不断增加。它是美国最昂贵的疾病，每年直接费用超过2260亿美元 预计到2050年将增加到1万亿美元。如果AD的发病延迟几年，改变临床病程和延迟症状进展的疾病修饰药物每年可以减少数百亿美元的经济负担。迄今为止，所有基于淀粉样蛋白假设的已完成的III期临床研究均未能达到其临床终点，这强调了开发AD治疗方法的替代方法的迫切需求。该公司正在开发用于AD的疾病修饰小分子药物，其靶向tau聚集的初始步骤，导致tau寡聚体的形成，这种毒性tau聚集体导致神经元损失和记忆形成障碍。竞争程序使用方法来选择抑制tau纤维或大聚集体形成的化合物，这些纤维或大聚集体以前被认为是毒性最大的tau种类。我们假设，通过靶向tau蛋白自结合的第一步，所有形式的tau蛋白聚集体都应该减少。该项目的长期目标是将AD的疾病修饰药物推向临床研究和市场。该提案的目的是验证我们的靶向tau寡聚体形成的小分子发现平台。来自我们的先导化合物系列的最佳候选物将用于证明htau小鼠模型中的靶向接合。该计划的目的是1）从我们的先导系列中选择一种化合物用于体内研究2）生产和配制所选化合物用于体内研究3）证明htau小鼠模型中的靶向结合。将使用组织学和生物化学分析来评估化合物在体内减少tau病理的功效。据估计，只有美国的疾病修饰治疗药物在上市第一年的销售额超过5亿美元，并在上市后10年内超过100亿美元。商业化战略是与一家大型制药公司建立战略合作伙伴关系，以加速临床研究和市场。值得注意的是，该公司目前正在与三家不同的大型制药公司进行合作谈判。该计划将与Peter Davies博士合作，他是阿尔茨海默病tau病理学研究的主要思想领袖和世界知名专家，并在其实验室开发了htau小鼠模型。