Tau oligomer platform validation using lead series candidate in htau mice

标题：在htau小鼠中使用先导系列候选物的Tau寡聚体平台验证 SBIR资助机会：推进阿尔茨海默病（AD）的研究， 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改善疾病的小分子药物， 阿尔茨海默病（AD）和相关的tau蛋白病。目前存在一种严重的未满足需求， AD的药物慢性治疗策略需要经济上可行的方法，如小分子药物， 毒品该计划正在进行，以满足这一需要与疾病修饰药物，如果成功，将有一个 对目前患有AD的500多万美国人（预计为1600万）产生了巨大影响 到2050年）及其护理人员，并将有助于减少目前2590亿美元的成本（预计为1.1万亿美元 到2050年，我们的国家。在Ph II程序中，先导化合物抑制转基因小鼠中的tau聚集。 表达人tau（htau）的小鼠，使用预防性范例最好地代表AD中的tau聚集。这 本申请用于测试铅在JNPL 3小鼠中的功效，所述JNPL 3小鼠在额颞叶中模拟tau病理学， 使用预防性（目标1）和治疗性（目标2）治疗策略治疗痴呆症。此外，领导将 在老年htau小鼠的治疗研究中进行测试（Aim 3）。tau病理学分析（tau聚集， 过度磷酸化和错误折叠），以及行为研究 将对老年htau和JNPL 3小鼠进行评估，以评估小鼠功能如何随着tau的减少而跟踪 病理JNPL 3小鼠随着年龄的增长发展后肢麻痹，并将使用以下方法评估跌倒的潜伏期： 旋转杆装置。老年htau小鼠出现认知缺陷，将使用巴恩斯迷宫表征 作为空间学习和记忆的衡量标准。对于每个JNPL 3研究，将有三组小鼠（n=20 每组：饲料载体，10 mg/kg或40 mg/kg在饲料中研磨的化合物），对于HTAT研究， 四组（每组n=15：基线组，饲料媒介物，饲料中10 mg/kg或40 mg/kg化合物）， 为研究提供足够的动力。在开始治疗前，将合成化合物并配制成饲料 每个研究的开始时间错开。每项研究的治疗时间为4个月 根据治疗模式和疾病的特点， 小鼠模型的进展。体内研究，包括行为表征和tau蛋白的分析 病理学，将由Peter Davies，Ph.D.，他在费恩斯坦研究所的实验室 （Manhasset，NY）。在治疗期间，研究人员将对治疗组设盲， 进行行为和生化分析Oligomerix将管理该项目，进行额外的分析， 具有市售tau抗体的小鼠样本与其新的tau生物标志物Ab平行 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 具有统计学显著性的不溶性tau;研究的次要终点将具有剂量依赖性 不溶性tau蛋白的减少、磷酸化tau蛋白的减少和切割的tau蛋白的减少，以及 分别在年老的JNPL 3和htau小鼠中的运动或认知缺陷。

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.