DEVELOPMENT OF AN ANTI-SEPSIS THERAPEUTIC

这个I期研究的目标是证明开发一种抗败血症治疗方法的可行性。每年有50万美国人患有败血症。在这个庞大的人群中，近40%或20万人死于这种综合症。分子进化将用于进化增强乙酰氧酰基水解酶（AOAH）的特性，这是一种天然的人类溶酶体酶，可以解毒脂多糖（LPS或内毒素），是脓毒症的效应分子。分子进化将增加AOAH对LPS的亲和力，使其能够有效清除LPS与脓毒症介质的关联。本研究的主要挑战是开发选择性程序，有效地富集具有增强性质的AOAH分子。I期的成功将导致在II期分离出大大增强的AOAH抗败血症药。II期研究将包括增强AOAH抗脓毒症特性的体外验证和脓毒症动物模型系统中抗脓毒症特性的评估。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。随着对脓毒症的触发元素LPS（内毒素）的亲和力增加，乙酰氧酰基水解酶（AOAH），一种能解毒LPS的人类酶，将有很大的效用作为抗脓毒症的蛋白质治疗。

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.