A Dominantly Inherited AD network In Vitro Trial with a Gamma-Secretase Modulator

使用伽马分泌酶调节剂的显性遗传 AD 网络体外试验

• 批准号: 9795379
• 负责人: Steven Lee Wagner
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795379
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Amyloid beta-Protein; Animal Model; Award; Axon; Axonal Transport; Biological Markers; Brain-Derived Neurotrophic Factor; Cell model; Cells; Clinical Trials; Collaborations; DNA Sequence Alteration; Development; Diagnosis; Digit structure; Disease; Disease Progression; Dose; Early Endosome; Early Onset Familial Alzheimer' s Disease; Effectiveness; Enrollment; Evaluation; Event; Failure; Fibroblasts; Functional disorder; Funding; Generations; Goals; Human; In Vitro; Inherited; Investigational Drugs; Late Onset Alzheimer Disease; Lead; Link; MAPT gene; Measures; Mediating; Methods; Modeling; Mus; Mutation; Neurofibrillary Tangles; Neurons; No-Observed-Adverse-Effect Level; Non-Steroidal Anti-Inflammatory Agents; Onset of illness; Pathology; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Prevention trial; Primary Prevention; Process; Production; Rattus; Rodent; Rodent Model; Secure; System; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicity Tests; Toxicology; United States National Institutes of Health; Veterans; abeta accumulation; axonopathy; base; clinical candidate; cohort; drug development; efficacy study; efficacy testing; extracellular; gamma secretase; good laboratory practice; hyperphosphorylated tau; improved; in vivo; induced pluripotent stem cell; inhibitor/antagonist; mutant; mutation carrier; neuropathology; non-demented; nonhuman primate; novel; patient population; preclinical evaluation; presenilin-1; resistance mutation; response; safety testing; side effect; small molecule; success; tau Proteins

Alzheimer’s disease (AD) is defined neuropathologically by extracellular plaques composed of β-amyloid (Aβ42) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. Aβ accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose comprehensive in vitro analysis of a unique set of novel small molecule drugs known gamma- secretase modulators (GSMs) to further explore AD therapeutics. This proposal will focus on testing an optimal lead clinical candidate for efficacy in human neurons aimed at halting Aβ42- related pathologies AD. Our overarching hypothesis is GSM therapy aimed to disrupt production of Aβ42 will be an efficacious treatment approach for prodromal or early AD, as well as sporadic late-onset AD. The goal of this project is to validate target engagement in human neurons from selected patients.

阿尔茨海默氏病（AD）在神经病理学上被定义为细胞外斑块， β-淀粉样蛋白（Aβ42）和由过度磷酸化形式的 微管相关蛋白tau。Aβ的积累和tau蛋白的过度磷酸化是 被认为是导致完全AD神经病理学的关键事件。在这里我们建议 对一组独特的新型小分子药物进行全面的体外分析， 分泌酶调节剂（GSM），以进一步探索AD治疗。该提案将重点关注 在人类神经元中测试最佳先导临床候选药物的疗效，旨在阻止Aβ42- 相关疾病AD。我们的首要假设是GSM治疗旨在破坏生产 Aβ42将是前驱或早期AD以及散发性AD的有效治疗方法。 晚发性AD该项目的目标是验证人类神经元的目标参与， 选择患者。