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）：脓毒性休克是脓毒症的可怕后果，脓毒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 750,000 起败血症，死亡率达到 30%。这种破坏性后果的高发生率凸显了新型靶向抗炎疗法产生巨大影响的潜力。其中一种候选药物是抗凝血酶（AT）。 AT 是一种天然血浆蛋白，被认为是凝血级联最重要的抑制剂。然而，AT 还表现出独特的抗炎信号活性。因此，AT 的治疗性给药具有改善多种炎症性疾病的潜力。不幸的是，AT 的临床应用受到 AT 抗凝活性的限制，它会产生不良出血事件。为了规避这一限制，一种缺乏抗凝活性但保留抗炎活性的 AT 突变形式正在开发中。为了支持这一应用，已经产生并建立了以下内容：(1) ATRCL，一种突变的 AT 形式，具有最小的抗凝活性，但保持阻断 NF-:B 激活的能力（在体外测定中）和 (2)感染性休克小鼠模型，其中野生型 AT 治疗可改善脂多糖 (LPS) 诱导的心源性休克。 ATRCL 将根据其体外抗炎活性生成并标准化其剂量（目标 1）。将使用凝血测定（目标 2）对 ATRCL 的体内和体外安全性进行首次评估。最后，将在 LPS 诱导的感染性休克小鼠模型中测试疗效（目标 3）。还将监测肝素对安全性和有效性的影响。所描述的实验将确定一种极其有前途的化合物是否在体内发挥其概念和体外潜力。如果成功，ATRCL 将成为一种具有广泛和有价值的适用性以及出色的安全性的治疗方法。 公共卫生相关性：仅在美国，败血性休克每年就会导致 15 万人死亡。这个过程很复杂，但是由炎症驱动的。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，但没有出血风险。该项目的总体目标是开发这种药物来帮助人类。