Novel Therapy for Sepsis

描述(由申请人提供)：败血症仍然是一个重要的医学问题，在美国每年导致超过20万人死亡。由于全身炎症反应和凝血级联反应的激活，脓毒症综合征导致多系统器官衰竭。开发治疗脓毒症的有效疗法的努力一直令人失望，只有一种药物获得批准。最近的证据表明，载脂蛋白E基因多态性在调节全身炎症反应中起重要作用，这种反应可能在脓毒症综合征患者的预后中发挥重要作用，在脓毒症综合征患者中，APOE4等位基因的存在与择期手术和体外循环后脓毒症风险的增加有关。Cognosci公司发现了一种名为COG133的抗炎肽，它被证明可以抑制炎症介质的激活和减少炎症介质的分泌。最近，我们使用小鼠盲肠结扎-穿孔模型，在一项初步的脓毒症研究中证明了COG133改善了结果。为了进一步探索COG133作为一种治疗败血症的方法，我们建议在更相关的单种菌血症小鼠败血症模型中完成COG133的评估。将对革兰氏阳性菌(金黄色葡萄球菌)和革兰氏阴性菌(大肠杆菌)引起的脓毒症综合征进行评估，以确定降低死亡率所需的COG133剂量。优化的COG133剂量将用于进一步的实验，通过生化和组织学分析来表征疾病的进展。生化疾病的进展将通过测定全身炎症细胞因子水平(血清TNFa、IL-1、IL-6水平)、凝血时间和细胞信号的激活(磷酸化JNK、磷酸化IRAK、磷酸化P38)来监测。成功地证明了死亡率的提高、有害炎症反应的减少和凝血造成的器官损伤的减少，将导致在狒狒身上进行第二阶段研究，以评估用于开发FDA批准的唯一用于治疗脓毒症综合征的灵长类动物模型的疗效。

DESCRIPTION (provided by applicant): Sepsis remains an important medical problem that results in over 200,000 deaths each year in the United States. Sepsis syndrome results in multisystem organ failure due to a systemic inflammatory response and activation of the blood clotting cascade. Efforts to develop effective therapeutics to treat sepsis have been disappointing with only one drug being approved. Recent evidence has implicated apolipoprotein E polymorphisms in modulating the systemic inflammatory response, a response that may play an important role in the outcome of patients with sepsis syndrome where presence of the APOE4 allele is associated with increased risk of sepsis following elective surgical procedures and following cardiopulmonary bypass. Cognosci Inc. has discovered an anti-inflammatory peptide known as COG133 that was demonstrated to suppress activation of and reduce secretion of inflammatory mediators. More recently, we have demonstrated that COG133 improved outcome in a preliminary sepsis study using a murine cecal ligation-perforation model. In order to further pursue COG133 as a treatment for sepsis, we propose to complete evaluation of COG133 in more relevant single species bacteremia mouse models of sepsis. Sepsis syndrome induced by both gram positive (Staphylococcus aureus) and gram negative (Escherichia coli) bacterial species will be evaluated to determine the dose of COG133 required to reduce mortality. The optimized dose of COG133 will be used in further experiments to characterize disease progression through biochemical and histological analysis. Biochemical disease progression will be monitored through determination of systemic inflammatory cytokine levels (serum TNFa, Il-1?, IL-6 levels), clotting times and activation of cell signaling (phospho-JNK, phospho-IRAK, phospho-P38). Successful demonstration of improved mortality, reduced harmful inflammatory responses, and reduced organ damage from clotting will lead to Phase II studies in baboons to evaluate efficacy in a primate model that was used for development of the only FDA approved therapeutic for treatment of sepsis syndrome.