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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：
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
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/10686182
关键词：
Acceleration 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 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

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.

总结