Development of a Novel Anti-Inflammatory Therapeutic Based on Antithrombin

基于抗凝血酶的新型抗炎治疗药物的开发

• 批准号: 8058061
• 负责人: MICHAEL W FANGER
• 金额: $ 74.79万
• 依托单位: CELDARA MEDICAL, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058061
• 关键词: Abbreviations; Acute; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Antithrombin III; Antithrombins; Biological Assay; Blood Clot; Blood coagulation; Cardiogenic Shock; Clinical; Clinical Treatment; Coagulation Process; Complex; Consumption; Deep Vein Thrombosis; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Endotoxins; Event; Exhibits; Failure; Goals; Hemorrhage; Heparin; High Prevalence; Human; Hypotension; In Vitro; Infection; Inflammation; Inflammatory; Intravenous; Left ventricular structure; Lipopolysaccharides; Measures; Medical; Monitor; Morbidity - disease rate; Mutate; Mutation; Myocardial dysfunction; Outcome; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Plasma; Plasma Proteins; Preparation; Process; Production; Property; Risk; Safety; Sepsis; Sepsis Syndrome; Septic Shock; Signal Transduction; Supportive care; Testing; Therapeutic; Toxicology; base; body system; dosage; in vitro Assay; in vivo; inhibitor/antagonist; innovation; killings; mortality; mouse model; novel; novel therapeutics; research study; scale up; septic; suicidal

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.

描述(由申请人提供)：败血症休克是败血症的可怕后果，败血症是一种由感染引发的急性全身炎症状态。在美国，每年发生超过75万次脓毒症，死亡率高达30%。这种破坏性后果的高度流行突显了新型靶向抗炎疗法产生巨大影响的潜力。抗凝血酶(AT)就是这样一种候选药物。AT是一种天然血浆蛋白，被认为是凝血级联反应最重要的抑制因子。然而，AT也显示出明显的抗炎信号活性。因此，治疗性应用AT有可能改善许多炎症性疾病。不幸的是，AT的抗凝活性限制了其临床应用，这会产生不良的出血事件。为了绕过这一限制，一种突变形式的AT正在开发中，这种突变形式的AT缺乏抗凝活性，但仍具有抗炎活性。为了支持这一应用，已经产生和建立了以下内容：(1)ATRCL，一种具有最低抗凝活性但保持阻断核因子-B激活能力的突变AT形式(在体外试验中)和(2)败血症休克小鼠模型，在该模型中，野生型AT治疗改善了脂多糖(LPS)诱导的心源性休克。将产生ATRCL，并根据其体外抗炎活性对其剂量进行标准化(目标1)。将使用凝血试验(AIM 2)对ATRCL的体内和体外安全性进行第一次评估。最后，将在内毒素诱导的感染性休克小鼠模型上测试疗效(目标3)。肝素对安全性和有效性的影响也将得到监测。所描述的实验将确定一种非常有希望的化合物是否在体内发挥其概念上和体外证明的潜力。如果成功，ATRCL将成为一种治疗药物，具有广泛而有价值的适用性和出色的安全性。 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。这个过程很复杂，但却是由炎症驱动的。抗凝血酶(AT)是一种有效的天然抗炎药，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，而不存在出血风险。该项目的总体目标是开发这种药物来帮助人类。