Recombinant Lactoferrin and Necrotizing Enterocolitis

描述（由申请人提供）：本可行性研究基于我们的假设，即重组人乳铁蛋白[rhLF]可以预防或降低坏死性小肠结肠炎[NEC]的严重程度。NEC主要是极低出生体重儿（VLBW）的疾病。它是新生儿重症监护病房发病和死亡的主要原因，在极低体重婴儿中发病率约为10%，死亡率约为25%。与外科和医学NEC相关的医院费用非常高。研究表明，NEC在母乳喂养的婴儿中发生的频率较低。在出生后的关键日子里，通常无法获得足够的母乳来防止异常的细菌定植和促进肠道发育。我们预计，所有VLBW婴儿在出生后至少4周或直到建立全母乳喂养之前都将受益于rhLF。生物技术使rhLF可用于药物开发。众所周知，LF具有抗菌、抗炎和免疫刺激的特性。它还能促进肠道上皮细胞的生长。利用新生大鼠细菌易位模型，我们已经证明rhLF在减少大肠杆菌相关肠道感染引起的菌血症、疾病和死亡方面非常有效。配方奶喂养的新生大鼠暴露于缺氧环境中，会患上类似于人类NEC的肠道疾病。由于大鼠乳汁不含LF，我们计划使用这种长期接受的新生大鼠模型来测试添加rhLF是否可以预防或减轻这种疾病。因此，我们的主要具体目标是在新生大鼠模型中显示口服rhLF在预防或减轻NEC的功效。次要目标，利用从主要特定目标中使用的动物身上获得的组织，将在本应用程序的时间框架之外继续探索rhLF的益处可能发生的机制。这项研究产生的数据对于FDA授予rhLF研究新药（IND）地位至关重要，从而能够在人类新生儿中进行NEC临床试验。

DESCRIPTION (provided by applicant): This feasibility study is based on our hypothesis that recombinant human lactoferrin [rhLF] can prevent or reduce severity of necrotizing enterocolitis [NEC]. NEC is mainly a disease of very low birth weight [VLBW] human infants. It is a leading cause of morbidity and mortality in neonatal intensive care units, with incidence of approximately 10 percent in VLBW infants and mortality of about 25 percent. Hospital costs associated with surgical and medical NEC are very high. Studies show NEC occurs less frequently in breast fed infants. Sufficient amounts of a mother's milk are often not available to prevent abnormal bacterial colonization and to enhance gut development in the crucial days following birth. We anticipate that all VLBW infants would benefit from receiving rhLF for at least 4 weeks after birth or until full human milk feedings are established. Biotechnology has made rhLF available for drug development. LF is known to have anti-bacterial, anti-inflammatory and immuno-stimulating properties. It also promotes gut epithelial growth. Using a neonatal rat model of bacterial translocation, we have shown already that rhLF is highly effective in decreasing bacteremia, illness and death from Escherichia coil-related intestinal infection. Formula-fed newborn rats exposed to hypoxia develop an intestinal disease similar to human NEC. As rat milk does not contain LF, we plan to use this long-accepted neonatal rat model to test whether adding rhLF could prevent or attenuate this disease. Our primary specific aim is therefore to show the efficacy of oral rhLF in preventing or attenuating NEC in the newborn rat model. Secondary aims, utilizing the tissues obtained from animals used in the primary specific aim, will continue beyond the time-frame of this application to explore the mechanisms by which the benefits of rhLF might occur. The data generated by this research are essential for the FDA to grant Investigational New Drug [IND] status for rhLF, and thus enable a NEC clinical trial in human neonates.