MICA: Evaluation of AZD1080 (GSK-3 inhibitor) in a preclinical mouse model of motor neuron disease (MND)

运动神经元病（MND，也称为肌萎缩性侧索硬化症）是一种进行性、使人衰弱的神经退行性疾病，其中控制肌肉运动的运动神经元逐渐退化并死亡。这会导致肌肉消耗并导致死亡，因为患者的胸部肌肉无法产生足够的呼吸力来清除血液中的二氧化碳。不幸的是，疾病进展通常非常迅速，预期寿命约为3-5年。有一种药物可以延长患者的寿命2-3个月，但迫切需要新的治疗方法。一种称为糖原合成酶激酶-3（GSK-3）的酶在MND患者的脑细胞中以更高的水平表达，并且更活跃。我们还发现，在MND患者中存活的运动神经元中，有一条阻止GSK-3发挥作用的途径是活跃的。对这种疾病的动物模型的研究表明，如果你阻止GSK-3与药物一起工作，你可以减缓疾病的进程。然而，到目前为止使用的药物并不理想，数据还不够清楚，无法给患者足够的信心来测试这些药物。制药公司阿斯利康（AstraZeneca）希望与我们合作，在我们的MND动物模型中测试他们的一种GSK-3阻断化合物，一种名为AZD 1080的药物。他们的药物对GSK-3有特异性，并且没有与其他GSK-3阻滞剂（如锂）相关的副作用。重要的是，它也在健康的人类志愿者中进行了测试，并显示出安全性。我们研究药物在MND小鼠模型中作用的方法非常稳健，并且将提供比现有更好的质量信息。我们设计了一系列实验，这些实验将为我们提供关于血液中AZD 1080浓度的明确信息，以观察我们模型中的效果。这将有助于未来的临床试验，因为它为我们治疗患者提供了一个目标。这项工作的另一个方面是将AZD 1080与一些我们已经在MND小鼠模型中显示有效的药物联合使用。这些药物激活一种途径，增加对自由基的防御（氧化应激）。他们通过激活一种叫做Nrf 2的蛋白质来做到这一点。氧化应激在MND中也是活跃的，并有助于运动神经元损伤。使用AZD 1080与我们的Nrf 2激活剂可能会导致更好的抗氧化应激保护，并在我们的小鼠模型中改善效果。我们还将进一步了解GSK-3如何在动物中调节Nrf 2的生物学特性。最终，如果我们能找到一种药物或药物组合，在我们的动物模型中效果良好，我们的目标是启动一个新的项目，将其用于测试住院患者。

Motor neurone disease (MND, also known as amyotrophic lateral sclerosis) is a progressive, debilitating neurodegenerative disease where the motor neurones which control muscle movement gradually degenerate and die. This causes the muscles to waste away and leads to death because patients chest muscles cannot generate enough force in breathing to remove carbon dioxide from the blood. Unfortunately the disease progression is usually very rapid and life expectancy is about 3-5 years. There is a drug available which extends the lifespan of patients by 2-3 months but new therapies are urgently needed.An enzyme called glycogen synthase kinase-3 (GSK-3) is expressed at a higher level and is more active in MND patients brain cells. We have also shown that a pathway which stops GSK-3 from working is active in motor neurones that survive in MND patients. Studies in animal models of the disease suggest that if you block GSK-3 from working with drugs, you can slow down the disease process. However the drugs used so far are not ideal and the data isn't clear enough yet to give enough confidence to test these drugs in patients. AstraZeneca (AZ), a pharmaceutical company, want to work with us to test one of their GSK-3 blocking compounds, a drug called AZD1080, in our animal models of MND. Their drug is specific for GSK-3 and doesn't have the side-effects associated with some other GSK-3 blockers such as lithium. Importantly, it has also been tested in healthy human volunteers and shown to be safe. Our methods for studying the effects of drugs in our mouse model of MND are very robust and will give better quality information than is already available. We have designed a series of experiments which will give us definitive information on the concentrations of AZD1080 we need in blood to see effects in our model. This will help in future clinical trials as it gives us a target to aim for when we treat patients.Another strand to this work is to look at AZD1080 in combination with some drugs which we have already shown to work in our mouse model of MND. These drugs activate a pathway that increases defences against free radicals (oxidative stress). They do this by activating a protein called Nrf2. Oxidative stress is also active in MND and contributes to motor neuron injury. Using AZD1080 with our Nrf2 activators may lead to better protection against oxidative stress, and an improved effect in our mouse model. We will also understand more of the biology of how GSK-3 regulates Nrf2 in animals.Ultimately if we can find a drug or drug combination that works well in our animal model we aim to start a new project take this forward to testing inpatients.