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

项目总结 目前的药物心脏安全性评价策略已显示出明显的局限性。在过去的时间里 5年来，FDA和制药行业领导者一直在推动开发更具预测性的倡议 与人类相关的临床前平台来纠正这个问题。在这种情况下，AnaBios建立了一个成年人 人类初级心肌细胞收缩能力模型，该模型可可靠地预测药物诱发心律失常的风险 具有90%的准确性，以及与正性和负性肌力药物相关的收缩风险 化疗药物。基于如此高的预测性，国际协调理事会(ICH) 《人用药品技术要求》，最近提出将人类 临床前心脏安全性评估中用于调控目的的初级心肌细胞模型。要解决这个问题 预计制药行业的筛选需求，AnaBios已经开始发展一个光明的领域 基于成像的平台，MyoBLAZER™，专为成年人的特定生理而定制 原代心肌细胞；新平台允许同时测量多个成年人的收缩能力 与商业上可用的仪器相比，显著提高了产量。 目前SBIR第二阶段直接拨款的目标是全面开发和优化MyoBLAZER™ 平台，在明场和荧光成像、数据分析和细胞黏附方面，以便 在临床前药物开发的早期阶段有效筛选大量化合物。加法 对MyoBLAZER™进行基于荧光的成像将进一步使后续机制研究成为可能 药物活性，并允许测试其他细胞途径。此外，优化了细胞与测试板的粘附性， 将改善MyoBLAZER™的性能，并具有增强细胞存储和允许 工业用成人原代心肌细胞的运输和分配。为了确保 该计划的成功，AnaBios将结合其在供体器官恢复，心肌细胞的专业知识 分离、明视场显微镜、心脏药理学和药物发现，拥有世界级的专业知识 丹尼尔·阿哈罗尼博士，成像、显微镜、生物工程和物理专家，在加州大学洛杉矶分校和 由哈佛大学博士拉马斯瓦米·克里希南领导的Live Cell Technologies LLC公司的技术和专业知识， 生物材料和细胞-基质相互作用方面的专家。

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.