The goal of the proposed research is to demonstrate that Inter-alpha serine protease inhibitor proteins (IaIp) are an effective therapy for sepsis. In sepsis, normally high plasma levels of IaIp drop dramatically in adult and newborn patients. We hypothesize that IaIp are consumed while mitigating the damaging effects of circulating proteases. We hypothesize that administration of IaIp will correct the imbalance between IaIp and plasma proteases, thereby preventing organ injuries and high mortality rates in sepsis. Animal studies in a rat cecal ligation/puncture model for sepsis have demonstrated that IaIp helps maintain hemodynamic stability, prevents organ injury, and improves survival. SBIR Phase I studies with highly purified Ialp confirmed Ialp as the preventive agent and showed beneficial effects of Ialp even when administration was delayed up to 10 hrs. after sepsis induction. These results strongly support further development of Ialp as a novel anti-inflammatory agent. In this study, we will scale up the production of human Ialp for preclinical studies in animals and humans to assess its safety, pharmacokinetic properties and efficacy in septic patients. These pilot Phase I/IIa studies will lead to development of novel anti-inflammatory agents for management of sepsis.
