Year 3

Cardiac arrhythmias are a major cause of morbidity and mortality. Yet we lack appropriate human tissue models to develop new therapies of this deadly disease. Despite the importance of this disease, the current in vitro models utilize overexpressed channels in fibroblasts that do not accurately recapitulate human cardiac myocytes. With our CIRM funding, we greatly improved our in vitro models by using cardiomyocytes derived from human induced pluripotent stem cells (iPS cells) from donors who harbor cardiac arrhythmia mutations. We enrolled a series of research subjects with genetic forms of LQTS. All participants in our study signed a consent form that was approved by the UCSF human subjects committee. We found that iPS cell–derived cardiomyocytes developed disease-related phenotypes in vitro that could be readily demonstrated by electrophysiological techniques. Such measurements enabled the pharmacological characterization of underlying mechanisms of disease and may point to potential novel therapies. The CIRM funding has allowed our laboratory develop new methods for human disease modeling in iPS cell–derived tissues. This project served as a critical catalyst for human disease research that would otherwise be impossible.