ABSTRACT. This application is being submitted to PA-18-591 in accordance with NOT-AI-20-031. The recent emergence of SARS-CoV-2 and COVID-19 has created an urgent need for rapid deployment of therapeutic strategies to combat the current pandemic, and major efforts are underway to develop new vaccines and antiviral medications, however, results from these efforts are not expected in the near term. A more immediate approach is to repurpose existing therapeutics approved by the FDA for other conditions to remediate symptoms associated with the most severe COVID-19 outcomes, potentially saving lives and reducing the burden on the healthcare system. Within this framework, cytokine release syndrome (CRS) also known as cytokine storm or hypercytokinemia, has been implicated in acute respiratory distress syndrome, heart failure, and death in patients with COVID-19 (1-5). However, although diverse immune-suppressive strategies to attenuate the cytokine storm are being tested in clinical trials for COVID-19, there is a dearth of pre-clinical data supporting their use to attenuate cytokine-driven pathology. Therefore, we propose here to test the ability of FDA-approved inhibitors of Janus Kinases (JAKs) to mitigate rampant cytokine production and multi-organ inflammation in a mouse model of non-infectious lethal immune hypersensitivity. This mouse model has arisen directly from our work over the past five years that revealed a major role for immune dysregulation in Down syndrome (DS). We demonstrated that individuals with Trisomy 21 (T21), the molecular cause of DS, exhibit constitutively active interferon (IFN) signaling driven by presence of four of the six IFN receptors (IFNRs), located in a single locus on chromosome 21 (chr21) (6). Follow-up studies have revealed 1) signs of IFN activation and chronic inflammation, including numerous cytokines related to CRS, in the plasma proteome of people with T21 (7, 8) and 2) widespread immune dysregulation and IFN hypersensitivity in the blood of people with DS (9, 10). As part of our ongoing work to understand the role of interferon dysregulation in Down syndrome (DS), we recently discovered that the Dp16 mouse model of DS is lethally hypersensitive to chronic innate immune stimulation with the TLR3 agonist polyinosinic: polycytidylic acid [P(I:C)]. Unpublished preliminary data in this proposal include: · P(I:C) treatment of Dp16 mice triggers release of cytokines, including several recently linked to poor prognosis in COVID-19, such as MCP-1, MIP-1α, and IP-10. · The lethal immune hypersensitivity in this model is associated with multi-organ inflammation and liver damage in particular. · The lethality, cytokine release, and inflammation induced by P(I:C) can all be blocked with the JAK1- specific inhibitor INCB054707. We hypothesize that JAK inhibitors are a therapeutically viable strategy to ameliorate COVID-19 associated cytokine release syndrome and associated morbidities. As such, our proposal is resp...