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

项目摘要 目前的药物心脏安全性评价策略已显示出明显的局限性。过去 5年来，FDA和制药行业的领导者推动了制定更具预测性的举措， 人类相关的临床前平台来纠正这个问题。在这种情况下，AnaBios建立了一个成人 可靠预测药物诱导的促心律失常风险的人原代心肌细胞收缩力模型 准确率>90%，以及与阳性和阴性正性肌力药物相关的收缩风险， 化疗剂。基于如此高的预测性，国际人用药品注册技术要求协调理事会（ICH） 人用药品技术要求，最近提出将人 用于监管目的的临床前心脏安全性评估的原代心肌细胞模型。解决 预期制药行业的筛选需求，AnaBios已经开始开发一个明亮的领域， 基于成像的平台，MyoBLAZER™，针对成年人的特定生理学进行定制 原代心肌细胞;新平台允许同时测量多个成人心肌细胞的收缩力。 原代心肌细胞，与市售仪器相比，显著提高了通量。 目前SBIR直接进入第二阶段赠款的目标是全面开发和优化MyoBLAZER™ 平台，关于明场和荧光成像、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。添加 基于荧光的成像到MyoBLAZER™将进一步使后续的机制研究， 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， 将改善MyoBLAZER™的性能，并具有增强细胞储存和允许 成年人原代心肌细胞的运输和分配用于工业范围的利用。确保 该计划的成功，AnaBios将联合收割机结合其在供体器官回收，心肌细胞， 分离，明场显微镜，心脏药理学和药物发现，具有世界一流的专业知识， 博士丹尼尔阿哈罗尼是加州大学洛杉矶分校的成像、显微镜、生物工程和物理学专家， 由哈佛大学的Ramaswamy Krishnan博士领导的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.