Treatment of Sepsis using Recombinant Human Lactoferrin

使用重组人乳铁蛋白治疗脓毒症

• 批准号: 7053288
• 负责人: KAREL PETRAK
• 金额: $ 13.06万
• 依托单位: AGENNIX, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7053288
• 关键词: Escherichia coli; antibacterial agents; antibiotics; combination therapy; dosage; dosage forms; human genetic material tag; laboratory mouse; lactoferrin; lipopolysaccharides; nonhuman therapy evaluation; recombinant proteins; septicemia; staphylococcal enterotoxin; statistics /biometry

DESCRIPTION (provided by applicant): Severe sepsis is a major cause of mortality and morbidity in the US (Angus DC et al., 2001) with some 751,000 cases annually, costing on average over $22,000/case, and resulting in 215,000 deaths (28.6% mortality rate). The incidence of sepsis cases has been projected to increase by 1.5% per annum. Xigris, the first FDA-approved drug therapy for sepsis has been in use since .2001. However, Xigris is limited to severe sepsis patients only and shows only a 6% reduction in mortality, still leaving an enormous unmet medical need. Lactoferrin has been shown to provide protection in several models of sepsis. However, much of the work so far has been carried out with bovine lactoferrin (e.g., Lee et al., 1998; endotoxemia in neonatal piglets, mortality reduced from 83% to 26%). The use of bovine lactoferrin in humans may be limited by the lack of its pharmaceutical-grade quality. The use of native human LF is limited by its availability. Agennix has demonstrated that recombinant human lactoferrin (rhLF) given orally is efficacious in murine models of LPS-induced endotoxemia. RhLF has also been shown to be effective in attenuating the effects of bacterial infection (Edde et al., 2001), in E. coli-infected neonatal rats, the number of dead/dying animals decreased from 46% to zero (P<0.0001)). A clear unmet medical need in sepsis and the opportunity for an effective intervention offered by the observed pre-clinical efficacy of oral rhLF merits further development to make oral rhLF a subject of sound clinical investigations in sepsis indication. To this end, using both gram negative and gram positive (E. coli IPS, Staphylococcus aureus enterotoxin B toxin) challenge models, this projects aims to establish therapeutic effectiveness of rhLF by demonstrating statistical significance of the effect of oral rhLF (Specific Aim 1). Further, we plan to establish therapeutic effectiveness of oral rhLF in murine bacterial infection models (E. coli, Staphylococcus aureus), using both the systemic and gut-associated bacteremia, with and without the use of antibiotics (Specific Aim 2). The overall aim of this proposed project is to assemble experimental evidence compelling enough to allow clinical examination of the possible efficacy of rhLF in human sepsis. NIH funding for this project would directly support the development of potentially important drug therapy to treat human sepsis.

描述（由申请人提供）：严重脓毒症是美国死亡率和发病率的主要原因（安格斯DC等人，2001年），每年约751，000例，平均每例费用超过22，000美元，并导致215，000例死亡（死亡率28.6%）。脓毒症病例的发病率预计每年增加1.5%。Xigris是FDA批准的第一种治疗败血症的药物，自2001年以来一直在使用。然而，Xigris仅限于严重脓毒症患者，死亡率仅降低6%，仍然存在巨大的未满足的医疗需求。乳铁蛋白已被证明在几种脓毒症模型中提供保护。然而，到目前为止，大部分工作都是用牛乳铁蛋白进行的（例如，Lee等人，1998;新生仔猪内毒素血症，死亡率从83%降低至26%）。牛乳铁蛋白在人体中的使用可能受到缺乏其医药级质量的限制。天然人LF的使用受到其可用性的限制。Agennix已证明口服重组人乳铁蛋白（rhLF）在脂多糖诱导的内毒素血症小鼠模型中有效。RhLF也已显示在减弱细菌感染的作用方面是有效的（Edde等人，2001），E.大肠杆菌感染的新生大鼠，死亡/濒死动物的数量从46%下降到零（P<0.0001））。脓毒症中明显未满足的医疗需求以及观察到的口服rhLF临床前疗效提供的有效干预机会值得进一步开发，以使口服rhLF成为脓毒症适应症的合理临床研究对象。为此，使用革兰氏阴性和革兰氏阳性（E。coli IPS，金黄色葡萄球菌肠毒素B毒素）攻击模型，该项目旨在通过证明口服rhLF的作用的统计学显著性来确定rhLF的治疗有效性（具体目的1）。此外，我们计划在小鼠细菌感染模型中建立口服rhLF的治疗效果（E.大肠杆菌，金黄色葡萄球菌），使用全身性和肠道相关菌血症，使用和不使用抗生素（具体目标2）。该项目的总体目标是收集足够有力的实验证据，以允许临床检查rhLF在人类脓毒症中的可能疗效。NIH对该项目的资助将直接支持开发治疗人类败血症的潜在重要药物疗法。