INSTINCT Study: Intranasal Stem Cells for Improving Neurodevelopmental Outcomes in Neonatal Encephalopathy

INSTINCT 研究：鼻内干细胞可改善新生儿脑病的神经发育结果

• 批准号: MR/T044586/1
• 负责人: Nicola Robertson
• 金额: $ 306.66万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT044586%2F1
• 关键词: INSTINCT; Study; Intranasal; Stem; Cells

Problems around the time of birth causing a lack of oxygen to the baby can cause disordered brain function called neonatal encephalopathy (NE), which can result in long term brain damage and cerebral palsy. Cooling a baby by 3 degrees Celsius for three days as soon as possible after birth has been shown to be safe and leads to long term brain protection and improved outcome even to school age. Cooling is endorsed by NICE and adopted in neonatal intensive care units in UK for moderate to severe NE. However, although cooling is a major step forward for babies with NE, 44-53% still have adverse outcomes. This may be because cooling may be less effective with severe injury or there was prior exposure to infection and inflammation. Supplemental interventions to improve outcomes with and without cooling are greatly needed. Over the last 10 years, several therapeutic agents have been studied as adjuncts to HT for babies, such as erythropoietin, melatonin, allopurinol, but there is currently no therapy apart from cooling for NE. The use of stem cells to successfully treat neonatal brain injury is emerging as a promising therapy. Human umbilical cord mesenchymal stem cells (huMSC) self renew and stimulate host brain cells to regenerate and repair, with superior anti-inflammatory properties than MSC from adult tissues. Importantly, although huMSC do not survive long term and replace damaged tissues themselves, they react to the needs of the ischemic cerebral environment by secretion of growth factors, cytokines and extracellular vesicles (EVs) to regulate damage and repair. These intrinsic adaptive properties of huMSC make them excellent candidates to treat the devastating effects of NE. The newborn brain is still in a developmentally active phase, leading to high efficiency of huMSC.In a pilot pre-clinical model of NE, we observed brain protection with 2 doses of 30 million huMSC given intranasally 24h after a period of oxygen deprivation, whereas intravenous huMSC were not protective. We were able to detect these huMSC within the brain tissue. These data from male subjects suggest that huMSC (given intranasally) augment brain protection based on clinically relevant markers (recovery of aEEG and brain energy metabolism). For clinical translation, there is insufficient data on whether huMSC are protective in both normothermic and hypothermic milieu and whether there is different neuroprotective response from males and females. Recently, EVs have been identified as the key mediators of stem cell paracrine signalling. EVs deliver their contents in the form of proteins, lipids, and nucleic acids; they overcome some limitations of cell therapies, including easier storage, low immunogenicity, passage through small vessels and no tumorigenic potential. We propose the following 3 milestones as preparation for future clinical trials in babies with NE.The first milestone will prepare the huMSC and EVs. We have access to clinical-grade huMSC manufactured by UCL. The second and key milestone will assess safety and efficacy of 2 doses huMSC given intranasally at 12 and 36h after oxygen deprivation in both male and female subjects with and without cooling. We will assess outcome based on aEEG recovery, brain energy metabolism and histology. If positive we will meet MHRA with the aim to move to clinical trials. The third milestone will assess safety and efficacy of 2 doses of EVs given intranasally at 12 and 36h after oxygen deprivation. The volume of EVs that produce an equivalent anti-inflammatory effect as 30 million huMSC will be used (previously determined in vitro studies in milestone 2b). This will inform the mechanism(s) through which beneficial effects of MSC therapy are mediated and may lead to refining the strategy for future clinical trials in babies with NE.

出生时的问题导致婴儿缺氧，可能会导致被称为新生儿脑病(NE)的大脑功能紊乱，这可能导致长期的脑损伤和脑性瘫痪。已经证明，婴儿出生后尽快给婴儿降温3摄氏度3天是安全的，可以长期保护大脑，甚至可以改善结果，甚至到上学年龄也是如此。NICE认可降温，并在英国新生儿重症监护病房中对中到重度NE采用降温。然而，尽管降温对患有NE的婴儿来说是向前迈出的一大步，但44%-53%的婴儿仍然有不良后果。这可能是因为严重受伤时降温效果较差，或者先前曾暴露于感染和炎症中。迫切需要补充干预措施，以改善在降温和不降温情况下的结果。在过去的10年里，已经研究了几种治疗剂作为婴儿高血压的辅助治疗药物，如促红细胞生成素、褪黑素、别嘌醇，但目前除了降温外还没有治疗NE的方法。使用干细胞成功治疗新生儿脑损伤是一种很有前途的治疗方法。人脐带间充质干细胞(HuMSC)可以自我更新，刺激宿主脑细胞再生和修复，具有比成人组织MSC更优越的抗炎特性。重要的是，虽然huMSC不能长期存活并修复受损的组织，但它们通过分泌生长因子、细胞因子和细胞外小泡(EVS)来调节损伤和修复，从而对缺血脑环境的需要做出反应。HuMSC的这些内在适应特性使其成为治疗去甲肾上腺素破坏性效应的极佳候选者。在NE的临床前试验模型中，我们观察到在缺氧一段时间后24小时鼻内注射两剂3000万的huMSC对脑保护作用，而静脉注射huMSC则没有保护作用。我们能够在脑组织中检测到这些huMSC。这些来自男性受试者的数据表明，huMSC(鼻内给药)基于临床相关指标(AEEG和大脑能量代谢的恢复)增强了脑保护。对于临床翻译，对于huMSC在常温和低温环境下是否具有保护作用，以及男性和女性是否有不同的神经保护反应，还缺乏足够的数据。近年来，EVS被认为是干细胞旁分泌信号的关键介体。EV以蛋白质、脂类和核酸的形式传递其内容物；它们克服了细胞疗法的一些局限性，包括更容易储存、免疫原性低、通过小血管和没有致瘤潜力。我们提出了以下3个里程碑，作为未来NE婴儿临床试验的准备。第一个里程碑将准备HuMSC和EVS。我们有权使用UCL生产的临床级HuMSC。第二个也是关键的里程碑将评估在男性和女性受试者缺氧后12小时和36小时，在降温和不降温的情况下，鼻内注射两剂huMSC的安全性和有效性。我们将根据AEEG恢复情况、脑能量代谢和组织学来评估结果。如果呈阳性，我们将与MHRA会面，目标是进入临床试验。第三个里程碑将评估两种剂量的EVS在缺氧后12小时和36小时鼻腔给药的安全性和有效性。将使用与3000万huMSC产生同等抗炎效果的EVS的体积(之前在里程碑2b的体外研究中确定)。这将揭示骨髓间充质干细胞治疗的有益效果的调节机制(S)，并可能导致完善未来NE婴儿临床试验的策略。