Therapeutic Development for COVID‑19 Coronavirus Induced Sepsis and ARDS Targeting Vascular Leakage

Lee, Warren L | $953,819

Ontario Unity Health Toronto 2020 CIHR Operating Grant

The new coronavirus COVID‑19 is threatening to become a global pandemic for which currently no effective drugs exist. Although development of vaccines and drugs targeting the virus are ramping up, none of these addresses host response of COVID‑19 infections directly. CAVID-19 death is mainly caused by Acute Respiratory Distress Syndrome (ARDS), which arises from a dysregulated host immune response and associated vascular leakage from viral induced sepsis. Our proposed drug development efforts aim to control the host response and protect patients from ARDS and death. My lab developed a novel zebrafish sepsis model to screen and identify drug compounds that rescue sepsis-associated mortality and vascular leakage. This project will pursue two main research objectives: (1) develop our best anti-sepsis candidate drug UNC0642 for treatment of COVID‑19 induced sepsis/ARDS, and (2) carry out drug screens to identify and repurpose existing drugs as anti-COVID-19 therapeutics. UNC0642 inhibits G9a and GLP enzymes responsible for gene regulation. Severe viral infection leads to an immune over-response which drives vascular leakage and results in multiple organ swelling and ARDS. We hypothesize that UNC0642 will protect coronavirus patients from organ swelling and decrease ARDS and mortality by controlling immune-associated gene expression. Dr. Wen has extensive expertise in virology, transgenic animal modelling, clinical medicine and drug development needed to carry out the proposed project. A collaboration with Dr. Samira Mubareka is in place to start COVID‑19 virus work at University of Toronto’s CL3 lab. Once developed, UNC0642 will become a first line treatment of severe COVID‑19 infection. Because of the tragic outbreak of COVID‑19 infection in China, regulatory filing for clinical trials in China are likely expedited, especially for repurposing existing drugs. COVID‑19 mouse and zebrafish models developed will be rapidly shared with other coronavirus research groups.

With funding from the Government of Canada

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