Early O-GlcNAc Stimulation as a trEatment for the acute shock – hErOiSmE

Shock situations (whether hemorrhagic or septic) share common pathophysiological mechanisms (implementation of inflammatory processes, cardiovascular failures, hypoperfusion of peripheral organs, etc.) that require rapid and appropriate management. They are both associated with high morbidity and mortality with a cost to society that increases each year. Unfortunately, the available treatments are very limited and mainly target symptoms. All recent studies have failed, we are facing a therapeutic impasse. It is therefore urgent to develop new strategies for new targets. In this context, our project aim to develop new approaches. In collaboration with JC Chatham (University of Birmingham, Alabama, US), we have developed an approach to stimulate O-GlcNAcylation[2] in hemorrhagic shock or septic shock. O-GlcNAcylation is a post-translational modification responsible for cell survival that plays a major role in the cell response to stress. The approaches developed by our two teams aim to increase O-GlcNAc levels very early on, and are associated with a significant reduction in stress markers, an improvement in cardiovascular function and a significant reduction in mortality in both types of shock. They demonstrate that the stimulation of O-GlcNAcylation has significant therapeutic potential for patient survival and on the battlefield to limit the damage associated with shock situations.
The consortium we have built with the chemists of the Ceisam team (univ Nantes), JC Chatham and the IIb team of the Thorax Institute will enable us to develop a stable molecule, injectable intramuscularly or intravenously with targeting properties. With this funding, we hope to ensure its safety and validate its efficacy at different times / dose in order to quickly offer injectable treatment to patients and on the battlefield to reduce the morbidity and mortality associated with hemorrhagic and septic shock.