DEVELOPMENT OF AN ANTI-SEPSIS THERAPEUTIC

这项I期研究的目的是证明开发一种抗菌治疗的可行性。 每年有50万美国人患有败血症。 在这么多人中，将近40%或20万人死于这种综合症。 分子进化将用于进化酰氧酰基水解酶（AOAH）的增强特性，AOAH是一种天然的人类溶酶体酶，可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对LPS的亲和力，使其能够有效地清除LPS与脓毒症介质的结合。 这项研究的主要挑战是开发选择性程序，有效地富集具有增强特性的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抗菌剂。 第二阶段的研究将涉及增强AOAH的抗菌特性的体外验证和在脓毒症动物模型系统中的抗菌特性的评估。脓毒症是一个主要的卫生保健问题，在美国每年有50万人感染这种疾病，造成20万人死亡。 随着对脓毒症中的触发元件LPS（内毒素）的亲和力增加，酰氧酰基水解酶（AOAH），一种使LPS解毒的人酶，将具有作为抗脓毒症蛋白治疗剂的巨大效用。

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.