Development of a Novel Anti-Inflammatory Therapeutic Based on Antithrombin

描述（由申请人提供）：脓毒症休克是脓毒症的可怕结局，脓毒症是由感染引发的急性全身炎症状态。在美国，每年发生超过750，000次败血症发作，死亡率达到30%。这种破坏性结果的高患病率突出了新型靶向抗炎治疗的巨大影响的潜力。一种这样的候选药剂是抗凝血酶（AT）。AT是一种天然血浆蛋白，被认为是凝血级联反应的最重要抑制剂。然而，AT也表现出不同的抗炎信号传导活性。因此，AT的治疗性施用具有改善许多炎性疾病的潜力。不幸的是，AT的抗凝活性限制了AT的临床部署，这会产生不良出血事件。为了规避这一限制，正在开发缺乏抗凝活性但保留抗炎活性的AT的突变形式。为了支持本申请，已经产生并建立了以下：（1）ATRCL，一种具有最小抗凝活性但保持阻断NF-：B活化的能力的突变AT形式（在体外测定中）和（2）脓毒性休克的小鼠模型，其中用野生型AT治疗改善脂多糖（LPS）诱导的心源性休克。将生成ATRCL，并基于其体外抗炎活性对其剂量进行标准化（目的1）。将使用凝血试验（目的2）对ATRCL的体内和体外安全性进行首次评估。最后，将在LPS诱导的败血性休克的小鼠模型中测试功效（目的3）。还将监测肝素对安全性和疗效的影响。所描述的实验将确定一个非常有前途的化合物是否在体内表现出其概念和体外证明的潜力。如果成功，ATRCL将成为一种具有广泛和有价值的适用性和突出的安全性的治疗。 公共卫生相关性：仅在美国每年就有15万人死于感染性休克。这个过程是复杂的，但由炎症驱动。抗凝血酶（AT）是一种有效的天然抗炎剂，但它经常导致严重出血。我们有一种新形式的AT，它具有抗炎作用，而没有出血风险。该项目的总体目标是开发这种药物来帮助人类。

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 the blood 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 the following 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.