PROJECT SUMMARY The primary goal of this one-year competitive revision is to assess the potential of two novel therapeutics (DS-iKL and DAPT) to mitigate the extrinsic and intrinsic cardiac effects of SARS-CoV-2, respectively. This is important because, while acute respiratory distress is a major cause of morbidity and mortality of COVID-19, the clinical disease caused by the SARS-CoV-2 coronavirus, it has more recently become widely evident that other organ systems are involved including the heart and blood. For example, cardiac arrhythmias are a major source of morbidity and mortality (44-60%) associated with COVID-19 disease, especially in individuals with pre-existing cardiovascular disease in ICU settings. Two recent reports have indicated that 20-22% of hospitalized patients with SARS-Cov-2 experience cardiac injury, and these patients suffer a staggering 50% mortality rate, more than an order of magnitude greater than those patients without cardiac injury. Cardiac arrythmias or myocardial injury are acutely life threatening and can be caused by a host of factors including co- morbidities (e.g., hypertension), drugs, but also viral infection and systemic inflammation. In addition, a state of hyper coagulation has also been described as a central feature of COVID-19, leading to blood clots that can be life threatening as pulmonary emboli and right-sided cardiac failure. The specific aims of the project are to: 1) Assess the potential of DS-iKL as a novel therapeutic to mitigate the cardiac effects of SARS-CoV-2 initiated cytokine storm (coagulation and vascular permeability) using a multi-organ microphysiological system of iPS- derived human cardiomyocytes and vascular endothelium; 2) Assess the potential of the Notch signaling inhibitor, DAPT, on viral infectivity and thus intrinsic cardiac effects of SARS-CoV-2, in an organotypic tissue slice model of healthy and predisposed adult human cardiac tissue. We anticipate a rich data set resulting from these experiments that should demonstrate the exciting potential of DS-iKL and DAPT to mitigate the extrinsic and intrinsic cardiac effects of SARS-CoV-2. The research plan will also produce a path to in vivo human studies to accelerate translation. Finally, the potential impact of DS-iKL and DAPT to mitigate the effects of SARS-CoV-2 are likely to also be applicable to other inflammatory and infectious diseases that share similar disease etiology.

PROJECT NARRATIVE The central objective of this one-year competitive revision is to assess the potential of two novel therapeutics (DS-iKL and DAPT) to mitigate the extrinsic and intrinsic cardiac effects of SARS-CoV-2, respectively. In addition, the potential impact of DS-iKL and DAPT to mitigate the effects of SARS-CoV-2 are likely to also be applicable to other inflammatory and infectious diseases that share similar disease etiology.