Engineered tissue-based, high-throughput compound profiling

DESCRIPTION provided by applicant Current NIGMS SBIR funding supported InvivoSciences LLCandapos s IVS launch of several product lines in IVS generated revenues from the sales of three dimensional D cell culture tools MC TM and IVS InsertsTM that can grow various hydrogel tissues without any support layers The culture tools enable Palpator TM and Tissue StretcherTM to stretch the hydrogel tissues for biomechanical measurements and mechanical conditioning e g cyclic stress applications respectively IVS also performed contract research services using our tools and devices for industry and academic laboratories for profiling compound induced effects on cell and tissue physiology To further demonstrate our ability to screen drug candidates especially for drug developers the market demands benchmark studies against compounds and drugs whose pharmacological functions including toxicity information have been well characterized To fully commercialize our current start up activities IVS will improve its rapid drug screening system that uses engineered heart tissues EHTs to monitor the effects of test compounds on cardiac contractility and associated regulatory molecules In Aim EHTs will be developed using cardiomyocytes derived from human induced pluripotent stem iPS cells to commercialize a drug screening system using human samples Using this system we will determine the beneficial and toxic effects of a panel of drugs based on the drug induced changes in the cardiac functions of EHTs as well as the signal transduction pathways that underlie their activities In Aim we will establish ISO specified requirements for a quality management system so that we may more confidently provide contract research services for drug developers In addition using a list of well known cardio effective and toxic drugs compounds we will measure drug induced cardiac function changes using EHTs to establish the benchmark In Aim we will identify mechanisms of cardiotoxicity and will demonstrate the ability of the EHTs to predict cardiotoxicity in vitro without the need for establishing animal studies Our approach will advance drug target identification and optimization as well as biomarker discovery critical for diagnosing cardiotoxicity As a demonstration of the ability of our approach to elucidate a mechanism of cardiotoxicity we will use as an example genetic knockdown with shRNA and drugs to inhibit mTOR mammalian target of rapamycin Successful completion of our aims will prove the ability of our in vitro system to predict drug induced cardiotoxicity in humans clearly benefiting early stage drug discovery Existing cardiotoxicity testing in vitro is not sufficient to accurately predict drug induced cardiotoxicity The proposed project will establish a comprehensive cardiotoxicity assessment system using engineered heart tissues fabricated with cardiomyocytes derived from human induced pluripotent stem cells With the new technology drug developers can predict potential drug induced cardiotoxicity at the early stages of drug discovery so will reduce late stage attrition and protect patients from developing cardiac failure