Amyloid-Beta and Tau/Glycosaminoglycan Dual Inhibitor for Alzheimer's Disease

β 淀粉样蛋白和 Tau/糖胺聚糖双重抑制剂治疗阿尔茨海默病

• 批准号: 10545235
• 负责人: Paul Gregor
• 金额: $ 98.39万
• 依托单位: GISMO THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10545235
• 关键词: 3xTg-AD mouse; AD transgenic mice; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloidosis; Award; Biochemical; Biochemical Pathway; Biological Assay; Biological Availability; Blinded; Bone Marrow; Brain; Brain Diseases; Canis familiaris; Cardiovascular system; Chemicals; Chronic; Cognitive; Conscious; Data; Development; Disease; Dose; Drug Kinetics; Exhibits; Family Caregiver; Formulation; GAG Gene; Glycosaminoglycans; Goals; Half-Life; Heparitin Sulfate; Hepatocyte; Hippocampus (Brain); Hour; Human; In Vitro; Kentucky; Knock-in; Memory Loss; Metabolic; Methods; Microsomes; Modeling; Monkeys; Mus; Mutagenicity Tests; Nerve Degeneration; Neuraxis; Occupational; Oral; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Plasma; Positioning Attribute; Process; Property; Rattus; Recovery; Risk; Rodent; Safety; Seeds; Series; Small Business Innovation Research Grant; Tauopathies; Testing; Therapeutic; Toxic effect; Toxicokinetics; Toxicology; Transgenic Mice; Transgenic Organisms; United States; Universities; Validation; Work; aged; amyloid peptide; base; care costs; chemical property; cognitive performance; efficacy evaluation; family burden; glycosaminoglycan receptor; hyperphosphorylated tau; improved; inhibitor; method development; micronucleus; mouse model; nervous system disorder; neuropathology; novel; physical property; polysulfated glycosaminoglycan; pre-clinical; preclinical development; preclinical evaluation; preclinical study; prion-like; programs; protein aggregation; respiratory; safety assessment; scale up; small molecule; social; standard of care; tau Proteins; tau interaction; transgenic model of alzheimer disease; β-amyloid burden

ABSTRACT The aim of this project is to support an IND application for GTC-3295 for the treatment of Alzheimer's Disease (AD). Neurodegenerative amyloid diseases such as AD have common underlying biochemical pathways leading to oligomerization and aggregation of amyloidogenic peptides and prion-like spreading of amyloid proteopathic seeds throughout the Central Nervous System (CNS). Recent data suggest that heparan sulfate glycosaminoglycans (HS-GAGs) are the receptors responsible for internalization and spreading of amyloid-beta (Abeta) and tau neuropathologies in the brain. We are developing a novel class of therapeutics, Glycosaminoglycan-Interacting Small Molecules (GISMOs), for the treatment of AD. GISMOs are drug-like small molecule compounds that inhibit Abeta and tau interactions with HS-GAGs, each of which is a key molecule implicated in AD pathogenesis, and may reduce propagation of these aggregated proteins in the Alzheimer's brain. GTC-3295 is a New Chemical Entity (NCE) and has dual activity as it efficiently inhibits both Abeta as well as Tau interactions with HS- GAGs. In previous studies in a transgenic mouse model of AD, GTC-3295 decreased amyloid burden in the mouse brain by as much as five-fold, and significantly decreased hyperphosphorylated tau levels in CA1 region of hippocampus. Initial preclinical studies indicate that GTC-3295 is an orally available and brain penetrant compound possessing favorable properties in in vitro ADME, pharmacokinetics, toxicity and other studies. These results provide justification to continue developing GTC-3295. In this SBIR project, we will perform a number of IND-enabling preclinical studies including GLP Toxicology studies in two species, scale-up synthesis, formulation studies, and development of bioanalytical methods. We will also evaluate efficacy of GTC-3295 in two transgenic models of AD, that separately address Abeta and tau neuropathologies. Completion of these requisite development activities should position this project towards a successful IND submission to the FDA and advancing into Phase I clinical trials in humans.

摘要 本项目的目的是支持GTC-3295的IND申请，用于治疗 阿尔茨海默病（AD）。神经退行性淀粉样蛋白疾病如AD具有常见的 潜在的生化途径导致淀粉样蛋白的寡聚化和聚集 肽和朊病毒样传播的淀粉样蛋白的蛋白质病种子整个中枢神经系统 系统（CNS）。最近的数据表明，硫酸乙酰肝素糖胺聚糖（HS-GAG）是 负责β淀粉样蛋白（Abeta）和tau蛋白内化和扩散的受体 大脑中的神经病变我们正在开发一种新的治疗方法， 糖胺聚糖相互作用小分子（GISMO），用于治疗AD。GISMOs 是抑制Abeta和tau与HS-GAG相互作用的药物样小分子化合物， 其中每一种都是与AD发病机制有关的关键分子，并且可以减少 这些聚集在阿尔茨海默氏症大脑中的蛋白质。GTC-3295是一种新的化学实体（NCE） 并且具有双重活性，因为它有效地抑制Abeta以及Tau与HS的相互作用。 搞笑在先前的AD转基因小鼠模型研究中，GTC-3295降低了淀粉样蛋白 小鼠大脑中的负担高达五倍，并显着降低 海马CA 1区的过度磷酸化tau水平。初步临床前研究表明 GTC-3295是一种口服有效的脑渗透化合物，具有良好的 在体外ADME、药代动力学、毒性和其他研究中的性质。这些结果提供 继续开发GTC-3295的理由。在这个SBIR项目中，我们将执行一些 IND使能临床前研究，包括两个种属的GLP毒理学研究，规模扩大 合成、制剂研究和生物分析方法的开发。我们还将评估 GTC-3295在分别针对Abeta和tau两种AD转基因模型中的功效 神经病理学完成这些必要的开发活动， 该项目旨在向FDA成功提交IND并进入I期临床 人体试验