Towards the development of a clinically and regulatory approvable treatment for Necrotizing Enterocolitis (NEC)

NEC是一种严重的新生儿疾病，通常影响早产儿，具有显著的发病率和死亡率(在需要手术的患者中，高达50%，在过去30年中改善有限)。NEC的发病机制尚不完全清楚，但已知与肠道灌注不良、细菌移位和进行性炎症最终导致坏死和/或肠穿孔有关。目前，NEC尚无有效的治疗方法。在美国，NEC的经济成本约占新生儿支出的19%，每年住院费用估计为50-60亿美元。因此，NEC对患者、他们的家庭和整个社会具有重大意义。UCL团队与Micregen(非学术合作伙伴)一起已经证明，羊水干细胞(AFSC)产生的分泌体改变了NEC小鼠模型中的关键细胞活动，导致组织结构和功能大大改善2，4，5。作为转化为临床使用的一步，Micregen开发了一种新型AFSC疗法(开发名称MRG1061)，可按GLP/GMP标准规模化生产。在小鼠NEC模型中，这证明了一种减轻疾病严重程度的能力。Micregen已经与药品和保健品监管机构(MHRA)举行了两次科学建议会议，目的是与伦敦大学学院合作开发I/II期临床试验。MHRA的主要建议之一是需要一系列证据来证明NEC的二级啮齿动物模型(即大鼠模型)的有效性和剂量。该项目将产生关键数据，通过确定MRG1061治疗NEC大鼠模型的有效性和最佳剂量、给药途径以及配方，对开发NEC临床试验至关重要。

NEC is a severe neonatal condition that commonly affects premature neonates with significant morbidity and mortality (up to 50% in patients requiring surgery, with limited improvement in the last 30 years). The pathogenesis is not completely understood, but it is known to be associated with poor intestinal perfusion, bacterial translocation and progressive inflammation ultimately leading to necrosis and/or intestinal perforation1,2. Presently there are no effective treatments for NEC. The economic cost of NEC accounts for ~ 19% of neonatal expenditures and an estimated $5-6 billion per year for hospitalizations in the United States. Thus, NEC has major implications for the patient, their family and society as a whole3.The UCL team together with Micregen (non-academic partner) have shown that the secretome produced by amniotic fluid stem cells (AFSC) alter key cell activities in mouse model of NEC leading to greatly improved tissue structure and function2,4,5. As a step towards translation towards clinical use, Micregen have developed a novel AFSC therapeutic (development name MRG1061) which can be produced at scale to GLP/GMP standards. This has demonstrated an ability to attenuate disease severity in the mouse NEC model. Micregen have held two scientific advice meetings with the Medicines and Healthcare products Regulatory Agency (MHRA) with the aim of developing a Phase I/II clinical trial in partnership with UCL. One of the key recommendations from the MHRA was the need for a portfolio of evidence for efficacy and dosing a secondary rodent model of NEC (namely the rat model).This project will generate key data, essential for developing a clinical trial for NEC by determining the effectiveness and optimal dosing, route of administration as well as formulation of MRG1061 in treating rat model of NEC.