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

MICA：AZD1080（GSK-3 抑制剂）在运动神经元疾病 (MND) 临床前小鼠模型中的评估

基本信息

批准号：
MR/K015273/1
负责人：
Richard James Mead
金额：
$ 36.07万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2013
资助国家：
英国
起止时间：
2013 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FK015273%2F1
关键词：
MICA Evaluation AZD1080 GSK inhibitor

项目摘要

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.

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、衰弱性神经退行性疾病，其中控制肌肉运动的运动神经元逐渐退化和死亡。这会导致肌肉萎缩并导致死亡，因为患者的胸部肌肉在呼吸时无法产生足够的力量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。有一种药物可以将患者的寿命延长2-3个月，但迫切需要新的治疗方法。一种名为糖原合成酶激酶3 （GSK-3）的酶在MND患者的脑细胞中表达水平更高，也更活跃。我们还表明，在MND患者存活的运动神经元中，阻止GSK-3工作的途径是活跃的。对动物模型的研究表明，如果阻断GSK-3与药物的作用，就可以减缓疾病的进程。然而，迄今为止使用的药物并不理想，数据也不够清晰，不足以让我们有足够的信心在患者身上测试这些药物。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AZD1080的药物。他们的药物是针对GSK-3的，并且没有其他GSK-3阻滞剂（如锂）的副作用。重要的是，它也在健康的人类志愿者身上进行了测试，证明是安全的。我们研究药物在MND小鼠模型中的作用的方法是非常可靠的，并且将提供比现有的更好质量的信息。我们设计了一系列实验，这些实验将为我们提供关于AZD1080浓度的明确信息，我们需要血液中AZD1080的浓度来观察我们的模型的效果。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研究AZD1080与一些药物的结合，我们已经证明这些药物在我们的MND小鼠模型中起作用。这些药物激活了一种增强抵抗自由基（氧化应激）的途径。它们通过激活一种叫做Nrf2的蛋白质来做到这一点。氧化应激在MND中也很活跃，并有助于运动神经元损伤。使用AZD1080和我们的Nrf2激活剂可以更好地保护氧化应激，并且在我们的小鼠模型中效果更好。我们还将进一步了解GSK-3如何在动物体内调节Nrf2的生物学原理。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，我们的目标是开始一个新的项目，将其推向住院病人。