Development of an Integrated Platform for the Use of Adult Human Primary Cardiomyocytes in Preclinical Safety Assessment

开发使用成人原代心肌细胞进行临床前安全性评估的综合平台

基本信息

批准号：
9908263
负责人：
Najah Abi Gerges
金额：
$ 113.23万
依托单位：
ANABIOS CORPORATION
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：
2020-03-04 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908263
关键词：
Address Adult Adverse event Area Arrhythmia Automation B-Lymphocytes Biocompatible Materials Biomedical Engineering Brightfield Microscopy Cardiac Cardiac Myocytes Cardiotoxicity Cell Adhesion Cell Separation Cells Collaborations Custom Dangerousness Data Analyses Detection Development Drug Evaluation Drug Industry Ensure Exposure to Fluorescence Gel Generations Grant Heart Human Image Industry International Investigational Drugs Laboratories Life Liquid substance Measurement Measures Methodology Microscopy Modeling Organ Donor Pathway interactions Performance Perfusion Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Physics Physiological Physiology Preclinical Drug Development Process Property Recovery Risk Safety Services Shipping Ships Small Business Innovation Research Grant Substrate Interaction System Technology Temperature Testing base chemotherapeutic agent cost effective data acquisition drug discovery exposed human population fluorescence imaging follow-up graphical user interface heart pharmacology imaging capabilities improved instrument novel therapeutics pre-clinical preclinical safety programs response safety assessment screening success temporal measurement user-friendly

项目摘要

PROJECT SUMMARY Current strategies for cardiac safety evaluation of drugs have shown significant limitations. Over the past 5 years, the FDA and pharmaceutical industry leaders have promoted initiatives to develop more predictive human-relevant preclinical platforms to rectify this problem. In this context, AnaBios established an adult human primary cardiomyocyte contractility model, which reliably predicts drug-induced pro-arrhythmia risk with >90% accuracy, as well as contractility risks associated with positive and negative inotropic drugs and chemotherapeutic agents. Based on such a high predictivity, the International Council for Harmonization (ICH) of Technical Requirements for Pharmaceuticals for Human Use, recently proposed to incorporate the human primary cardiomyocyte model in preclinical cardiac safety assessment for regulatory purposes. To address the anticipated screening needs of the pharmaceutical industry, AnaBios has begun the development of a bright-field imaging-based platform, MyoBLAZER™, customized towards the specific physiology of the adult human primary cardiomyocytes; the new platform allows simultaneous contractility measurements of multiple adult primary cardiomyocytes, significantly increasing throughput compared to commercially available instruments. The objective of the current SBIR Direct to Phase II grant is to fully develop and optimize the MyoBLAZER™ platform, with respect to bright-field and fluorescence imaging, data analysis, and cell adhesion, in order to effectively screen large numbers of compounds in the early stages of preclinical drug development. The addition of fluorescence-based imaging to the MyoBLAZER™ will further enable follow up mechanistic investigations of drug activity and allow testing of other cell pathways. Moreover, optimization of cell adhesion to the test plates, will improve the MyoBLAZER™ performance and has a high potential to enhance cell storage and permit the shipment and distribution of the adult human primary cardiomyocytes for industry-wide utilization. To ensure the success of the program, AnaBios will combine its expertise in donor organ recovery, cardiomyocyte cell isolation, bright-field microscopy, cardiac pharmacology and drug discovery, with the world class expertise of Dr. Daniel Aharoni, an expert in imaging, microscopy, bioengineering and physics, at UCLA and with the technologies and expertise of Live Cell Technologies LLC, a company led by Harvard’s Dr. Ramaswamy Krishnan, an expert in biomaterials and in cell-substrate interactions.

项目概要过去，当前的药物心脏安全性评估策略已显示出明显的局限性。 5 年来，FDA 和制药行业领导者推动了开发更具预测性的举措在此背景下，AnaBios 建立了一个成人相关的临床前平台。人类原代心肌细胞收缩力模型，可可靠预测药物诱发的致心律失常风险准确度 >90%，以及与正性和负性肌力药物相关的收缩风险基于如此高的预测性，国际协调委员会（ICH）人用药品技术要求，最近提议将人类用于监管目的的临床前心脏安全性评估中的原代心肌细胞模型。预期医药行业筛选需求，AnaBios已开始明场开发基于成像的平台 MyoBLAZER™，针对成年人的特定生理机能进行定制原代心肌细胞；新平台允许同时测量多个成年人的收缩力原代心肌细胞，与市售仪器相比显着提高了通量。当前 SBIR Direct 第二阶段资助的目标是全面开发和优化 MyoBLAZER™ 平台，涉及明场和荧光成像、数据分析和细胞粘附，以便在临床前药物开发的早期阶段有效筛选大量化合物。 MyoBLAZER™ 基于荧光的成像将进一步实现后续机制研究药物活性并允许测试其他细胞途径，此外，优化细胞对测试板的粘附，将提高 MyoBLAZER™ 性能，并具有增强细胞存储并允许成人原代心肌细胞的运输和分配以确保全行业的利用。该计划的成功，AnaBios 将结合其在供体器官恢复、心肌细胞等方面的专业知识分离、明场显微镜、心脏药理学和药物发现，拥有世界一流的专业知识 Daniel Aharoni 博士是加州大学洛杉矶分校成像、显微镜、生物工程和物理学方面的专家 Live Cell Technologies LLC（一家由哈佛大学 Ramaswamy Krishnan 博士领导的公司）的技术和专业知识，生物材料和细胞与基质相互作用方面的专家。