Development of a Novel Anti-Inflammatory Therapeutic Based on Antithrombin

DESCRIPTION (provided by applicant): Septic shock is a dire outcome of sepsis, an acute systemic inflammatory state triggered by an infection. In the USA, over 750,000 episodes of sepsis occur each year and mortality reaches 30%. The high prevalence of such devastating outcomes highlights the potential for enormous impact by novel targeted anti-inflammatory therapeutics. One such candidate agent is antithrombin (AT). AT is a natural plasma protein that is considered to be the most important inhibitor of theblood clotting cascade. However, AT also exhibits distinct anti-inflammatory signaling activities. Thus, therapeutic administration of AT has the potential to ameliorate numerous inflammatory diseases. Unfortunately, clinical deployment of AT has been limited by AT's anticoagulant activity, which produces adverse bleeding events. To circumvent this limitation, a mutated form of AT that lacks anticoagulant activity but retains anti-inflammatory activity is being developed. In support of this application thefollowing have been generated and established: (1) ATRCL, a mutated AT form with minimal anticoagulant activity but which maintains the ability to block activation of NF-:B (in an in vitro assay) and (2) a mouse model of septic shock, in which treatment with wild-type AT ameliorates lipopolysaccharide (LPS) induced cardiogenic shock. ATRCL will be generated and its dosage standardized based on its in vitro anti-inflammatory activity (Aim 1). The first assessments of ATRCL's in vivo and in vitro safety using coagulation assays (Aim 2) will be conducted. Finally, efficacy will be tested in mouse models of LPS induced septic shock (Aim 3). The effect of heparin on safety and efficacy will also be monitored. The experiments described will determine whether an extremely promising compound performs in vivo to its conceptual and demonstrated in vitro potential. If successful, ATRCL will become a therapeutic with broad and valuable applicability and an outstanding safety profile. PUBLIC HEALTH RELEVANCE: Septic shock kills 150,000 people per year in the US alone. The process is complex, but is driven by inflammation. Antithrombin (AT) is a potent natural anti-inflammatory agent, but it often leads to serious bleeding. We have a new form of AT which imparts anti-inflammatory benefits without the bleeding risks. The overall goal of this project is to develop this drug to help humans.