Tau oligomer platform validation using lead series candidate in htau mice

标题：在htau小鼠中使用铅系列候选物验证tau寡聚体平台 项目摘要-SBIR资助机会：推进阿尔茨海默病(AD)研究和 阿尔茨海默病相关痴呆(ADRD)(R43/R44)，PAS-17-064 该计划的长期目标是开发一种治疗疾病的小分子药物 阿尔茨海默病(AD)和相关的神经官能症。有一种严重的未得到满足的疾病治疗需求 治疗AD的药物。慢性治疗策略需要经济上可行的方法，如小分子 毒品。这项计划正在进行中，以满足这一需求的疾病修改药物，如果成功，将有 对目前500多万患有AD的美国人(预计为1600万人)产生了巨大的影响 到2050年)及其照顾者，并将有助于降低目前2590亿美元的成本(预计为1.1万亿美元 到2050年)对我们的国家。在Ph II程序中，先导化合物抑制了转基因中tau的聚集 表达人tau(Htau)的小鼠，使用预防性范例最好地代表了AD中tau的聚集。这 应用于测试铅对额颞部tau病理模型JNPL3小鼠的疗效 采用预防性(目标1)和治疗性(目标2)两种治疗策略。此外，销售线索将 在老年htau小鼠的治疗性研究中进行测试(目标3)。Tau病理分析(tau聚集性， 过度磷酸化和错误折叠)，使用ELISA和免疫细胞化学方法，以及行为研究 对于衰老的htau和JNPL3小鼠，将进行测试，以评估小鼠的功能如何随着tau的减少而变化 病理学。随着年龄的增长，JNPL3小鼠会出现后肢瘫痪，并将使用 转杆装置。衰老的htau小鼠出现认知缺陷，这将通过巴恩斯迷宫来描述 作为空间学习和记忆的一种衡量标准。每项JNPL3研究将有三组小鼠(n=20 每组：饲料载体，饲料中碾磨的化合物10 mg/kg或40 mg/kg)，htau研究将 四组(n=15，每组：基础队列、饲料载体、饲料中化合物10 mg/kg或40 mg/kg) 为研究提供足够动力。在开始处理之前，化合物将被合成并配制成饲料 对于每一项研究来说，开始时间都会错开。每项研究的疗程为四个月 这将在不同的年龄开始，取决于治疗模式和疾病的特征 小鼠模型的研究进展。体内研究，包括tau的行为特征和分析 病理学，将由Peter Davies博士和他在范斯坦研究所的实验室独立完成 医学研究(纽约州曼哈塞特)。研究人员将在治疗和治疗期间对治疗组盲目 用于行为和生化分析。寡头公司将管理该项目，执行额外的分析 带有商品化tau抗体的小鼠标本及其新的tau生物标志物abs 碎片，并将分析和报告所有数据。每项研究的主要终点将是减少 具有统计学意义的不溶性tau；研究的次要终点将取决于剂量 不溶性tau的减少、磷酸化tau的减少、裂解tau的减少和改善 老年jnpl3和htau小鼠的运动或认知缺陷。

TITLE: Tau oligomer platform validation using lead series candidate in htau mice PROJECT SUMMARY - SBIR Funding Opportunity: Advancing Research on Alzheimer's Disease (AD) and Alzheimer's-Disease-Related Dementias (ADRD) (R43/R44), PAS-17-064 The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer’s disease (AD) and related tauopathies. There is a critical unmet need for a disease modifying drug for AD. Chronic treatment strategies require economically feasible approaches such as small molecule drugs. This program is progressing to fill this need with a disease modifying drug that, if successful, will have a tremendous impact on the more than five million Americans who currently have AD (projected to be 16 million by 2050) and their caregivers, and will help reduce the current cost of $259 billion (projected to be $1.1 trillion by 2050) to our nation. In the Ph II program the lead compound inhibited tau aggregation in transgenic mice expressing human tau (htau), best representing tau aggregation in AD using a preventive paradigm. This application is for testing the efficacy of the lead in JNPL3 mice that model tau pathology in frontotemporal dementia using both preventive (Aim 1) and therapeutic (Aim 2) treatment strategies. Additionally, the lead will be tested in a therapeutic study in aged htau mice (Aim 3). Analysis of tau pathology (tau aggregation, hyperphosphorylation and misfolding) using ELISAs and immunocytochemistry methods, and behavioral studies for the aged htau and JNPL3 mice will be performed to evaluate how mouse function tracks with reduction of tau pathology. JNPL3 mice develop hind limb paralysis as they age and will be evaluated for latency to fall using a rotarod apparatus. Aged htau mice develop cognitive deficits that will be characterized using the Barnes maze as a measure of spatial learning and memory. For each JNPL3 study there will be three groups of mice (n=20 per group: feed vehicle, 10 mg/kg or 40 mg/kg of compound milled in feed), and for the htau study there will be four groups (n=15 per group: baseline cohort, feed vehicle, 10 mg/kg or 40 mg/kg of compound in feed) to sufficiently power the studies. Compound will be synthesized and formulated into feed prior to starting treatment for each study that will have staggered start times. The length of treatment will be four months for each study that will start at different ages depending on the treatment paradigm and the characteristics of disease progression in the mice models. The in vivo studies, including behavioral characterization and analyses of tau pathology, will be performed independently by Peter Davies, Ph.D., and his laboratory at the Feinstein Institute for Medical Research (Manhasset, NY). Researchers will be blinded to treatment groups during treatment and for behavioral and biochemical analyses. Oligomerix will manage the project, perform additional analyses of mouse specimens with commercially available Abs for tau in parallel with its novel biomarker Abs for tau fragments, and will analyze and report all data. The primary endpoint for each study will be the reduction of insoluble tau with statistical significance; the secondary endpoints for the studies will be dose-dependent reduction of insoluble tau, reduction of phosphorylated tau, and reduction of cleaved tau, and amelioration of motor or cognitive deficits in aged JNPL3 and htau mice, respectively.