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.

项目摘要/摘要 阿尔茨海默氏病（AD）是一种致命的神经退行性疾病，全球流行率接近5000万 人们预计到2040年将翻一番。找到有效的广告疗法已被证明很困难，因为 由许多引人注目的3期临床试验失败证明，其中大多数直接针对 ß-淀粉样蛋白。这是越来越紧迫的，制定新的药物策略来打击广告。 当药物成功协商药物开发管道并获得FDA批准时，药物的可能性是 他们的靶标得到了人类疾病遗传研究的支持。人类遗传研究表明 小胶质细胞参与阿尔茨海默氏病进展的关键作用，最近发现了这一点 转录因子pu.1是小胶质细胞在 衰老和疾病。因此，该建议旨在开发新的，新发现的PU.1抑制性调节剂 （PIMS）用于临床前开发，长期目标是临床测试降低pu.1的假设 小胶质细胞的活性将安全延迟处于危险人群中的AD发病年龄（AAO）。 该提案中的研究利用了神经退行性联盟的跨学科结构 基础科学研究人员与行业药物开发退伍军人开展的独特合作 根据协作协议，以推动旨在治疗阿尔茨海默氏病和 其他神经退行性疾病。在特定的目标1下，PIM的体内安全性和效率将是 在AD的鼠标模型中确定。在特定的目标2下，将进行平行目标参与研究 识别PIM的目标，并将使用确定的目标用于开发阿萨斯以确定效率 AD和离体模型中的PIM。在特定的目标3下，将使用PK/PD优化选定的PIM，并且 ADMET筛选以将铅工具化合物开发成适合将来I期研究的候选化合物。 神经退行性财团中的生物学，化学和药理学专业知识， 德克萨斯大学医学博士安德森癌症中心，马萨诸塞理工学院和山 西奈医学院使这组研究人员非常适合执行拟议的目标。