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: 10435506
• 负责人: ALISON M GOATE
• 金额: $ 158.77万
• 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/10435506
• 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; Persons; 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; 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; rational design; 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.

项目概要/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 年将增加一倍。事实证明，寻找 AD 的有效治疗方法很困难，因为 大量引人注目的 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 因此，开发新的药理学策略来对抗 AD 变得越来越紧迫。 药物成功谈判药物开发管道并获得 FDA 批准的可能性是其两倍 他们的目标得到了人类疾病遗传学研究的支持。人类遗传学研究揭示了一个事实。 最近发现小胶质细胞在阿尔茨海默病进展中发挥着关键作用 转录因子 PU.1 是小胶质细胞在神经退行性变过程中采用的促神经退行性表型的驱动因素 因此，该提案旨在开发新发现的新型 PU.1 抑制调节剂。 (PIM) 用于临床前开发，长期目标是临床测试减少 PU.1 的假设 小胶质细胞的活动将安全地延迟高危人群的 AD 发病年龄 (AAO)。 本提案中的研究利用了神经退行性疾病联盟的跨学科结构，该联盟是一个 基础科学研究人员和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的新疗法 在具体目标 1 下，PIM 的体内安全性和有效性将受到影响。 在特定目标 2 下，将在 AD 小鼠模型中进行平行目标参与研究。 确定 PIM 的目标，确定的目标将用于开发测定法以确定功效 在特定目标 3 下，将使用 PK/PD 和体外模型对选定的 PIM 进行优化。 ADMET 筛选将先导工具化合物开发为适合未来 I 期研究的候选化合物。 神经退行性疾病联盟汇集了生物学、化学和药理学专业知识，涵盖 德克萨斯大学 MD 安德森癌症中心、麻省理工学院和山。 西奈医学院使这组研究人员成为实现拟议目标的理想人选。