Development of a human placental extract for the prevention of necrotizing enterocolitis in premature babies

项目总结 坏死性小肠结肠炎(NEC)是最常见的肠道急性炎症性坏死。 早产儿极低出生体重儿获得性胃肠道和外科急症 重症监护室。尽管在新生儿护理方面取得了相当大的进步，但NEC仍然是一种毁灭性的疾病 (死亡率从15%到30%不等)缺乏治愈方法。管理在很大程度上是非特定的，包括 给予广谱抗生素，开始肠道休息，提供液体和变力作用 支持维持心肺功能。高达50%的NEC病例需要手术治疗 通常包括切除坏死肠。使用抗生素和抗生素使肠道微生物群正常化 益生菌在异常肠道品种中消除内毒素引起的炎症和血管毒性 最近流行的治疗策略。此外，研究表明，吞下羊水是抗炎的。 发炎，成熟胎儿的肠道，并可能防止感染。重要的是，没有任何治疗方法可以模仿 羊水或其在胎儿肠道中的功能。Plakous已经开发并申请了专利的方法来提取和 保存储存在胎盘内的细胞因子和生长因子。结果是一个脱细胞的 我们命名为Protego-PDTM的足月、产后人胎盘的制备。我们的方法产生了 高浓度趋化因子与低得多的促炎趋化因子组成相比 足月羊水。我们推测，口服治疗类似于16-20周的羊水 在出生和正常喂食量之间的过渡期间，支持和维持肠道成熟 减少导致早产儿肠道粘膜损伤的高炎症环境 变成了NEC。我们的初步数据表明，Protego-PDTM可以增加肠道细胞数量和 并通过减少肿瘤坏死因子-α的分泌来调节其对内毒素的反应。在……里面 此外，Protego-PDTM已被证明可以提高仔猪的存活率，降低NEC的发病率。 这种疾病。在这份FastTrack SBIR中，我们建议开发检测方法来确保我们产品的质量测试， 评估剂量和安全概况检查，为监管审批做准备。这些目标将是 通过以下目标完成：1)开发一种生物活性分析来测试Protego的效力- 2)在NEC仔猪模型中评价Protego-PDTM的疗效和剂量反应；3)评价Protego-PDTM对NEC仔猪模型的疗效 在啮齿动物的标准毒理学测试评估中使用Protego-PDTM的安全性。成功完成这项工作 该项目将允许Plakous将批准所需的研究新药档案整合在一起 Protego-PDTM的生物治疗进展此外，这些数据将提交给办公室。 孤儿产品公司支持将Protego-PDTM指定为治疗NEC的罕见儿科药物 疾病。

PROJECT SUMMARY Necrotizing enterocolitis (NEC), an acute inflammatory necrosis of the intestinal tract, is the most common acquired gastrointestinal and surgical emergency for preterm very low-birth weight infants in the neonatal intensive care unit. Despite considerable advances in neonatal care, NEC remains a devastating disease (mortality rates range from 15% to 30%) that lacks a cure. Management is largely nonspecific and includes the administration of broad-spectrum antibiotics, initiation of bowel rest and the provision of fluid and inotropic support to maintain cardiorespiratory function. Surgical intervention is required in up to 50% of the NEC cases and typically includes the removal of necrotic intestine. Normalizing the gut microbiome with antibiotics and probiotics to remove the inflammatory and vascular toxicities caused by endotoxins in abnormal gut cultivars is a popular recent treatment strategy. In addition, studies have shown that swallowed amniotic fluid is anti- inflammatory, matures the fetal gut, and may prevent infection. Importantly, there are no treatments that mimic amniotic fluid or its function in the fetal gut. Plakous has developed and patented methods to extract and preserve the cytokines and growth factors stored within the placental disc. The result is an acellular preparation of full-term, post-delivery human placenta that we have named Protego-PDTM. Our methods yield high concentrations of chemokines with a much lower pro-inflammatory chemokine composition compared to term amniotic fluid. We hypothesize that an orally administered therapeutic similar to 16-20 week amniotic fluid during the transition between birth and normal feeding volumes will bolster and sustain gut maturation while reducing the hyperinflammatory milieu which drives intestinal mucosal injury of the premature gut that becomes NEC. Our preliminary data indicate that Protego-PDTM can increase gut cell number and differentiation as well as modulate their response to lipopolysaccharides by decreasing TNF-α secretion. In addition, Protego-PDTM has been shown to increase survival and decrease NEC incidence in a piglet model of the disease. In this FastTrack SBIR, we propose to develop assays to ensure quality testing of our product, assess dosing and safety profile examination in preparation for regulatory clearance. These objectives will be accomplished through the following aims: 1) To develop a bioactivity assay to test the potency of Protego- PDTM, 2) To evaluate Protego-PDTM efficacy and dose-response in a piglet model of NEC, 3) To evaluate the safety of Protego-PDTM in a standard toxicology testing assessment in rodents. Successful completion of this project will allow Plakous to put together an Investigational New Drug dossier necessary in the approval process of a Biologic Therapeutic for Protego-PDTM. Additionally, the data will be presented to the Office of Orphan Products to support the designation of Protego-PDTM as a therapeutic for NEC as a Rare Pediatric Disease.