DEVELOPMENT OF AN ANTI-SEPSIS THERAPEUTIC

这项第一阶段研究的目标是证明开发一种抗败血症疗法的可行性。每年有50万美国人患有败血症。在这个庞大的人口中，近40%或20万人死于这种综合征。分子进化将被用于进化酰氧酰水解酶(AOAH)的增强特性，AOAH是一种天然的人类溶酶体酶，可以解毒脓毒症的效应分子脂多糖(LPS或内毒素)。分子进化将增加AOAH与内毒素的亲和力，使其能够有效地清除与脓毒症介质相关的内毒素。这项研究中的主要挑战是开发选择性程序，以有效地丰富具有增强性质的AOAH分子。第一阶段的成功将导致在第二阶段分离出大大增强的AOAH抗败血症药物。第二阶段的研究将涉及增强型AOAH抗败血症特性的体外验证和在脓毒症动物模型系统中的抗败血症性能评估。拟议的商业应用脓毒症是一个主要的医疗保健问题，美国每年有50万人感染这种疾病，导致20万人死亡。随着脓毒症的触发因子--内毒素与内毒素亲和力的增强，人类解毒酶--酰氧基水解酶(AOAH)作为一种抗脓毒症蛋白治疗将具有很大的应用价值。

The goal of this Phase I research is to demonstrate the feasibility of developing an anti-sepsis therapeutic. A half million Americans each year are afflicted with sepsis. Of this large number of people, nearly 40 percent or 200,000 people die of this syndrome. Molecular evolution will be used to evolved enhanced properties of acyloxyacyl hydrolase (AOAH), a natural human lysosomal enzyme that detoxifies lipopolysaccharide (LPS or endotoxin), the effector molecule of sepsis. The molecular evolution will increase the affinity of AOAH for LPS to enable it to effectively remove LPS from associating with mediators of sepsis. The major challenge in this investigation is the development of selective procedures that will effectively enrich for AOAH molecules with enhanced properties. Success in Phase I will lead to the isolation of greatly enhanced AOAH anti-sepsis agent in Phase II. Investigations in Phase II will involve in vitro validation of the anti-sepsis character of enhanced AOAH and assessment of the anti-sepsis properties in sepsis animal model systems. PROPOSED COMMERCIAL APPLICATION Sepsis is a major health care problem with half a million people in America contracting this disease each year causing 200,000 fatalities. With increased affinity to LPS (endotoxin) the triggering element in sepsis, acyloxyacyl hydrolase (AOAH), a human enzyme which detoxifies LPS, would have great utility as an anti-sepsis protein therapeutic.