Novel treatment for DIC

Project Summary Several diseasesincluding endotoxemiaand sepsis can cause disseminated intravascular coagulationDICDIC can induce the formation of microvascular thrombicausing organ failure and death in the absence of the appropriate treatmentTo datethere are no drugs to treat DICand several reagents have been tested buttheir strong doses can lead to severe bleedingsignificantly diminishing their benefitsA severe insult like systemic inflammation activates both endothelium and coagulation systemThis is characterized by the increment of a widespread of fibrin deposition that is a hallmark in DICOur candidate drugthe Aprotein binds to fibrinIn vitrothe Aprotein delayed fibrin formation and blocked platelet adhesion to fibrin ogenunder high shear stressImportantlythe Aprotein efficiently reduced the formation of microvascular thrombosis in two different animal species and models for DICa murine model for endotoxemia induced DICanda pig model for bacteria induced DICNote that the Aprotein was given to the micehours after the insult with endotoxinwhile the Aprotein was administered to the pigshours after the intravenous inoculation of bacteriaFurthermorein the murine model the Aprotein prevented organ failureand markedly improved the survival of the treated miceNotablythe Aprotein had no effect on platelet aggregation in vitro nor affected the tail bleeding time in miceThe Aims for this STTR areAimTo determine the pharmacological benefit of the Aprotein on reducing microvascular thrombosis in a porcine model of bacteria induced sepsisThis aim will demonstrate that the Aprotein is effective in reducing microvascular thrombosis and proinflammatory markers using a gram positive or gram negative bacteria induced DIC modelAimTo determine the safety of the Aprotein for hemostasisThis aim will investigate the effect of the Aprotein on hemostasis using large animal modelsIn Phase IIwe will optimize the production of the candidate productand will perform pharmacokineticpharmacologicaland toxicological studiesFinallywe will perform time window studies using larger animals Narrative This project will further investigate the beneficial effect of Aprotein in treating disseminated microvascular thromboses such as disseminated intravascular coagulationDICas seen in conditions like sepsisDifferent primary disordersincluding sepsisendotoxemiacancerand malariacan cause DIC and currentlythe management of DIC is restricted to treat the underlying conditionand use of antibiotics in sepsisThe development of the candidate drug addresses this unmet medical need by providing a safe and effective novel therapeutic approach