The main objective of this Phase II application is to continue in vitro and preclinical studies to evaluate a potential biologic therapeutic for septic shock. Phase I purified a TNF inhibitor that is homologous to human MRP-8, a molecule of unknown function. It was also discovered that nanomolar concentrations of this peptide could inhibit LPS-induced production of reactive nitrogen intermediates (RNI) by macrophages. Since overproduction of both TNF and RNI is implicated in the pathogenesis of septic shock, this new activity makes MRP-8 even more promising as a treatment for sepsis. Phase II plans are to clone the human gene for MRP-8, express, and purify the recombinant molecule. Purified rMRP-8 will be evaluated in vitro and in vivo models of sepsis and inflammation. In vitro studies will focus on determining RMRP-8's spectrum of activities and analyzing mechanism of action. In vivo studies will evaluate efficacy in mouse models of endotoxemia and sepsis and in a guinea pig model of LPS-induced adult respiratory distress syndrome. The results of these studies will be crucial to determine whether further clinical studies planned for Phase III are warranted.
