Phase II year
2023
(last award dollars: 2024)
Phase II Amount
$1,177,299
Cardiotoxicity is a leading cause of drug discovery attrition across all of preclinical and clinical drug discovery.While the FDA and the Comprehensive in vitro Proarrhythmia Assay initiative (CiPA) are focused primarily onpredicting proarrhythmic effects, drug attrition due to cardiomyopathy, or primary cardiac cytotoxicity, may beeven more prevalent, is typically currently only carried out via animal studies, and limits dosage for manycancer chemotherapeutics. Due to improving cancer survival, it is increasing common for more cancersurvivors of some cancer types to die of cardiac diseases due to cancer treatment side effects than cancerrecurrence. Cardiac contractions are initiated by electrical depolarizations (action potentials, APs) thatpropagate through the heart and initiate calcium (Ca2+) transients that activate the contractile apparatus.Importantly, dysregulation of Ca2+ can trigger inappropriate early-after- and delayed-after- depolarizations(EADs and DADs) that initiate arrhythmias, inhibit mitochondrial function, and pathologically alter expression ofcontractile proteins. Chemotherapy and other drugs can also directly impair mitochondrial function, which isprimarily thought to cause cytotoxicity, but can also cause arrhythmias. Cardiomyocytes are alsoheterogeneous in their voltage, calcium, and contractile functions, and in their responses to therapeuticcandidates. Thus, it is highly desirable to simultaneously measure AP, Ca2+ and contractile function on a cell-by-cell basis, in human cardiomyocytes, but this is not possible with current test methods. To address thisunmet need we propose to develop a high throughput (robotic) Kinetic Image Cytometry that simultaneouslyquantifes voltage, calcium, and contractile motion in cardiomyocytes derived from human induced pluripotentstem cells (hiPSC-CMs). The hiPSC-CMs will be labeled with fluorescent indicators of calcium and voltage,and the cells imaged via high-speed automated microscopy during contractile activity. The use of hiPSC-CMswill enable "clinical trials" in a dish, in which test compounds are tested across cells representing severaldonors. Phase I of this Fast-Track STTR project will develop the basic protocol and perform a proof-of-conceptscreen of 30 test compounds on hiPSC-CMs representing 5 donors. In Phase II, a large validation study (~350compounds, 7-concentration dose-response, 30 min and 72 hr exposures) will be performed. Artificialintelligence will be utilized to optimize the sensitivity and specificity of the assay by detecting complexarrhythmia waveforms. This assay represents a human-based preclinical model that will be less expensiveand more predictive for cardiotoxicity testing than animal models and will be marketed to the pharmaceuticalindustry for contract research.
Public Health Relevance Statement: FDA guidelines stipulate that all new drugs be tested for dangerous side-effects on the heart as part of
preclinical research; however, the current tests are poorly predictive of both dangerous and safe drugs leading
to unwarranted attrition and dangerous drugs reaching clinic. Human cardiomyocytes derived from donor
tissue (iPSC-derived cardiomyocytes) are widely considered to hold great promise for clinical trial in a dish
studies of drug cardiotoxicity. This STTR proposal is to commercialize a high throughput platform to accurately
identify drug candidates that have cardiac side effects, in particular adding the ability to detect the type of
primary heart cell damage common with anti-cancer drugs in a fully automated (high throughput) robotic assay
for the first time, to improve the efficiency of preclinical research and the safety of human clinical trials, which
will also likely have the added benefit of reducing animal research.
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