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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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.

概括阿尔茨海默病（AD）是一种多因素神经退行性疾病，由多种因素相互作用引起遗传和环境因素 AD 最强的遗传因素是载脂蛋白（APO）E 基因型—— APOE4 增加 AD 风险并降低 AD 发病年龄，APOE4 携带者约占所有 AD 病例的 60%；其余约 40% 是 APOE3 携带者阿尔茨海默病的遗传复杂性和多因素性质。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，新药开发努力针对特定的 AD 相关蛋白或通路在动物研究中显示出希望，但在开发新产品的过程中却在人体试验中失败了。治疗阿尔茨海默病的药物复杂、耗时、成本高，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。与新药开发相比，药物再利用方法具有许多优点，并且具有广泛的应用前景。已成功用于各种疾病状况，已批准药物的安全性和耐受性。可以降低与筛查、剂量优化、毒理学相关的繁重的财务门槛，重新利用已批准的药物也可以大大缩短时间。最近两个因素的结合提供了前所未有的机会。首先是大规模基因组公共数据库的可用性，其次是人类主要疾病的转录组学和其他分子谱研究的发展。计算方法和算法以及药物靶标的网络概念，这使我们能够研究治疗剂扰乱整个分子网络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现有药物的重新利用药物靶标的网络概念。中枢神经系统（CNS）疾病的药物再利用，包括阿尔茨海默氏病是最近才开始的，迄今为止取得的成功有限，包括我们最近对布美他尼的重新利用用于治疗 APOE4 相关的阿尔茨海默病是中枢神经系统疾病药物重新利用的主要挑战，包括阿尔茨海默病在内，缺乏经过批准的全基因组基因表达扰动数据库与中枢神经系统疾病（包括 AD）相关的人类细胞类型药物。该提案旨在解决中枢神经系统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 (hCNS-CMAP) 涵盖约 12,000 种药物，使用人 iPSC 衍生的 CNS 细胞证明了对人体的安全性（目标 1）然后，我们将应用这些 hCNS-CMAP 进行 AD 药物的再利用并验证已确定的顶级药物。一种新型 AD 小鼠模型（目标 2）。该项目的成果将为研究和药物开发提供帮助。这些领域拥有宝贵的资源，可以将已批准的药物重新用于治疗 AD 和其他中枢神经系统疾病。