Soluble E NTPDase for sepsis

SUMMARY Sepsis is a medical condition caused by an overwhelming systemic inflammatory response to infection Although the underlying infection can now be efficiently treated with antibiotics there are no effective therapies to control the organ damage caused by the inflammatory response of the host As a result sepsis is the leading cause of mortality in intensive care units and is the tenth leading cause of death overall in the US The ectonucleoside triphosphate diphosphohydrolase E NTPDase CD is a cell surface associated anti inflammatory enzyme It has multiple anti inflammatory actions which include degradation of the endogenous proinflammatory molecule adenosine triphosphate and triggering of the production of the anti inflammatory agent adenosine We have discovered that endogenous CD protects mice against polymicrobial sepsis induced mortality organ damage and inflammation Similarly injecting a soluble E NTPDase CD mimic apyrase is protective Based on these results we propose exogenously administered soluble E NTPDase as a novel and effective therapy for sepsis However apyrase an E NTPDase CD mimic of plant origin is likely to provoke a hazardous antibody response in humans preventing its use as a therapeutic agent for septic patients To overcome this problem in the current proposal we will evaluate the effect of an optimized human recombinant soluble E NTPDase APT in sepsis Our hypothesis is that APT would reduce mortality organ injury and inflammation in sepsis To address this hypothesis we propose two Specific Aims In Specific Aim we will test the efficacy of APT in preventing mortality in polymicrobial sepsis induced by cecal ligation and puncture in mice In Specific Aim we will delineate the effect of APT on organ injury and inflammation in sepsis We expect that APT will reduce mortality organ injury and inflammation in septic mice The long term goal of this study is to develop APT as a safe and effective treatment option for the management of patients with sepsis NARRATIVE Sepsis remains the leading cause of mortality and morbidity in critically ill patients because it triggers an overwhelming inflammatory response in the host In the proposed studies we will test a soluble ectonucleoside triphosphate diphosphohydrolase APT which has broad anti inflammatory effects for efficacy in protecting against mortality organ damage and inflammation in sepsis The long term goal is to develop APT as a safe and effective therapeutic intervention for sepsis patients