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: 10456220
• 负责人: Michael Bentley Berger
• 金额: $ 75.57万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456220
• 关键词: Acute; Affect; Amniotic Fluid; Animals; Anti-Inflammatory Agents; Antibiotics; Autopsy; Biological Assay; Biological Products; Biological Response Modifier Therapy; Birth; Birth Weight; Blood Vessels; Brain Hypoxia-Ischemia; Breast Feeding; Cell Count; Cell Culture Techniques; Cell Differentiation process; Cells; Childhood; Clinical; Conduct Clinical Trials; Data; Deglutition; Development; Disease; Disease model; Dose; Electrical Resistance; Emergency Situation; Endotoxins; Ensure; Excision; Growth Factor; Histologic; Human; Human Milk; Hypoxia; In Vitro; Incidence; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune Response; Intestinal Diseases; Intestinal Mucosa; Intestines; Investigational Drugs; Lead; Legal patent; Licensing; Life; Lipopolysaccharides; Liquid substance; Membrane; Methods; Microvascular Dysfunction; Monitor; Names; Necrosis; Necrotizing Enterocolitis; Neonatal Intensive Care Units; Newborn Infant; Operative Surgical Procedures; Oral; Orphan; Pathogenesis; Pathway interactions; Perforation; Performance; Phase; Placenta; Placental Extracts; Powder dose form; Premature Infant; Premature Rupture Fetal Membranes; Preparation; Prevention; Probiotics; Process; Proteins; Rare Diseases; Reperfusion Injury; Rest; Rodent; Rupture; Safety; Saline; Second Pregnancy Trimester; Seeds; Small Business Innovation Research Grant; Stress; TNF gene; Testing; Therapeutic; Toxic effect; Toxicology; Tube; United States Food and Drug Administration; Very Low Birth Weight Infant; base; chemokine; crystallinity; cytokine; efficacy evaluation; experimental study; feeding; fetal; gastrointestinal; gut microbiome; ileum; in vivo; ischemic injury; microbial; microbial colonization; microbiome; mortality; neonatal care; neonate; point of care; porcine model; potency testing; premature; preservation; preterm newborn; prevent; reconstitution; response; stem cells; targeted treatment; treatment strategy; tumor

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.

项目摘要 坏死性小肠结肠炎（NEC）是肠道急性炎症性坏死，是最常见的 在新生儿的早产婴儿中获得的胃肠道和外科紧急情况 重症监护室。尽管新生儿护理方面取得了长足的进步，但NEC仍然是一种毁灭性的疾病 （死亡率从15％到30％）缺乏治愈。管理很大程度上是非特异性的，包括 宽光谱抗生素，肠休息的启动以及液体和肌力的提供 支持维持心肺功能。最多50％的NEC病例需要手术干预 通常包括去除坏死肠。用抗生素和 益生菌去除异常肠道毒素引起的炎症和血管毒素是 一种流行的近期治疗策略。此外，研究表明，吞咽羊水是抗的 炎症，使胎儿肠道成熟，并可能阻止感染。重要的是，没有任何模仿的治疗方法 羊水或其在胎儿肠道中的功能。 Plakous已开发并获得专利的方法来提取和 保留储物盘中存储的细胞因子和生长因子。结果是细胞 我们命名为Protego-PDTM的完整，交付后的人物的准备。我们的方法产生 与促炎性趋化因子组成相比，高浓度的趋化因子相比 术语羊水。我们假设一种口服治疗类似于16-20周的羊水 在出生和正常喂养之间的过渡期间，将增强和维持肠道成熟 减少过度炎性环境，从而驱动肠道肠损伤的过早肠道损伤 成为NEC。我们的初步数据表明protego-pDTM可以增加肠道细胞数和 通过减少TNF-α分泌来分化和调节它们对脂多糖的反应。在 此外，已证明Protego-PDTM会增加生存率和降低NEC的发病率 疾病。在这个FastTrack Sbir中，我们建议开发Assas，以确保我们产品的质量测试， 评估剂量和安全性检查检查以准备监管清除。这些目标将是 通过以下目的完成：1）开发生物活性评估以测试protego-的效力 PDTM，2）评估NEC仔猪模型中的Protego-PDTM效率和剂量反应，3） 在啮齿动物的标准毒理学测试评估中，Protego-PDTM的安全性。成功完成 项目将允许Plakous汇总一份研究性的新药档案，以批准 用于Protego-PDTM的生物学治疗过程。此外，数据将显示给 孤儿产品支持Protego-PDTM作为NEC的疗法的设计 疾病。