Does exenatide in conjunction with therapeutic hypothermia reduce cerebral palsy in neonatal hypoxic-ischemic encephalopathy?

艾塞那肽联合低温治疗能否减少新生儿缺氧缺血性脑病的脑瘫？

• 批准号: MR/X004724/1
• 负责人: Suresh Victor
• 金额: $ 184.02万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX004724%2F1
• 关键词: Does; exenatide; conjunction; therapeutic; hypothermia

Hypoxic-ischemic encephalopathy (HIE) occurs when a baby experiences reduced blood flow and oxygen delivery to the brain near the time of birth. When the amount of blood and oxygen supplied to the brain is reduced, the baby may sometimes sustain injury to the brain. Not all newborn babies exposed to this condition suffer brain injury. However, if brain injury occurs, there is high risk for death or neurologic disabilities including cerebral palsy, learning difficulties, epilepsy, and visual impairment. HIE is a global problem resulting in 400,000 babies with devastating neurodevelopmental impairment every year accounting for 2.4% of the total Global Burden of Disease.This Group have previously successfully developed therapeutic hypothermia (cooling) as treatment for HIE. Cooling the baby's body temperature for 3 days reduces the risk of brain injury after HIE. However, cooling therapy only helps about 1 in 7 infants with HIE. Therefore, additional treatments are needed to further improve brain function and brain recovery after HIE. Furthermore, it has been shown in clinical trials that cooling is not effective in low- and middle-income countries. We now propose that exenatide will reduce the incidence of cerebral palsy in babies born with HIE when combined with cooling treatment. Exenatide is a licensed anti-diabetic medicine which is now available as a generic drug. It is known to act on receptors present in the brain to protect it from further injury. In Parkinson's disease, results from animal studies and early human studies were encouraging leading to a large phase III clinical trial that is currently ongoing. We have investigated the potential brain protective effects of exenatide using rodent models of neonatal HIE. We know that if exenatide is administered as four injections 12-hours apart, in rodents who have experienced reduced blood flow and oxygen delivery to the brain, there is a significant reduction in brain injury. We also know that we can wait up to 6-hours after injury before starting treatment which is helpful for babies who need to travel to another hospital to receive treatment. In this proposal, we want to repeat the experiments in a higher animal model (piglets). We will first confirm the optimum dose of exenatide needed for brain protection in piglets. We will then randomise piglets who have been exposed to lack of blood and oxygen supply to either receive or not receive exenatide and find out if there are differences between the groups in their brains. Exenatide is currently commercially available as pens which allow for subcutaneous injections in adults. When medicines are given subcutaneously in babies their absorption can be slow and erratic. Since we want to reliably achieve high concentrations of exenatide rapidly in the body, we want to administer exenatide as an intravenous infusion. To do this and to make sure the medicine is safe for newborn babies, we aim to develop a new intravenous formulation of exenatide. Exenatide has proven safe in high dose animal studies and in human over-dose case reports. However, since we are administering exenatide to babies for the first time, we want to make sure it doesn't cause any developmental problems in newborn animals. To do this, we will conduct toxicology studies using the new intravenous formulation of exenatide in newborn minipigs. We will always care for the research animals, minimise the pain, suffering, distress or lasting harm that may be experienced. Completing the proposed research will bring us to readiness for clinical trials. In summary, this is an exciting opportunity to provide some real benefit to babies affected by this devastating condition throughout the world. The potential benefits are likely to outweigh any anticipated safety concerns. Exenatide has the potential to enhance the brain protective effects of cooling treatment and be a first line treatment in low-income countries where cooling treatment is not an option.

当婴儿在出生时大脑的血流量和氧气输送减少时，就会发生缺氧缺血性脑病 (HIE)。当供应大脑的血液和氧气量减少时，婴儿有时可能会受到大脑损伤。并非所有接触这种情况的新生儿都会遭受脑损伤。然而，如果发生脑损伤，死亡或神经功能障碍（包括脑瘫、学习困难、癫痫和视力障碍）的风险很高。 HIE 是一个全球性问题，每年导致 400,000 名婴儿出现严重的神经发育障碍，占全球疾病总负担的 2.4%。该小组此前已成功开发出治疗性低温（冷却）作为 HIE 的治疗方法。降低婴儿体温 3 天可降低 HIE 后脑损伤的风险。然而，降温疗法只能帮助大约七分之一的 HIE 婴儿。因此，需要额外的治疗来进一步改善 HIE 后的大脑功能和大脑恢复。此外，临床试验表明，降温在低收入和中等收入国家并不有效。我们现在提出，艾塞那肽与降温治疗相结合可降低患有 HIE 的婴儿脑瘫的发生率。艾塞那肽是一种获得许可的抗糖尿病药物，现已作为仿制药上市。众所周知，它作用于大脑中的受体，以保护大脑免受进一步伤害。在帕金森病方面，动物研究和早期人体研究的结果令人鼓舞，目前正在进行一项大型 III 期临床试验。我们使用新生儿 HIE 啮齿动物模型研究了艾塞那肽的潜在脑保护作用。我们知道，如果每隔 12 小时分四次注射艾塞那肽，对于大脑血流和氧气输送减少的啮齿动物来说，脑损伤会显着减少。我们还知道，我们可以在受伤后等待最多 6 小时再开始治疗，这对于需要前往另一家医院接受治疗的婴儿很有帮助。在这个提案中，我们希望在高等动物模型（仔猪）中重复实验。我们将首先确定仔猪脑保护所需的艾塞那肽的最佳剂量。然后，我们将暴露于缺乏血液和氧气供应的仔猪随机分组，接受或不接受艾塞那肽，并找出各组之间的大脑是否存在差异。艾塞那肽目前以笔的形式市售，允许成人皮下注射。当婴儿皮下注射药物时，其吸收可能缓慢且不稳定。由于我们希望在体内快速可靠地达到高浓度的艾塞那肽，因此我们希望将艾塞那肽作为静脉输注给药。为了做到这一点并确保该药物对新生儿来说是安全的，我们的目标是开发一种新的艾塞那肽静脉注射制剂。艾塞那肽在高剂量动物研究和人类过量用药病例报告中已被证明是安全的。然而，由于我们是第一次给婴儿服用艾塞那肽，我们希望确保它不会对新生动物造成任何发育问题。为此，我们将使用新的艾塞那肽静脉注射制剂对新生小型猪进行毒理学研究。我们将始终关心研究动物，尽量减少可能经历的疼痛、痛苦、痛苦或持久伤害。完成拟议的研究将使我们为临床试验做好准备。总之，这是一个令人兴奋的机会，可以为全世界受这种毁灭性疾病影响的婴儿提供一些真正的好处。潜在的好处可能超过任何预期的安全问题。艾塞那肽有潜力增强降温治疗的脑保护作用，并成为无法选择降温治疗的低收入国家的一线治疗方法。