Drug-induced QT prolongation is a common cardiac disorder associated with an increased risk for the ventricular arrhythmia torsades de pointes and sudden death. Recognition of this condition has led to increased focus on cardiac toxicity in drug development. The FDA now requires cardiac safety studies prior to drug approval. Since compound development costs a drug company approximately $45,000 per day, identifying candidate drugs with the potential for cardiac toxicity early in the development process produces significant savings for pharmaceutical companies. The market for such screening services is estimated to exceed $113M in 2007 (D&MD Publications, 2005). ? ? Current cardiac safety assays using either animal cells or heterologous expression systems have limitations in their predictive capacity, and typically multiple assays are employed. Human heart cells represent the ideal cell system for determination of cardiac toxicity, but adult human heart cells are not readily available and cannot easily be maintained or propagated in culture. Cellular Dynamics Intl. Inc. (CDI) will develop human embryonic stem cell-derived cardiomyocytes (hESC-CMs) to predict cardiac toxicity in humans. The goals of this proposal are: 1) to establish genetically modified hESCs that will enable the purification of a relatively homogeneous population of ventricular CMs and 2) to validate the ability of this population of ventricular hESCCM as an in vitro model for cardiac safety. ? ? CDI was founded by Drs. James Thomson, Craig January, and Timothy Kamp, three noted researchers in the field of human stem cells and cardiology. Dr. James Thomson was the first one to isolate hESCs and remains a leader in hESC research. HEK cell hERG screening was first developed in the lab of Dr. Craig January and is currently a widely accepted tool for cardiac safety testing. Research in Dr. Tim Kamp's lab has demonstrated that hESC-derived CMs are a functional surrogate for primary CMs and that the hERG channel blocker (e.g., E-4031) produced a prolongation of action potential recorded from such cells. CDI's combined expertise in hESC biology, cardiac electrophysiology, cardiac safety pharmacology, and clinical cardiology makes it highly feasible to achieve the Phase I goals. Preliminary study using lentiviral transfection system to validate potential ventricular CM-specific promoter's activity in hESC-derived CMs increases the likelihood of accomplishing the research objectives. Successful completion of Phase I goals will lead to scaling up the homogeneous population of ventricular-CMs and commercialization of products by developing high throughput assays in Phase II. Using renewable hESCs lines to generate a homogeneous population of ventricular-CMs will not only have significant commercial impact on cardiac safety testing, but these cells may provide opportunities for development of new assays to be used in the cardiac drug discovery process as well as provide a potential cell source for cardiac cell therapy with potential benefit to millions of patients suffering from advanced heart disease. ? ? ? ?
