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

缺氧缺血性脑病（HIE）发生时，婴儿经历减少血流量和氧气输送到大脑的时间接近出生。当供应给大脑的血液和氧气量减少时，婴儿有时可能会遭受大脑损伤。并不是所有暴露在这种情况下的新生儿都会受到脑损伤。然而，如果发生脑损伤，死亡或神经系统残疾的风险很高，包括脑瘫、学习困难、癫痫和视力障碍。HIE是一个全球性问题，每年导致40万婴儿患有毁灭性的神经发育障碍，占全球疾病总负担的2.4%。该小组以前已经成功地开发了治疗性低温（冷却）作为HIE的治疗方法。降低婴儿体温3天可以降低HIE后脑损伤的风险。然而，冷却疗法只能帮助七分之一的HIE婴儿。因此，需要额外的治疗来进一步改善HIE后的脑功能和脑恢复。此外，临床试验表明，冷却在低收入和中等收入国家并不有效。我们现在建议艾塞那肽与冷却治疗相结合，可以降低新生儿HIE脑瘫的发病率。艾塞那肽是一种获得许可的抗糖尿病药物，现在是一种仿制药。众所周知，它可以作用于大脑中的受体，以保护大脑免受进一步的伤害。在帕金森氏症方面，动物研究和早期人体研究的结果令人鼓舞，导致目前正在进行的大型III期临床试验。我们利用新生儿HIE啮齿动物模型研究了艾塞那肽潜在的脑保护作用。我们知道，如果每隔12小时注射四次艾塞那肽，对那些脑部血流量和氧气输送减少的啮齿动物来说，脑损伤会显著减少。我们也知道，我们可以在受伤后等待6个小时才开始治疗，这对需要前往另一家医院接受治疗的婴儿很有帮助。在本提案中，我们希望在更高的动物模型（仔猪）中重复实验。我们将首先确定艾塞那肽对仔猪脑保护所需的最佳剂量。然后，我们将随机选取暴露于血液和氧气供应不足的仔猪，让它们接受或不接受艾塞那肽，并观察两组仔猪的大脑是否存在差异。艾塞那肽目前作为笔在市场上销售，允许成人皮下注射。当给婴儿皮下注射药物时，它们的吸收可能缓慢而不稳定。由于我们想要可靠地在体内快速获得高浓度的艾塞那肽，我们想要静脉输注艾塞那肽。为了做到这一点，并确保药物对新生儿是安全的，我们的目标是开发一种新的静脉注射制剂艾塞那肽。艾塞那肽已在高剂量动物研究和人类过量病例报告中证明是安全的。然而，由于我们是第一次给婴儿使用艾塞那肽，我们要确保它不会对新生动物造成任何发育问题。为此，我们将在新生迷你猪中使用艾塞那肽的新静脉注射制剂进行毒理学研究。我们将始终照顾研究动物，尽量减少可能经历的疼痛，痛苦，困扰或持久伤害。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。潜在的好处很可能超过任何预期的安全问题。艾塞那肽有可能增强冷却治疗的脑保护作用，并成为无法选择冷却治疗的低收入国家的一线治疗药物。

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.