Develop AD Connectivity Maps with Human iPSC-Derived Brain Cells and their Use

使用人类 iPSC 衍生脑细胞开发 AD 连接图及其用途

• 批准号: 10504728
• 负责人: YADONG HUANG
• 金额: $ 94.18万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504728
• 关键词: Address; Age of Onset; Algorithms; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Animals; Apolipoprotein E; Area; Astrocytes; Bar Codes; Bumetanide; Cell Nucleus; Cells; Central Nervous System Agents; Central Nervous System Diseases; Computer Analysis; Consumption; Data; Data Set; Databases; Development; Dimethyl Sulfoxide; Disease; Dose; Drug Targeting; Environmental Risk Factor; Formulation; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic; Genomics; Genotype; Goals; Hour; Human; Malignant Neoplasms; Maps; Microglia; Molecular; Molecular Profiling; Mus; Nature; Neuraxis; Neurodegenerative Disorders; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Process; Protein Isoforms; Proteins; Reporting; Resources; Safety; Testing; Therapeutic; Therapeutic Agents; Time; Toxicology; Validation; base; brain cell; cell type; cost; differential expression; drug candidate; drug development; drug repurposing; drug testing; excitatory neuron; induced pluripotent stem cell; inhibitory neuron; large-scale database; mouse model; novel; novel therapeutics; public database; research and development; screening; single-cell RNA sequencing; success; tau Proteins; transcriptomics; whole genome

SUMMARY Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder caused by interactions among multiple genetic and environmental factors. The strongest genetic factor of AD is apolipoprotein (APO) E genotype— APOE4 increases AD risk and lowers age-onset of AD and APOE4 carriers account for ~60% of all AD cases; the remaining ~40% are APOE3 carriers. The genetic complexity and multifactorial nature of Alzheimer’s disease pose unique challenges for traditional drug development that usually targets a specific gene, protein, or pathway. For the past several decades, new drug development efforts to target specific AD-related proteins or pathways have shown promise in animal studies, only to fail during human trials. Since the process of developing new drugs for Alzheimer’s disease is complicated, time-consuming, and costly, there is a pressing need to consider unconventional drug development strategies, such as repurposing drugs currently approved for other conditions. The approach of drug repurposing has a number of advantages over the development of new drugs and has been used successfully for various disease conditions. The established safety and tolerability of approved drugs can lower the burdensome financial thresholds associated with screening, dose optimization, toxicology, formulation, and manufacturing development. Repurposing approved drugs can also drastically shorten the time for a drug to reach patients. The recent convergence of two factors presents an unprecedented opportunity to advance rational drug repurposing. First is the availability of public databases from large-scale genomic, transcriptomic, and other molecular profiling studies for major diseases in humans. Second is the development of computational approaches and algorithms as well as the network concept of drug targets, which allows us to investigate the ability of a therapeutic agent to perturb entire molecular networks away from disease states. Many therapeutic areas including cancer have benefited from repurposing existing drugs based on the network concept of drug targets. Drug repurposing for central nervous system (CNS) diseases, including Alzheimer’s disease, started recently, with limited success so far, including our recent repurposing of bumetanide for treating APOE4-related Alzheimer’s disease. A major challenge of drug repurposing for CNS diseases, including Alzheimer’s disease, is the lack of whole genome gene expression perturbation databases of approved drugs in human cell types relevant to CNS diseases, including AD. This proposal aims to address this major bottleneck for CNS disease drug repurposing, focusing on AD drug repurposing, by establishing APOE-genotype-dependent and human CNS cell-type-specific Connectivity Maps (hCNS-CMAPs) covering ~12,000 drugs demonstrated safety in humans, using human iPSC-derived CNS cells (Aim 1). We will then apply these hCNS-CMAPs for AD drug repurposing and validate the identified top drugs in a novel mouse model of AD (Aim 2). The outcomes of this project will provide the research and drug development fields with invaluable resources for repurposing the approved drugs toward AD and other CNS diseases.

总结 阿尔茨海默病（Alzheimer's disease，AD）是一种多因素神经退行性疾病， 遗传和环境因素。AD最强的遗传因素是载脂蛋白（APO）E基因型- APOE 4可增加AD的发病风险，降低AD的发病年龄，APOE 4携带者占所有AD病例的约60%; 其余约40%为APOE 3携带者。阿尔茨海默病的遗传复杂性和多因素性质 这对通常针对特定基因、蛋白质或途径的传统药物开发提出了独特的挑战。 在过去的几十年里，针对特定AD相关蛋白或通路的新药开发努力 在动物研究中显示出了希望，只是在人体试验中失败了。由于开发新的 阿尔茨海默病的药物是复杂的，耗时的，昂贵的，有迫切需要考虑 非常规药物开发策略，例如重新利用目前批准用于其他疾病的药物。 药物再利用的方法与新药开发相比具有许多优势， 已成功用于各种疾病。已批准药物的既定安全性和耐受性 可以降低与筛选、剂量优化、毒理学 配方和制造开发。重新使用批准的药物也可以大大缩短时间 让药物到达患者手中最近两个因素的结合为以下方面提供了前所未有的机会： 推进合理用药再利用。首先是大规模基因组公共数据库的可用性， 转录组学和其他用于人类主要疾病的分子谱研究。二是发展 计算方法和算法以及药物靶点的网络概念，这使我们能够 研究治疗剂扰乱整个分子网络使其远离疾病状态的能力。 包括癌症在内的许多治疗领域都受益于基于药物的现有药物的再利用。 药物靶点的网络概念。药物再利用以治疗中枢神经系统（CNS）疾病，包括 阿尔茨海默氏症，最近开始，迄今为止成功有限，包括我们最近重新利用布美他尼 用于治疗APOE 4相关的阿尔茨海默病。中枢神经系统疾病药物再利用的一个主要挑战， 包括阿尔茨海默病，是缺乏全基因组基因表达扰动数据库的批准 在与CNS疾病相关的人类细胞类型中的药物，包括AD。 该提案旨在解决CNS疾病药物再利用的这一主要瓶颈，重点关注AD药物 通过建立APOE基因型依赖性和人类CNS细胞类型特异性连接图来重新利用 使用人iPSC衍生的CNS细胞，涵盖约12，000种药物的hCNS-CMAP在人类中证明了安全性 (Aim 1）。然后，我们将应用这些hCNS-CMAP进行AD药物再利用，并验证在 一种新的AD小鼠模型（Aim 2）。该项目的成果将提供研究和药物开发 这些领域拥有宝贵的资源，可将已批准的药物重新用于AD和其他CNS疾病。