Development of PU.1 Inhibitory Modulators as Novel Therapeutics for Alzheimer's Disease

开发 PU.1 抑制调节剂作为阿尔茨海默病的新疗法

• 批准号: 10159826
• 负责人: ALISON M GOATE
• 金额: $ 159.55万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10159826
• 关键词: Adopted; Affect; Age; Age of Onset; Aging; Agreement; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Animals; Basic Science; Binding Proteins; Biological Assay; Biological Markers; Biology; Brain; Canis familiaris; Cell Line; Cell physiology; Cells; ChIP-seq; Chemistry; Clinical; Collaborations; Data; Development; Disease; Disease Progression; Disease susceptibility; Drug Industry; Drug Targeting; Failure; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Haplotypes; Healthcare Systems; Human; Human Genetics; Immune; Innate Immune System; Institutes; Lead; Mass Spectrum Analysis; Measurement; Mediation; Microglia; Modeling; Modification; Molecular Target; Molecular and Cellular Biology; Mus; Myeloid Cells; Nerve Degeneration; Neurodegenerative Disorders; No-Observed-Adverse-Effect Level; Onset of illness; Peripheral; Peripheral Blood Mononuclear Cell; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase III Clinical Trials; Plasma; Populations at Risk; Post-Translational Protein Processing; Prevalence; Primates; Rattus; Research Personnel; Risk; Role; Route; SPI1 gene; Safety; Sentinel; Series; Structure; Technology; Testing; Tissues; Toxicology; University of Texas M D Anderson Cancer Center; Validation; Veterans; Wild Type Mouse; base; biomarker development; bone marrow hyperplasia; combat; design; drug development; drug discovery; effective therapy; genome wide association study; genotoxicity; human genomics; in vivo; induced pluripotent stem cell; innovation; lead optimization; macrophage; medical schools; mouse model; neurodegenerative phenotype; neuroinflammation; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; phase 1 study; preclinical development; preclinical study; programs; risk variant; safety study; scale up; screening; small molecule; small molecule therapeutics; tool; transcription factor; transcriptome sequencing; transcriptomics

Project Summary/Abstract Alzheimer's disease (AD) is a fatal neurodegenerative disease with a global prevalence close to 50 million people, which is expected to double by 2040. Finding an effective treatment for AD has proven difficult, as evidenced by numerous high profile Phase 3 clinical trial failures, most of which directly target the reduction of ß-amyloid. Thus, it is becoming increasingly urgent to develop new pharmacological strategies to combat AD. Drugs are twice as likely to successfully negotiate the drug development pipeline and obtain FDA approval when their targets are supported from human genetic studies of disease. Human genetic studies have revealed a critical role for microglia involvement in Alzheimer’s disease progression, and it has recently been discovered that the transcription factor PU.1 is a driver of the pro-neurodegenerative phenotype adopted by microglia during aging and disease. This proposal therefore aims to develop novel, newly-discovered PU.1 Inhibitory Modulators (PIMs) for preclinical development, with the long term goal of clinically testing the hypothesis that reducing PU.1 activity in microglia will safely delay the age of AD onset (AAO) in at-risk populations. The studies in this proposal leverage the interdisciplinary structure of the Neurodegeneration Consortium, a unique collaboration between basic science researchers and industry drug development veterans operating under a collaborative agreement to push forward novel therapeutics aimed at treating Alzheimer’s diseaes and other neurodegenerative diseases. Under Specific Aim 1, the in vivo safety and efficacy of PIMs will be determined in mouse models of AD. Under Specific Aim 2, parallel target engagement studies will be performed to identify the target of PIMs, and the identified targets will be used to develop assays to determine the efficacy of PIMs in AD and in ex vivo models. Under Specific Aim 3, selected PIMs will be optimized using PK/PD and ADMET screening to develop lead tool compounds into candidate compounds suitable for future Phase I studies. The combined biology, chemistry, and pharmacology expertise in the Neurodegeneration Consortium, spanning The University of Texas MD Anderson Cancer Center, the Massachussets Institute of Technology, and the Mt. Sinai School of Medicine, make this group of researchers ideally suited to execute the proposed aims.

项目摘要/摘要 阿尔茨海默病(AD)是一种致命的神经退行性疾病，全球患病率接近5000万 预计到2040年，这一数字将翻一番。事实证明，找到治疗阿尔茨海默病的有效方法很困难，因为 大量备受瞩目的3期临床试验失败证明了这一点，其中大多数直接针对减少 β-淀粉样蛋白。因此，开发新的药理策略来对抗阿尔茨海默病变得越来越迫切。 在以下情况下，药物成功谈判药物开发流水线并获得FDA批准的可能性会增加一倍 他们的目标得到了人类对疾病的基因研究的支持。人类基因研究揭示了一种 小胶质细胞在阿尔茨海默病进展中的关键作用，最近发现 转录因子PU.1是小胶质细胞在发育过程中采用的神经变性表型的驱动因素 衰老和疾病。因此，该提议旨在开发新发现的新型PU1抑制调制剂 (PIMS)用于临床前开发，长期目标是在临床上测试降低PU.1的假设 在高危人群中，小胶质细胞的活动将安全地推迟AD的发病年龄(AAO)。 这项建议中的研究利用了神经变性联合会的跨学科结构，一个 基础科学研究人员与行业药物开发资深人士之间的独特合作 根据一项合作协议，推动旨在治疗阿尔茨海默病和 其他神经退行性疾病。在具体目标1下，注射用注射剂的体内安全性和有效性将是 在阿尔茨海默病小鼠模型中确定。在具体目标2下，将进行平行目标交战研究 确定PIMs的靶点，识别的靶点将用于开发确定疗效的分析方法 在AD和体外模型中PIMs的表达。在具体目标3下，将使用PK/PD和 ADMET筛选，将先导工具化合物开发为适用于未来第一阶段研究的候选化合物。 神经退行性变协会的生物学、化学和药理学的综合专业知识 德克萨斯大学MD安德森癌症中心、麻省理工学院和Mt. 西奈医学院，使这组研究人员成为执行拟议目标的理想人选。