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

开发用于预防早产儿坏死性小肠结肠炎的人胎盘提取物

• 批准号: 10404156
• 负责人: Michael Bentley Berger
• 金额: $ 77万
• 依托单位: PLAKOUS THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404156
• 关键词: Development; human; placental; extract; prevention

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.

项目概要 坏死性小肠结肠炎 (NEC) 是一种急性肠道炎性坏死，是最常见的疾病 新生儿早产极低出生体重儿的获得性胃肠道和外科急症 尽管新生儿护理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）缺乏治疗方法，治疗基本上是非特异性的，包括 给予广谱抗生素、开始肠道休息以及提供液体和正性肌力药物 高达 50% 的 NEC 病例需要手术干预来维持心肺功能。 通常包括用抗生素去除坏死的肠道和使肠道微生物组正常化。 益生菌可消除异常肠道品种中内毒素引起的炎症和血管毒性 此外，研究表明吞咽羊水具有抗病毒作用。 炎症，使胎儿肠道成熟，并可能预防感染，重要的是，没有类似的治疗方法。 Plakous 已开发出羊水或其在胎儿肠道中的功能，并已获得专利方法。 保留胎盘内储存的细胞因子和生长因子，结果是无细胞的。 足月分娩后人胎盘的制备，我们将其命名为 Protego-PDTM。 与相比，高浓度的趋化因子具有低得多的促炎趋化因子成分 我们勇敢地接受了类似于 16-20 周羊水的口服治疗。 在出生和正常喂养量之间的过渡期间，将加强和维持肠道成熟，同时 减少导致过早肠道肠粘膜损伤的高炎症环境 我们的初步数据表明 Protego-PDTM 可以增加肠道细胞数量，并成为 NEC。 分化以及通过减少 TNF-α 分泌来调节其对脂多糖的反应。 此外，Protego-PDTM 已被证明可以提高仔猪模型的存活率并降低 NEC 发生率 在这个 FastTrack SBIR 中，我们建议开发以确保我们的检测产品的质量测试， 评估剂量和安全概况检查，为监管许可做好准备。 通过以下目标实现：1) 开发生物活性测定法来测试 Protego-的效力 PDTM，2) 评估 Protego-PDTM 在 NEC 仔猪模型中的功效和剂量反应，3) 评估 Protego-PDTM 在啮齿动物标准毒理学测试评估中的安全性成功完成。 项目将允许 Plakous 整理批准所需的研究性新药档案 Protego-PDTM 的生物治疗过程此外，数据将提交给办公室。 孤儿产品支持 Protego-PDTM 被指定为罕见儿科 NEC 的治疗药物 疾病。