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.

概括阿尔茨海默氏病（AD）是由多个相互作用引起的多因素神经退行性疾病遗传和环境因素。 AD的强遗传因素是载脂蛋白（APO）E基因型 - APOE4增加了AD风险，降低了AD和APOE4载体的年龄率占所有AD病例的60％；其余约40％是APOE3载体。阿尔茨海默氏病的遗传复杂性和多因素性质通常针对特定基因，蛋白质或途径的传统药物开发构成独特的挑战。在过去的几十年中，新的药物开发旨在针对特定的广告相关蛋白或途径在动物研究中表现出了希望，只是在人类试验中失败。由于开发新的过程阿尔茨海默氏病的药物很复杂，耗时且昂贵，需要考虑非常规的药物开发策略，例如重新利用目前已批准用于其他疾病的药物。与新药的开发相对于新药的开发具有许多优势，并且成功用于各种疾病。批准药物的既定安全性和耐受性可以降低与筛查，剂量优化，毒理学，毒理学，形成和制造开发。重新利用批准的药物也可能会大大缩短时间吸毒可以接触患者。最近两个因素的融合为前所未有的机会提供了提前合理的药物重新利用。首先是大规模基因组的公共数据库的可用性，转录组和其他针对人类主要疾病的分子分析研究。第二是发展计算方法和算法以及药物目标的网络概念，这使我们能够研究治疗剂使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根据基于药物目标的网络概念。中枢神经系统（CNS）疾病的药物重新利用，包括阿尔茨海默氏病最近开始，到目前为止取得了有限的成功，包括我们最近重新利用Busetanide 用于治疗与APOE4相关的阿尔茨海默氏病。中枢神经系统疾病的药物再利用的主要挑战，包括阿尔茨海默氏病，是缺乏批准的整个基因组基因表达扰动数据库与CNS疾病有关的人类细胞类型的药物，包括AD。该提案旨在解决此主要瓶颈，以重新利用CNS疾病药物，重点关注AD药物通过建立APOE基因型依赖性和人CNS细胞类型特异性连通图来重新利用（HCNS-CMAPS）使用人IPSC衍生的CNS细胞覆盖约12,000种药物在人类中证明了安全性（目标1）。然后，我们将将这些HCNS-CMAP应用于AD药物重新利润，并验证已确定的顶级药物 AD的新型鼠标模型（AIM 2）。该项目的结果将提供研究和药物开发具有宝贵资源的领域，将批准的药物用于AD和其他中枢神经系统疾病。