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: 10686182
• 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/10686182
• 关键词: Acceleration; 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; 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; Genes; Genetic; Genomics; Genotype; Goals; Hour; Human; Libraries; Malignant Neoplasms; Maps; Microglia; Molecular; Molecular Profiling; Nature; Neurodegenerative Disorders; Neurons; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Process; Protein Isoforms; Proteins; Reporting; Resources; Safety; Testing; Therapeutic; Therapeutic Agents; Time; Toxicology; Validation; apolipoprotein E-3; apolipoprotein E-4; 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; manufacture; 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.

摘要 阿尔茨海默病(AD)是一种由多种因素相互作用引起的多因素神经退行性疾病。 遗传和环境因素。阿尔茨海默病最强的遗传因素是载脂蛋白(APO)E基因。 ApoE4增加AD的危险性，降低AD的发病年龄，ApoE4携带者约占AD病例的60%； 剩下的~40%是APOE3携带者。阿尔茨海默病的遗传复杂性和多因素特性 对通常针对特定基因、蛋白质或途径的传统药物开发构成独特的挑战。 在过去的几十年里，针对特定AD相关蛋白或通路的新药开发努力 在动物实验中显示出了希望，但在人体试验中失败了。由于开发新技术的过程 治疗阿尔茨海默病的药物复杂、耗时和昂贵，迫切需要考虑 非常规药物开发战略，例如改变目前批准用于其他条件的药物的用途。 与新药的开发相比，药物再利用的方法具有许多优势，并具有 已成功用于各种疾病的治疗。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、 配方，以及制造业发展。改变已批准药物的用途也可以大大缩短时间。 让一种药物到达患者手中。最近两个因素的汇聚提供了一个前所未有的机会 推进合理的药物再利用。首先是大规模基因组的公共数据库的可用性， 转录学和其他人类主要疾病的分子图谱研究。二是发展 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 毒品靶点的网络概念。治疗中枢神经系统(CNS)疾病的药物再利用，包括 阿尔茨海默病，最近开始的，到目前为止只取得了有限的成功，包括我们最近改变了布美他尼的用途 用于治疗与APOE4相关的阿尔茨海默氏症。中枢神经系统疾病药物再利用的一个主要挑战， 包括阿尔茨海默病在内，是缺乏全基因组基因表达扰动数据库的认可 与包括阿尔茨海默病在内的中枢神经系统疾病相关的人类细胞类型的药物。 该建议旨在解决中枢神经系统疾病药物再利用的这一主要瓶颈，重点是AD药物 通过建立载脂蛋白E基因依赖的和人类中枢神经系统细胞类型特异的连接图谱来改变用途 (hCNS-CMAP)覆盖约12,000种药物，使用人类IPSC来源的CNS细胞证明在人类身上是安全的 (目标1)。然后，我们将把这些hCNS-CMAP应用于AD药物的再利用，并验证在 一种新的阿尔茨海默病小鼠模型(目标2)。该项目的成果将为研究和药物开发提供 具有宝贵资源的领域，用于重新调整已批准用于AD和其他中枢神经系统疾病的药物的用途。