Sepsis remains an important medical problem that results in over 200,000 deaths each year in the United States. Sepsis syndrome results in multisystem organ failure due to a systemic inflammatory response and activation of the blood clotting cascade. Efforts to develop effective therapeutics to treat sepsis have been disappointing with only one drug being approved. Recent evidence has implicated apolipoprotein E polymorphisms in modulating the systemic inflammatory response, a response that may play an important role in the outcome of patients with sepsis syndrome where presence of the APOE4 allele is associated with increased risk of sepsis following elective surgical procedures and following cardiopulmonary bypass. Cognosci Inc. has discovered an anti-inflammatory peptide known as COG133 that was demonstrated to suppress activation of and reduce secretion of inflammatory mediators. More recently, we have demonstrated that COG133 improved outcome in a preliminary sepsis study using a murine cecal ligation-perforation model. In order to further pursue COG133 as a treatment for sepsis, we propose to complete evaluation of COG133 in more relevant single species bacteremia mouse models of sepsis. Sepsis syndrome induced by both gram positive (Staphylococcus aureus) and gram negative (Escherichia coli) bacterial species will be evaluated to determine the dose of COG133 required to reduce mortality. The optimized dose of COG133 will be used in further experiments to characterize disease progression through biochemical and histological analysis. Biochemical disease progression will be monitored through determination of systemic inflammatory cytokine levels (serum TNFa, Il-1?, IL-6 levels), clotting times and activation of cell signaling (phospho-JNK, phospho-IRAK, phospho-P38). Successful demonstration of improved mortality, reduced harmful inflammatory responses, and reduced organ damage from clotting will lead to Phase II studies in baboons to evaluate efficacy in a primate model that was used for development of the only FDA approved therapeutic for treatment of sepsis syndrome. ? ? ?
| Christensen, Dale J; Ohkubo, Nobutaka; Oddo, Jessica et al. (2011) Apolipoprotein E and peptide mimetics modulate inflammation by binding the SET protein and activating protein phosphatase 2A. J Immunol 186:2535-42 |
