A novel, multiparametric cardiac safety assay using human myocytes

使用人类肌细胞进行新型多参数心脏安全测定

基本信息

批准号：
8769228
负责人：
KENNETH LAURITA
金额：
$ 19.2万
依托单位：
SOVELIS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-03 至 2014-11-07
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769228
关键词：
Action Potentials Acute Adverse event Algorithms Arrhythmia Biological Assay Calcium Calcium Signaling Cardiac Cardiac Myocytes Cardiotoxicity Collaborations Coupled Data Development Drug Compounding Drug Industry Drug Interactions Electrocardiogram Event Fluorescence Funding Future Goals Guidelines Human Hypokalemia Incidence Income Institutes Laboratories Lead Left Link Long QT Syndrome Marketing Measurement Measures Monitor Muscle Cells Optics Patient Care Patients Pharmaceutical Preparations Physiological Predictive Value Public Health Reporting Risk Risk Factors Safety Sensitivity and Specificity Signal Transduction Small Business Innovation Research Grant Staging System Techniques Testing Therapeutic Torsades de Pointes Validation Variant base commercial application cost design drug candidate drug development improved induced pluripotent stem cell interest monolayer novel operation preclinical safety public health relevance safety testing sudden cardiac death

项目摘要

DESCRIPTION (provided by applicant): A major public health concern in recent years has been increasing reports of adverse cardiac events, including sudden cardiac death, that have been associated with use of non-cardiac drugs. In fact, in the last 15 years six non-cardiac drugs had to be withdrawn from the market after being linked to acquired long QT syndrome (acLQTS) which is characterized by torsades de pointes arrhythmias and sudden cardiac death. Since acLQTS has enormous consequences for patient care as well as for the development of future therapeutic compounds, it is important that the cardiac liability of therapeutic compounds be recognized early on. To reduce the incidence of acLQTS, regulatory agencies in collaboration with pharmaceutical industry have instituted guidelines that assess the potential of novel test compounds to delay cardiac repolarization. Unfortunately, most safety tests that have been instituted do not reliably identify compounds that produce arrhythmias by mechanisms unrelated to action potential prolongation such as abnormal impulse conduction, repolarization dynamics or calcium dysregulation. In addition, most safety tests are performed either in heterologous expression systems or non-human cardiomyocytes which may further limit their predictive value for human risk due to interspecies variation in cardiac repolarization. Thus, many cardiotoxic compounds may go undetected in conventional safety screens yet demonstrate proarrhythmia during later stages of drug development or even after approval for human use. Given the significant shortcomings of most preclinical safety assays the present proposal has been designed to develop and validate a novel, integrated assay platform that detects a comprehensive range of proarrhythmia substrates with high specificity and sensitivity. Our assay platform utilizes human cardiomyocytes derived from induced pluripotent stem cells and fluorescent- based recordings of multiple physiological relevant parameters including action potential duration, calcium transients and conduction velocity to detect an increased risk for proarrhythmic events. The specific aims of the proposal are: 1. to validate our novel assay platform with a panel of well characterized test compounds. 2. To develop a novel multiparametric algorithm to assess proarrhythmic risk with high predictive value. The integrated assay platform described in the present proposal has the potential to supplant a whole battery of preclinical safety assays currently used at the interface between lead discovery and lead development as no other preclinical safety assay is as comprehensive.

描述（由申请人提供）：近年来，一个主要的公共卫生问题是与非心脏药物的使用相关的不良心脏事件的报告不断增加，包括心源性猝死。事实上，在过去 15 年中，有 6 种非心脏药物因与获得性长 QT 综合征 (acLQTS) 有关而不得不从市场上撤出，该综合征的特点是尖端扭转型室速心律失常和心源性猝死。由于 acLQTS 对患者护理以及未来治疗化合物的开发具有巨大影响，因此尽早认识治疗化合物的心脏责任非常重要。为了降低 acLQTS 的发生率，监管机构与制药行业合作制定了指南，评估新型测试化合物延迟心脏复极的潜力。不幸的是，大多数已制定的安全测试并不能可靠地识别通过与动作电位延长无关的机制（例如异常冲动传导、复极动力学或钙失调）产生心律失常的化合物。此外，大多数安全性测试都是在异源表达系统或非人类心肌细胞中进行，由于心脏复极的种间差异，这可能进一步限制其对人类风险的预测价值。因此，许多心脏毒性化合物可能在传统安全筛选中未被检测到，但在药物开发的后期阶段甚至在批准人类使用后却表现出致心律失常的作用。鉴于大多数临床前安全性测定的显着缺点，本提案旨在开发和验证一种新颖的集成测定平台，该平台可检测具有高特异性和敏感性的各种致心律失常底物。我们的检测平台利用源自诱导多能干细胞的人类心肌细胞和多个生理相关参数（包括动作电位持续时间、钙瞬变和传导速度）的荧光记录来检测致心律失常事件的风险增加。该提案的具体目标是： 1. 使用一组经过充分表征的测试化合物来验证我们的新型检测平台。 2. 开发一种新颖的多参数算法来评估具有高预测价值的致心律失常风险。本提案中描述的集成检测平台有可能取代目前在先导化合物发现和先导化合物开发之间使用的一整套临床前安全检测，因为没有其他临床前安全检测如此全面。