Treatment of Sepsis using Recombinant Human Lactoferrin

描述（由申请人提供）：严重败血症是美国死亡和发病的主要原因（Angus DC et al., 2001），每年约有75.1万例，平均每例花费超过2.2万美元，导致21.5万例死亡（死亡率28.6%）。脓毒症的发病率预计将以每年1.5%的速度增长。Xigris是fda批准的首个治疗败血症的药物，自2001年以来一直在使用。然而，Xigris仅局限于严重败血症患者，仅显示死亡率降低6%，仍然留下巨大的未满足的医疗需求。乳铁蛋白已被证明在几种败血症模型中提供保护。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年；新生仔猪内毒素血症，死亡率从83%降低到26%）。牛乳铁蛋白在人类中的使用可能受到其缺乏医药级质量的限制。本地人类LF的使用受到其可用性的限制。Agennix已经证明重组人乳铁蛋白（rhLF）口服给药对lps诱导的小鼠内毒素血症模型有效。RhLF也被证明能有效减轻细菌感染的影响（Edde et al., 2001），在大肠杆菌感染的新生大鼠中，死亡/垂死动物的数量从46%降至零（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临床前疗效所提供的有效干预机会，值得进一步发展，使口服rhLF成为脓毒症适应症的良好临床调查的主题。为此，本项目采用革兰氏阴性和革兰氏阳性（大肠杆菌IPS、金黄色葡萄球菌肠毒素B毒素）攻毒模型，通过证明口服rhLF的效果具有统计学意义，旨在建立rhLF的治疗效果（Specific Aim 1）。此外，我们计划在小鼠细菌感染模型（大肠杆菌，金黄色葡萄球菌）中建立口服rhLF的治疗效果，使用全身和肠道相关菌血症，使用或不使用抗生素（Specific Aim 2）。这个项目的总体目标是收集足够有说服力的实验证据，以允许临床检查rhLF对人类败血症的可能疗效。美国国立卫生研究院对该项目的资助将直接支持潜在的重要药物治疗的发展，以治疗人类败血症。

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.