A major public health concern in recent years has been increasing reports of adverse cardiac events, including sudden cardiac death, that have been associated with use of non-cardiac drugs. In fact, in the last 15 years six non-cardiac drugs had to be withdrawn from the market after being linked to acquired long QT syndrome (acLQTS) which is characterized by torsades de pointes arrhythmias and sudden cardiac death. Since acLQTS has enormous consequences for patient care as well as for the development of future therapeutic compounds, it is important that the cardiac liability of therapeutic compounds be recognized early on. To reduce the incidence of acLQTS, regulatory agencies in collaboration with pharmaceutical industry have instituted guidelines that assess the potential of novel test compounds to delay cardiac repolarization. Unfortunately, most safety tests that have been instituted do not reliably identify compounds that produce arrhythmias by mechanisms unrelated to action potential prolongation such as abnormal impulse conduction, repolarization dynamics or calcium dysregulation. In addition, most safety tests are performed either in heterologous expression systems or non-human cardiomyocytes which may further limit their predictive value for human risk due to interspecies variation in cardiac repolarization. Thus, many cardiotoxic compounds may go undetected in conventional safety screens yet demonstrate proarrhythmia during later stages of drug development or even after approval for human use. Given the significant shortcomings of most preclinical safety assays the present proposal has been designed to develop and validate a novel, integrated assay platform that detects a comprehensive range of proarrhythmia substrates with high specificity and sensitivity. Our assay platform utilizes human cardiomyocytes derived from induced pluripotent stem cells and fluorescent- based recordings of multiple physiological relevant parameters including action potential duration, calcium transients and conduction velocity to detect an increased risk for proarrhythmic events.
The specific aims of the proposal are: 1. to validate our novel assay platform with a panel of well characterized test compounds. 2. To develop a novel multiparametric algorithm to assess proarrhythmic risk with high predictive value. The integrated assay platform described in the present proposal has the potential to supplant a whole battery of preclinical safety assays currently used at the interface between lead discovery and lead development as no other preclinical safety assay is as comprehensive.
A major public health concern in recent years has been increasing reports of adverse cardiac events, including arrhythmias and sudden cardiac death that have been associated with use of non-cardiac drugs. To reduce the incidence of adverse events, we will develop a novel integrated assay platform that detects and flags cardiotoxic drugs with high specificity and sensitivity in human myocytes, before they can reach patients. It is our main goal to advance the safe use of effective therapeutic drug compounds.
|McPheeters, Matthew T; Wang, Yves T; Werdich, Andreas A et al. (2017) An infrared optical pacing system for screening cardiac electrophysiology in human cardiomyocytes. PLoS One 12:e0183761|