Tau Protein Aggregation Inhibitors for Tauopathies

Tau 蛋白聚集抑制剂治疗 Tau 病

• 批准号: 8521876
• 负责人: ALAN D. SNOW
• 金额: $ 108.14万
• 依托单位: PROTEOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8521876
• 关键词: Acute; Age-Months; Alzheimer' s Disease; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Aromatic Compounds; Back; Behavior assessment; Behavioral; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Brain; Cell model; Cells; Chemicals; Clinical Trials; Cytochrome P450; Dementia; Deposition; Development; Diagnosis; Dose; Drug Kinetics; Effectiveness; Elderly; Electron Microscopy; Filament; Fluorometry; Functional disorder; Housing; Human; Image Analysis; Immunohistochemistry; Impaired cognition; In Vitro; Injection of therapeutic agent; Lead; Learning; Legal patent; Literature; Measures; Memory impairment; Metabolic; Methodology; Modeling; Motor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Oral; Pathology; Patients; Penetration; Peripheral; Pharmaceutical Preparations; Phase; Plasma; Protein Binding; Publishing; Route; Senile Plaques; Small Business Innovation Research Grant; Spectrum Analysis; Staining method; Stains; Synapses; Tauopathies; Techniques; Technology; Testing; Therapeutic Agents; Thioflavin S; Toxic effect; Transgenic Mice; Western Blotting; astrogliosis; base; behavior test; cognitive function; commercialization; density; design; drug development; drug discovery; efficacy testing; fibrillogenesis; functional group; grape seed; improved; in vitro Assay; in vivo; inhibitor/antagonist; morris water maze; mouse model; neurofibrillary tangle formation; novel; novel therapeutics; pre-clinical; prevent; protein aggregate; protein aggregation; public health relevance; screening; small molecule; tau Proteins; tau aggregation; tau mutation; therapeutic target; treatment planning

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is characterized by brain amyloid plaques consisting of insoluble beta-amyloid protein (A?), and neurofibrillary tangles (NFTs) containing aggregated tau protein. AD drug discovery efforts have been largely focused on reducing brain A? levels, with much less emphasis on tau-directed strategies. ProteoTech Inc. has developed a number of different in vitro screening technologies and cellular models that identified new potent inhibitors of amyloidoses. We have designed, synthesized and tested a class of new chemical entities (NCE) consisting of small molecules (200-400 MW) containing polyhydroxylated aromatic rings spaced by a linker region. Results from our Phase I SBIR studies have identified ten (10) lead small molecule compounds that possess strong potency to inhibit/disrupt tau protein fibril formation in vitro. This discovery has been confirmed by several independent methodologies, including Thioflavin S fluorometry, CD spectroscopy, electron microscopy and cell-based assays. We hypothesize that specific lead polyhydroxylated aromatic compounds can also serve as direct inhibitors of tau aggregation/fibrillogenesis in mouse models of tauopathies. These compounds are believed to possess great potential as new therapeutic agents for AD and related tauopathies. The major objective of our Phase II SBIR project is to identify lead polyhydroxylated aromatic compounds in a relevant mouse model of tauopathy that have the ability to reduce tau-related pathology and to improve tau-induced behavioral deficits. In Specific Aim 1, we will assess the 10 lead small molecule compounds for their drugability, blood-brain-barrier penetration, pharmacokinetic (PK) profiles, and acute toxicity in mice. Three lead small molecule compounds that possess the best brain penetration, peripheral PK, drugability and tolerance in mice will be selected for animal studies in Aim 2. In Specific Aim 2, we will test the three best lead compounds (selected from Aim 1) for their in vivo efficacy in a transgenic mouse model expressing the human P301S mutant tau protein. We will treat mice with three compounds with one of two administration routes (orally or s.c. to be determined from Aim 1 studies) at 3 doses for each compound for 6 months (starting at 3 months of age). The effectiveness of these compounds in reducing tau aggregation/NFT formation, improving tau-related memory deficits, and improving CSF tau biomarker profiles will be determined using staining and quantitative immunohistochemistry, western blotting, ELISAs and behavioral testing including the Morris water maze test. This Phase II SBIR project will lead to a pre-clinical candidate (and back-up) for the treatment of tau aggregation in AD and other tauopathies.

描述（申请人提供）：阿尔茨海默氏病（AD）的特征是由不溶性β-淀粉样蛋白（Aβ）组成的脑淀粉样斑块和含有聚集的tau蛋白的神经原纤维缠结（NFT）。 AD 药物发现工作主要集中在减少大脑 A?水平，更少强调 tau 导向策略。 ProteoTech Inc. 开发了多种不同的体外筛选技术和细胞模型，用于鉴定新的有效淀粉样变抑制剂。我们设计、合成并测试了一类新的化学实体 (NCE)，其由小分子 (200-400 MW) 组成，其中含有由连接区域间隔的多羟基芳环。我们的 I 期 SBIR 研究结果已鉴定出十 (10) 种先导小分子化合物，它们在体外具有抑制/破坏 tau 蛋白原纤维形成的强大功效。这一发现已被多方证实 独立的方法学，包括硫磺素 S 荧光测定法、CD 光谱法、电子显微镜法和基于细胞的测定法。我们假设特定的先导多羟基芳香族化合物也可以作为 tau 蛋白病小鼠模型中 tau 蛋白聚集/原纤维形成的直接抑制剂。这些化合物被认为具有作为AD和相关tau蛋白病的新治疗剂的巨大潜力。我们 II 期 SBIR 项目的主要目标是在相关的 tau 蛋白病小鼠模型中鉴定出先导多羟基芳香族化合物，这些化合物能够减少 tau 相关病理并改善 tau 诱导的行为缺陷。在具体目标 1 中，我们将评估 10 种先导小分子化合物的成药性、血脑屏障渗透性、药代动力学 (PK) 特征和小鼠急性毒性。在目标 2 中，将选择在小鼠中具有最佳脑渗透性、外周 PK、成药性和耐受性的三种先导小分子化合物用于动物研究。在具体目标 2 中，我们将测试三种最佳先导化合物（从目标 1 中选择）在表达人 P301S 突变 tau 蛋白的转基因小鼠模型中的体内功效。我们将用三种化合物治疗小鼠，采用两种给药途径之一（口服或皮下注射，由 Aim 1 研究确定），每种化合物 3 剂，持续 6 个月（从 3 个月龄开始）。这些化合物在减少 tau 聚集/NFT 形成、改善 tau 相关记忆缺陷和改善 CSF tau 生物标志物谱方面的有效性将通过染色和定量免疫组织化学、蛋白质印迹、ELISA 和行为测试（包括 Morris 水迷宫测试）来确定。该 II 期 SBIR 项目将产生用于治疗 AD 和其他 tau 病中 tau 聚集的临床前候选药物（和后备药物）。