Several diseases, including endotoxemia, and sepsis can cause disseminated intravascular coagulation (DIC). DIC can induce the formation of microvascular thrombi, causing organ failure and death in the absence of the appropriate treatment. To date, there are no drugs to treat DIC, and several reagents have been tested but, their strong doses can lead to severe bleeding, significantly diminishing their benefits. A severe insult like systemic inflammation activates both endothelium and coagulation system. This is characterized by the increment of a widespread of fibrin deposition that is a hallmark in DIC. Our candidate drug, the A2 protein binds to fibrin. In vitro, the A2 protein delayed fibrin formation and blocked platelet adhesion to fibrin(ogen) under high shear stress. Importantly, the A2 protein efficiently reduced the formation of microvascular thrombosis in two different animal species and models for DIC: 1) a murine model for endotoxemia-induced DIC, and 2) a pig model for bacteria-induced DIC. Note that the A2 protein was given to the mice 1.5 hours after the insult with endotoxin, while the A2 protein was administered to the pigs 24 hours after the intravenous inoculation of bacteria. Furthermore, in the murine model the A2 protein prevented organ failure, and markedly improved the survival of the treated mice. Notably, the A2 protein had no effect on platelet aggregation in vitro nor affected the tail bleeding time in mice.
The Aims for this STTR are:
Aim 1 : To determine the pharmacological benefit of the A2 protein on reducing microvascular thrombosis in a porcine model of bacteria-induced sepsis.
This aim will demonstrate that the A2 protein is effective in reducing microvascular thrombosis and pro- inflammatory markers using a gram-positive or gram-negative bacteria-induced DIC model.
Aim 2 : To determine the safety of the A2 protein for hemostasis.
This aim will investigate the effect of the A2 protein on hemostasis using large animal models. In Phase II, we will optimize the production of the candidate product, and will perform pharmacokinetic, pharmacological, and toxicological studies. Finally, we will perform time window studies using larger animals.
This project will further investigate the beneficial effect of A2 protein in treating disseminated microvascular thromboses such as disseminated intravascular coagulation (DIC) as seen in conditions like sepsis. Different primary disorders, including sepsis, endotoxemia, cancer, and malaria, can cause DIC and currently, the management of DIC is restricted to treat the underlying condition, and use of antibiotics in sepsis. The development of the candidate drug addresses this unmet medical need by providing a safe and effective novel therapeutic approach.
