De Novo Designed Protein Nanoparticle Agonists Targeting the Tie2 Receptor for the Treatment of ARDS and Sepsis in Patients with COVID-19

Broader Impacts: The current COVID-19 outbreak is a global pandemic with over 45 million cases and 1,200,000 deaths officially reported. Epidemiological data emerging from Italy indicate that 40-96% of COVID- 19 patients admitted into the hospital develop ARDS and sepsis. Developing a functional treatment for these conditions would also have far reaching impacts beyond this current pandemic, as the underlying pathology can arise from a multitude of factors. Overview: The goal of this project is to engineer a Tie2 super-agonistic nanoparticle (NP) and optimize its production at large scale. Our NPs would be used to treat the lethal symptoms of the current COVID-19 viral outbreak. Acute respiratory distress syndrome (ARDS) and sepsis are major contributors to COVID-19 mortality. Currently there are no approved drugs to treat these conditions, because activation of the target receptors cannot be controlled. To bypass these limitations, we engineered a de novo protein therapeutic that overcomes the major limitations of manufacturing and rapid regeneration of vascular tissue needed to treat ARDS and sepsis. Such a technology could mitigate the dangers of COVID infection when patients enter clinics or quarantine. Our NP super-agonist overcomes the limitations of Ang1, the natural protein that signals through Tie2, which is too unstable to be used as an effective treatment for ARDS or sepsis. The proposed funding would allow for immediate development of the NP to improve bioavailability and validation of therapeutic utility in two murine infection models. We will achieve this in three separate aims: Aim 1: Measure PK/PD, Toxicity and Immunogenicity of Pegylated Ang1F-NP In Vivo. Aim 2: Validate In Vivo Efficacy of Ang1F NPs in C57Bl/6 mice infected with H1N1-PR8. Aim 3: Validate Whether Ang1-NPs Reduce Lung Injury in Murine COVID-19/SARS- CoV-2 Infection. Intellectual Merit: We aim to develop experimental and technological advances that will have a strong impact in the fields of structural biology, therapeutic discovery, and clinical medicine. We are working with one of the few medical branches that have access to the current COVID-19 strain and who are actively developing animal models to test out therapies prior to clinical trials. The proposed research could be a key solution to reduce the total number of deaths and enable healthcare professionals to better treat patients suffering from viral outbreaks.