Cardiotoxicity, as a result of adverse drug effects, is a serious problem that has yet to be effectively screened prior to patient exposure. Cardiac safety is one of the leading causes of compound attrition in the pharmaceutical industry and withdrawal of FDA-approved drugs from the market. The purpose of this proposal is to alleviate the financial burden of compound attrition due to cardiotoxicity, but more importantly, to improve public health through the development of an in vitro assay to predict a drug's ability to induce cardiotoxicity. Stemina Biomarker Discovery (Stemina) proposes to do so through the use of metabolomics on treated cardiomyocytes derived from human embryonic stem (hES) and human induced pluripotent stem (hiPS) cells. These technologies will be used to discover human endogenous small molecule biomarkers which predict cardiotoxicity, with an emphasis on cardiomyopathy. The use of metabolomics to measure small molecules secreted by human cardiomyocytes in response to drugs is a novel approach and may pave the way for a new generation of more accurate predictive toxicology screens. Stemina has already used such a paradigm to develop predictive methods to assess development toxicology in stem cells. Stemina's long-term goal is to fully develop this humanized, high throughput cardiotoxicity screen so that it would be a valuable tool to pharmaceutical and biotech companies during preclinical development of therapeutics. In order to achieve this long term goal, Stemina is first proposing to establish an experimental platform for each cardiomyocyte culture system (Aim 1). In Aim 2, we will use these systems to develop a dose response curve for each of the 24 compounds (16 cardiotoxic and 10 non-cardiotoxic) as a training set to establish a predictive metabolomic model. These dose response curves will be used to determine 3 concentrations for drug treatment to be utilized in Aim 3. Stemina will then establish a specific metabolic signature of candidate human biomarkers of drug-induced cardiotoxicity (Aim 3). To do so, human pluripotent stem (hPS) cell-derived cardiomyocytes will be treated with well-established known inducers and non-inducers of cardiotoxiciy. The spent medium from treated cells will be analyzed with mass spectrometry in order to study the secreted metabolites, or secretome, of these cells. Small molecules whose abundances vary dependent upon whether cells were treated with an inducer or non-inducer of cardiotoxicity will serve as candidate biomarkers of cardiotoxicity. In future studies, these candidate biomarkers will be validated through the use of specialized mass spectrometry techniques. Lastly, the ability of these biomarkers to adequately predict cardiotoxicity will be tested through the use of a blind study. Completion of these aims will encourage further discussions with partnering companies in order to develop a kit that can detect the validated biomarkers of cardiotoxicity. Stemina will then utilize this kit to market a service to predict whether or not a compound will induce cardiotoxicity that will serve pharmaceutical companies in pre-clinical screening trials. Such a service will provide the first humanized screening assay for cardiotoxicity based on cardiomyocyte metabolism and will likely improve public health. PUBLIC HEALTH RELEVANCE: Adverse effects of drugs to patients are the fourth leading cause of death in the United States; one such an adverse effect is drug-induced cardiotoxicity, illustrating a need for a better predictive assay for cardiotoxicity. Stemina Biomarker Discovery proposes to develop biomarkers of cardiotoxicity that would drive a service model to predict the cardiotoxicity-potential of drug candidates in order to prevent cardiotoxicity in patients. Such a product will greatly improve public health.
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