Grant: Alliance Grants

COVID-19 caused by the novel coronavirus, SARS-CoV2, is now a historical pandemic due to its ease of transmission, potential to overburden our healthcare systems, and massive disruption to the global economy and everyday life. About 15% of COVID-19 patients require hospitalization and 5% intensive care, ultimately leading to 1-5% of individuals to succumb. The largest source of morbidity and mortality related to COVID-19 is the development of acute respiratory distress syndrome (ARDS) that arises from lung tissue damage and vascular leakage, leading to fluid-filled lungs that make breathing difficult. ARDS is not directly caused by the virus, but rather it is due to an over-reactive immune response known as cytokine release syndrome, or cytokine storm. This is caused by a molecular feedback loop that greatly amplifies inflammation causing general tissue damage. The main culprit for ARDS in COVID-19 seems to be the release of the inflammatory signal interleukin-6 (IL-6) and activation of its receptor (IL-6R). There is significant interest in interrupting IL-6R signaling as a way to abate inflammation and help patients recover. Potential treatments include anti-inflammatory drugs, neutralizing monoclonal antibodies, and RNA therapeutics. However, these drugs are delivered intravenously leading to global reduction of immune function and potential secondary infections. Targeted delivery and release of IL-6R inhibitors in the affected lung tissue would reduce side-effects. Ultrasound and microbubble technologies are emerging as potential workhorses to target the release of and/or stimulate the cellular uptake of therapeutics. Microbubbles are injected into the blood carrying a therapeutic payload, which are released in the presence of ultrasound field aimed at the affected tissue. Here, in collaboration with MD Precision Inc., a company that develops and makes ultrasound devices and applications, we aim to test the use of USMB to deliver silencing RNAs and neutralizing antibodies against IL-6R using cell lines and a mice model of ARDS. If promising, these results will form the basis for USMB applications to treat the worst symptoms of COVID-19, reducing morbidity, mortality, and alleviating pressure on hospitals.