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

项目摘要 坏死性小肠结肠炎（NEC）是一种肠道急性炎性坏死， 新生儿期早产极低出生体重儿获得性胃肠和外科急症 加护病房尽管在新生儿护理方面取得了相当大的进步，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。管理在很大程度上是不具体的，包括 给予广谱抗生素，开始肠道休息，并提供液体和正性肌力药物 支持维持心肺功能。高达50%的NEC病例需要手术干预 并且通常包括坏死肠的切除。用抗生素使肠道微生物组正常化， 益生菌，以消除炎症和血管毒性引起的内毒素在异常肠道品种， 最近流行的治疗策略。此外，研究表明，吞咽羊水是抗- 炎症，使胎儿肠道成熟，并可预防感染。重要的是，没有治疗方法可以模拟 羊水或其在胎儿肠道中的功能。Plakous已经开发并获得专利的方法来提取和 保存胎盘盘内储存的细胞因子和生长因子。结果是一个无细胞的 我们将其命名为Protego-PDTM。我们的方法 高浓度的趋化因子和低得多的促炎性趋化因子组成， 足月羊水我们假设口服类似于16-20周羊水的治疗剂， 在出生和正常喂养量之间的过渡期间， 减少导致早产肠粘膜损伤的炎症环境， 成为NEC。我们的初步数据表明Protego-PDTM可以增加肠道细胞数量， 分化以及通过减少TNF-α分泌来调节它们对脂多糖的反应。在 此外，Protego-PDTM已被证明可以增加存活率并降低NEC在仔猪模型中的发病率。 这种疾病在本FastTrack SBIR中，我们建议开发检测方法，以确保我们产品的质量检测， 评估给药和安全性特征检查，为监管许可做准备。这些目标将 通过以下目的实现：1）开发生物活性测定以测试Protego-1的效力。 PDTM，2）评价Protego-PDTM在NEC仔猪模型中的功效和剂量-反应，3）评价Protego-PDTM在NEC仔猪模型中的功效和剂量-反应。 Protego-PDTM在啮齿动物标准毒理学试验评估中的安全性。成功完成本 该项目将允许Plakous将批准所需的研究性新药档案放在一起 Protego-PDTM的生物治疗方法。此外，这些数据将提交给 支持Protego-PDTM被指定为NEC罕见儿科治疗药物的孤儿产品 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.