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Engineered Human Heart Slice for Testing Drug-Induced Arrhythmia

用于测试药物引起的心律失常的工程人体心脏切片

基本信息

批准号：
10593346
负责人：
LESLIE TUNG
金额：
$ 5.89万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10593346
关键词：
Academia Adopted Adoption Advocate Affect Aleurites Area Arrhythmia Bioinformatics Biological Assay CD36 gene Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiac development Cell Maturation Cell model Cell surface Cells Cellular Assay Clinical Complement Consensus Dependence Development Developmental Biology Drug Interactions Engineering Event Exhibits Experimental Models Fingerprint Formulation Gene Expression Profiling Genetic Transcription Giant Cells Goals Government Growth and Development function Guidelines Heart Heterogeneity Histologic Human Human Engineering In Vitro Incidence Industry Ion Channel Knowledge Life Maintenance Measurement Metabolic Modeling Myocardium Pharmaceutical Preparations Pharmacologic Substance Pharmacology Physiological Positioning Attribute Regulation Research Research Contracts Rest Risk Risk Factors Safety Signal Pathway Slice Stimulant System Tachyarrhythmias Technology Testing Time Tissue Model Tissues Torsades de Pointes United States Food and Drug Administration Validation Variant Ventricular Tachycardia Verapamil base drug testing falls high risk high throughput screening improved in vitro Model in vivo induced pluripotent stem cell derived cardiomyocytes novel novel therapeutics pre-clinical public-private partnership research and development response safety testing

项目摘要

New standards are under development for cardiac safety testing of drugs for risk of arrhythmia, ultimately with the preclinical goal of predicting risk for Torsade de Pointes (TdP). In the U.S. the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative has been advocated by government regulatory agencies, public-private partnerships, industry and academia. One component of the initiative rests on the usage of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a validation platform of drug responses that can replace heterologous expression systems which dwell on block of a single ion channel (HERG). If adopted by the FDA, CiPA represents a major step forward for drug testing using cells that contain the major ion channels and signaling pathways found in human heart. This application of hiPSC-CMs is an area of active research and development, and numerous contract research organizations and most pharmaceutical companies have founded labs to perform high throughput screening of test compounds using these cells. However, current hiPSC-CM screens tend to be on single or small numbers of cells that exhibit immaturity and heterogeneity. In addition, arrhythmic events are limited to early afterdepolarizations (EADs) or irregular beating. TdP is ultimately a multicellular tissue phenomenon that results from reentrant or multifocal ectopic activity that require a minimum size to be revealed. The goal of this project is to develop an in vitro model suitable for testing pharmacological compounds and assessing risk for tissue-level arrhythmia. Three research labs at Hopkins will contribute their expertise for the project. The tissue platform used to support the hiPSC-CMs will be the Engineered Heart Slice developed in Tung’s cardiac electrophysiology lab. Version 2.0 of the slice with improved physiological function will be implemented using proven and putative maturation stimulants, and then used to test for drug-induced reentrant or multifocal arrhythmia. To this end, metabolic maturation of the cells will be pursued via the expertise of the Boheler lab, which has identified CD36 as a cell surface marker distinguishing cells that are metabolically more mature. A bioinformatics approach developed in Kwon’s cardiac developmental biology lab will be used to follow the maturation trajectory of the cardiomyocytes. The convergence of these technologies will result in an advanced in vitro tissue model that will be used to independently and mechanistically assess the proarrhythmic effects of selected compounds which have been identified clinically as low, intermediate, and high risk, and to determine whether the maturation state of the cardiomyocytes affects their drug responses. This approach represents a new paradigm for cardiac safety testing – one that is a step closer to predicting TdP-like arrhythmic events in the myocardium – and may establish new standards for the utility, validity, and maturation-dependence of hiPSC-CMs as an experimental model to assess arrhythmia risk.

最终，心律失常风险药物的心脏安全测试的新标准正在制定中