Pre-clinical safety studies of erythrocyte encapsulated thymidine phosphorylase

线粒体神经胃肠脑肌病(MNGIE)是一种威胁生命的遗传性代谢疾病，由胸苷磷酸化酶基因编码缺陷引起，导致患者产生很少或根本不产生活性酶。胸苷磷酸化酶对于DNA代谢物的正常代谢是必不可少的，在缺乏它的情况下，这些代谢物会在体内积累，对神经系统和骨骼肌产生毒性影响，导致胃肠道运动障碍(例如呕吐和厌食)、神经病变(神经损伤导致感觉丧失和异常眼球运动)和严重的肌肉无力。MNGIE是坚持不懈的进步，报告的患者平均死亡年龄为38岁。目前还没有具体的治疗方法。伦敦圣乔治？S大学的研究小组在开发红细胞作为血液中携带治疗性蛋白质的载体方面处于世界领先地位。在目前的研究中，他们正在调查使用患者S自己的红细胞携带循环中缺失的胸苷磷酸化酶的有效性。红血球为这种酶的功能提供了一个受保护的环境。这种被包裹的酶降低了血液中有毒代谢物的水平，从而减轻了神经系统和肌肉的毒性影响。这项建议的目的是在两种动物物种上进行临床前安全性研究，并建立生产临床级胸苷磷酸化酶的制造工艺；获得的数据将支持它们应用于英国和美国监管机构，将这项工作扩展到II/III期临床试验计划。这些研究的结果将提供给患者支持团体和专门研究罕见遗传性代谢障碍的慈善机构。

MNGIE (Mitochondrial neurogastrointestinal encephalomyopathy) is a life-threatening inherited metabolic disorder caused by a defect in the gene coding for the enzyme thymidine phosphorylase, resulting in affected individuals producing little or no active enzyme. Thymidine phosphorylase is essential for the normal metabolism of DNA metabolites, and in its absence, these metabolites accumulate in the body producing toxic effects on the nervous system and skeletal muscle, causing gastrointestinal dysmotility (e.g. vomiting and anorexia), neuropathy (nerve damage leading to, for example, loss of sensation and abnormal eye movements) and severe muscle weakness. MNGIE is relentlessly progressive with patients dying at an average reported age of 38 years. No specific treatment is currently available. The research team at St. George?s University of London are world leaders in developing the red blood cell as a vehicle for carrying therapeutic proteins in the blood. In the current study they are investigating the effectiveness of using patient?s own red blood cells to carry the missing thymidine phosphorylase in the circulation. The red blood cells provide a protected environment in which the enzyme can function. The encapsulated enzyme reduces the levels of toxic metabolites in the blood, thus relieving the nervous system and muscle of their toxic effects. The aim of this proposal is to conduct pre-clinical safety studies in two animal species and to establish a manufacturing process for the production of clinical grade thymidine phosphorylase; the data obtained will support their application to the UK and USA regulatory bodies to extend this work into a phase II/III clinical trials programme. Results from these studies will be made available to patient support groups and charities specialising in rare inherited metabolic disorders.