Novel Therapy for Sepsis

描述（由申请人提供）：脓毒症仍然是一个重要的医疗问题，在美国每年导致超过20万人死亡。脓毒症综合征由于全身炎症反应和凝血级联反应的激活而导致多系统器官衰竭。开发治疗败血症的有效疗法的努力令人失望，只有一种药物获得批准。最近的证据表明，载脂蛋白E多态性在调节全身炎症反应，反应可能发挥重要作用的脓毒症综合征患者的结果，其中存在的APOE 4等位基因与脓毒症的风险增加后，择期手术和心肺转流。Cognosci Inc.发现了一种称为COG 133的抗炎肽，该肽被证明可以抑制炎症介质的激活并减少炎症介质的分泌。最近，我们已经证明，COG 133改善了初步败血症研究中使用小鼠盲肠结扎穿孔模型的结果。为了进一步追求COG 133作为脓毒症的治疗，我们建议在更相关的单种菌血症脓毒症小鼠模型中完成COG 133的评估。将评价由革兰氏阳性（金黄色葡萄球菌）和革兰氏阴性（大肠杆菌）细菌物种诱导的脓毒症综合征，以确定降低死亡率所需的COG 133剂量。COG 133的优化剂量将用于进一步的实验，以通过生物化学和组织学分析表征疾病进展。将通过测定全身炎症细胞因子水平（血清TNF α、IL-1？、IL-6水平）、凝血时间和细胞信号传导激活（磷酸-JNK、磷酸-IRAK、磷酸-P38）。成功证明死亡率提高、有害炎症反应减少和凝血引起的器官损伤减少将导致在狒狒中进行II期研究，以评估灵长类动物模型的疗效，该模型用于开发唯一FDA批准的治疗败血症综合征的治疗药物。

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.