Abstract P2102: EB3 Inhibitor VT-109 Activated FOXM1 Pathways To Promote Resolution Of Acute Lung Injury

Abstract

Acute respiratory distress syndrome (ARDS) is the acute onset of non-cardiogenic pulmonary edema, hypoxemia, and respiratory failure, conditions associated with a high mortality rate. ARDS is frequently caused by lung infections including SARS-CoV-2. In light of the COVID-19 pandemic, development of therapeutic approaches to combat ARDS have become an urgent unmet medical need. As increased vascular leakage is a culprit of alveolar damage and lung inflammation, we hypothesize that an effective therapy against vascular leakage should improve the clinical outcome of ARDS patients. We have identified a drug candidate Vascular Therapeutics (VT)-109, an allosteric inhibitor of End Binding protein 3, which contributes to vascular leakage by amplifying pathological calcium signaling in endothelial cells. Treatment of mice with VT-109 reduced the leakage of proteinous fluids in lungs to 55.4% (n=7, p<0.05) after endotoxin challenge, 77.7% (n=6, p<0.01) after exposure to high volume mechanical ventilation, and 42.5% (n=7, p<0.05) in the two-hit model, a combination of polymicrobial sepsis with normal tidal volume mechanical ventilation. VT-109 reduced the mortality of both septic (n=10, p<0.01) and endotoxin-challenged (n=10, p<0.05) mice. Furthermore, treatment with VT-109 in mice expressing human ACE2 receptor blocked diffuse alveolar damage (n=5, p<0.0001) caused by SARS-CoV-2 infection. In this COVID-19 model, the therapeutic benefits of VT-109 were observed when treatment was initiated at either day 1 or day 3 post-viral infection. Transcriptome analysis of lung endothelial cells in mice challenged with endotoxin showed that VT-109 upregulated 23 FOXM1 target genes (>2-fold) suggesting that it promotes endothelial cell regeneration by activating the FOXM1 pathway. Our data demonstrate that VT-109 successfully treats vascular leakage and is a promising drug candidate for future clinical studies. Funding for this work is provided by the Congressionally Directed Medical Research Programs through the Peer Reviewed Medical Research Program (PRMRP) under award No. W81XWH-21-1-0639. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.