High-throughput nanoMEA-based Proarrhythmia Assay

基于 nanoMEA 的高通量致心律失常检测

• 批准号: 9046607
• 负责人: Alec Simon Tulloch Smith
• 金额: $ 21.4万
• 依托单位: CURI BIO INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046607
• 关键词: Accounting; Adoption; Adult; Area; Arrhythmia; Biological Assay; Biomedical Engineering; Blood capillaries; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cells; Chemicals; Clinical; Clinical Trials; Collection; Computer software; Cues; Cultured Cells; Data; Deposition; Detection; Development; Devices; Dose; Drug Recalls; Drug toxicity; Electrocardiogram; Electrodes; Electrophysiology (science); Eligibility Determination; Engineering; Ensure; Event; Gene Expression Profile; Generations; Glass; Grant; Heart; Human; Human Engineering; In Vitro; Industry Standard; Intellectual Property; Laboratories; Lead; Legal patent; Life; Marketing; Measures; Mediating; Metabolic; Methods; Microelectrodes; Modeling; Monitor; Myocardial; Myocardial tissue; Myocardium; Pattern; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Phenotype; Pluripotent Stem Cells; Preclinical Drug Evaluation; Process; Production; Property; Protocols documentation; Research; Resolution; Safety; Signal Transduction; Staging; Surface; System; Techniques; Technology; Testing; Time; Tissues; Titania; Titanium; Toxic effect; Validation; base; capillary; commercialization; cost effective; density; design; drug development; drug withdrawal; high throughput analysis; high throughput screening; human subject; improved; in vivo; interest; lithography; monolayer; nanopattern; novel; novel therapeutics; pre-clinical; pre-clinical trial; preclinical efficacy; prototype; public health relevance; research study; response; screening; theories; tool

 DESCRIPTION (provided by applicant): Attrition of new chemical entities at late preclinical and clinical stages of development is an extremely costly event, most commonly associated with the detection of unexpected arrhythmogenic properties in novel drugs. Undetected arrhythmia-inducing effects are also the most common reason for drug withdrawal from the market. To this end, the FDA now mandates that all new drugs be tested for potential arrhythmogenic properties, which has led to a growing market for accurate and cost effective preclinical screening tools. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent the means to generate superior in vitro cardiac tissues for such applications. However, an inability for hPSC-CMs to develop into adequate representations of adult myocardial tissue is a major impediment to the use of these cell-constructs in effective preclinical screening protocols. Generation of mature cardiac tissues that accurately recapitulate the form and function of the adult human myocardium is necessary to provide preclinical data capable of reliably predicting a compound's efficacy and/or toxicity when transferred to a clinical setting. This proposal focuses on the development of a nanopatterned microelectrode array (MEA) platform with which to evaluate the arrhythmogenic potential of novel compounds in a high throughput and predictive manner. Nanotopographic surfaces are known to promote the maturation of cultured hPSC-CMs towards phenotypes representative of the adult human myocardium. We hypothesize that the integration of such topographic signaling cues with MEAs will enable the analysis of the electrophysiological performance of these matured human cardiomyocytes in vitro. Furthermore, we posit that the topography-mediated maturation of hPSC-CMs will lead to the generation of cardiac monolayers with electrophysiological properties more closely representative of adult cardiac tissue in terms of conduction velocity, anisotropic conduction patterns, and field potential durations. Finally, we suggest that the establishment of this mature functional assay will enable the collection of compound arrhythmogenesis data with greater predictive capacity in terms of recreating in vivo drug effects in vitro. To test these hypotheses, this grant will focus n the design and production (Task 1) of topographically patterned multiwell MEAs. The ability for hPSC-CMs cultured within this platform to generate drug-induced arrhythmia data for known arrhythmogenic compounds that are representative of these drugs' activity in vivo will then be investigated (Task 2). Comparison of compound action on nanopatterned and flat cardiomyocyte monolayers to drug activity in vivo will be used to demonstrate the improvement our platform offers in terms of predicting myocardial responses to drug treatment. Successful validation of this nanopatterned MEA system will produce a new product for advancing the efficacy of preclinical drug screening with the potential to streamline current pharmaceutical development. This system, for which we own the Intellectual Property, will be of considerable interest to both academic and pharmaceutical screening laboratories, and we will seek to commercialize our prototype upon successful completion of this grant.

 描述（由申请人提供）：新化学实体在临床前和临床开发阶段的损耗是一种代价极其高昂的事件，最常见的是与新药中意外的心律失常特性的检测有关，而未检测到的心律失常诱发作用也是最常见的。为此，FDA 现在要求对所有新药进行潜在的致心律失常特性测试，这导致了准确且具有成本效益的市场不断增长。人类多能干细胞衍生的心肌细胞 (hPSC-CM) 代表了在体外生成心脏组织以用于此类应用的方法，但 hPSC-CM 无法发育成成人心肌组织的充分代表是一个主要问题。在有效的临床前筛选方案中使用这些细胞构建体的障碍是必要的，以提供准确再现成人心肌的形式和功能的成熟心脏组织。临床前数据能够可靠地预测化合物在转移到临床环境时的功效和/或毒性。该提案的重点是开发纳米图案微电极阵列（MEA）平台，用于以高通量和高通量评估新型化合物的致心律失常潜力。已知纳米地形表面可促进培养的 hPSC-CM 向代表成人心肌的表型成熟。与 MEA 的结合将能够在体外分析这些成熟的人类心肌细胞的电生理性能。此外，我们假设 hPSC-CM 的拓扑介导的成熟将导致产生具有更能代表成人心脏组织的电生理特性的心脏单层。最后，我们建议建立这种成熟的功能测定法将能够收集具有更大预测能力的复合心律失常发生数据。为了测试这些假设，这笔资助将重点关注拓扑图案化多孔 MEA 的设计和生产（任务 1），以便在该平台内培养 hPSC-CM 来生成药物诱导的心律失常数据。然后将研究代表这些药物体内活性的已知致心律失常化合物（任务 2），比较化合物对纳米图案和平坦心肌细胞单层的作用与药物活性。体内试验将用于证明我们的平台在预测心肌对药物治疗的反应方面所提供的改进，该纳米图案 MEA 系统的成功验证将产生一种新产品，用于提高临床前药物筛选的功效，并有可能简化当前的药物开发。我们拥有该系统的知识产权，它将引起学术界和药物筛选实验室的极大兴趣，我们将在成功完成这笔资助后寻求将我们的原型商业化。