STEMINA BIOMARKER DISCOVERY, INC — Department of Health and Human Services SBIR Phase II: 300

Description

DESCRIPTION provided by applicant Identification of Biomarkers of Cardiotoxicity using Metabolomics of Human Pluripotent Stem Cell Derived Cardiomyocytes Project Summary Abstract 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 improve public health as well as alleviate the financial burden of compound attrition due to cardiotoxicity through development of an in vitro assay to predict a compoundandapos s cardiotoxicity potential To accomplish this Stemina Biomarker Discovery andquot Steminaandquot proposes to use metabolomics of human induced pluripotent stem cell derived cardiomyocytes hiPSC CMs exposed to known human cardiotoxic and non cardiotoxic compounds These technologies will be used to discover human endogenous metabolite biomarkers which predict general cardiotoxicity as well as the specific type of cardiotoxicity e g functional structural The use of metabolomics to measure small molecules secreted by hiPSC CMs in response to compound exposure is a novel approach for evaluating cardiotoxicity and may pave the way for a new generation of more accurate predictive toxicology screens using human cells Stemina already used such a paradigm to complete the Phase I SBIR Application R GM as well as developed predictive methods to assess developmental toxicity potential in undifferentiated pluripotent stem cells devTOX tm Steminaandapos s long term goal is to develop a human cell based high throughput cardiotoxicity screen as a valuable tool to pharmaceutical biotech and agrichemical companies during early development of therapeutics and chemicals In order to achieve this goal Stemina first proposes to develop an optimized and reproducible experimental platform to evaluate spent media collected from hiPSC CMs aim We will evaluate various sample preparation methods LC MS columns and conditions and perform robustness testing in order to establish the most reproducible measurement of the complete set of secreted metabolites or secretome in hiPSC CMs using our system In aim we will use the above platform to evaluate spent media from hiPSC CMs response to a training set of compounds consisting of functional structural general and non cardiotoxicants to establish a predictive metabolomic model 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 The data acquired here will be used to establish a predictive metabolic signature indicative of general cardiotoxicity and specific type of cardiotoxicity e g functional structural Stemina will then test the performace of the predictive model s of biomarker signature s on a test set of compounds In aim Stemina will confirm the structural identity of the predictive metabolites and evaluate their biological significance as confirmed biomarkers Lastly in aim a targeted biomarker assay will be developed using targeted LC MS methods that measure the confirmed biomarkers Further the ability of our biomarkers to adequately predict cardiotoxicity will be tested through the use o a blind study comprised of compounds acquired from partnering companies Completion of these aims will enable the development of a commercial assay able to detect the validated biomarkers of cardiotoxicity similar to an existing test Stemina currently markets for developmental toxicity devTOX tm quickPredict Stemina will subsequently utilize this assay to market a service capable of predicting whether a compound will induce cardiotoxicity and serve pharmaceutical companies in preclinical screening trials Such a service provides the first human cell based screening assay for cardiotoxicity founded on cardiomyocyte metabolism PUBLIC HEALTH RELEVANCE Identification of Biomarkers of Cardiotoxicity using Metabolomics of Human Pluripotent Stem Cell Derived Cardiomyocytes Project Narrative Adverse effects of drugs to patients are the fourth leading cause of death in the United States Drug induced cardiotoxicity remains one of the most common adverse drug effects indicating the need for better predictions of cardiotoxicity prior to a new drug reaching the market Stemina Biomarker Discovery proposes to develop and commercialize an in vitro assay based on biomarkers of cardiotoxicity from induced pluripotent stem cell derived cardiomyocytes that will predict the cardiotoxicity potential of drug candidates in order to decrease drug induced cardiotoxicity in humans therefore greatly improving public health and safety