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

PROJECT SUMMARYCurrent 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 andgt;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.PROJECT NARRATIVE The identification of cardiotoxicity risk of drugs, in advance of adverse events in humans, remains an area of major challenge for pharmaceutical companies and Federal regulators. The present proposal aims at developing a predictive, robust and cost-effective laboratory methodology based on adult human primary cardiomyocytes derived from donor hearts. It is expected that the products and services resulting from this project will significantly improve the ability to identify potentially dangerous new drugs and therefore reduce or eliminate human exposure to such agents.