Pre-clinical safety studies of erythrocyte encapsulated thymidine phosphorylase

红细胞封装胸苷磷酸化酶的临床前安全性研究

• 批准号: G0902179/1
• 负责人: Bridget Bax
• 金额: $ 71.31万
• 依托单位: St George's, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2010
• 资助国家: 英国
• 起止时间: 2010 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0902179%2F1
• 关键词: Pre; clinical; safety; studies; erythrocyte

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.

MNGIE（线粒体神经胃肠脑肌病）是一种危及生命的遗传性代谢紊乱，由编码胸苷磷酸化酶的基因缺陷引起，导致受影响的个体产生很少或没有活性酶。胸苷磷酸化酶对于DNA代谢物的正常代谢是必需的，并且在其缺失的情况下，这些代谢物在体内积累，对神经系统和骨骼肌产生毒性作用，引起胃肠运动障碍（例如呕吐和厌食）、神经病（导致例如感觉丧失和异常眼球运动的神经损伤）和严重肌无力。MNGIE是无情的进步，患者死亡的平均报告年龄为38岁。目前没有具体的治疗方法。圣乔治的研究小组？伦敦伦敦大学的科学家们在发展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，他们正在调查使用病人？红细胞携带丢失的胸苷磷酸化酶进入血液循环。红细胞提供了一个受保护的环境，酶可以在其中发挥作用。包封的酶降低血液中有毒代谢物的水平，从而减轻神经系统和肌肉的毒性作用。本提案的目的是在两种动物种属中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生产工艺;获得的数据将支持其向英国和美国监管机构申请，以将本工作扩展至II/III期临床试验项目。这些研究的结果将提供给专门研究罕见遗传性代谢紊乱的患者支持团体和慈善机构。