MICA: Clinical development of erythrocyte encapsulated thymidine phosphorylase - a therapy for mitochondrial neurogastrointestinal encephalomyopathy

线粒体神经胃肠脑肌病(MNGIE)是一种几乎总是致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。胸苷磷酸化酶是代谢产物胸苷和脱氧尿苷正常代谢所必需的，在没有胸苷和脱氧尿苷的情况下，这些代谢物在体内积累，对细胞的动力源线粒体造成损害。因此，骨骼肌和神经系统等依赖能量的组织会受到不利影响，在临床上表现为胃肠动力障碍(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，据报道患者的平均死亡年龄为37.6岁。匹配的骨髓移植提供了一种潜在的治疗方法，但受到匹配捐赠者的限制，存在严重并发症的重大风险，据报道死亡率高达50%。目前，对于那些患有晚期疾病的患者，不推荐使用它们。伦敦大学圣乔治学院的研究小组在开发红细胞(红细胞)作为在血液中携带(即封装)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自己的红细胞在循环中携带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损害作用。对两名MNGIE患者同情地使用红细胞包裹的胸苷磷酸化酶(EE-TP)获得的数据表明，血浆胸苷和脱氧尿苷浓度的降低可能与临床益处有关。该项目的目的是在欧洲范围内对10名MNGIE患者进行临床研究，以证实EE-TP的安全性和临床有效性。这项研究的成功结果将支持向监管机构申请EE-TP的营销许可证，并确保全球患者有平等的机会。

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)) is an almost invariably fatal 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 required for the normal metabolism of the metabolites thymidine and deoxyuridine and in its absence these metabolites accumulate in the body causing damage to the mitochondria, the powerhouse of the cell. Energy dependent tissues such as skeletal muscle and nervous system are therefore adversely affected, manifesting clinically as gastrointestinal dysmotility (for example, 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 37.6 years. Matched bone marrow transplants offer a potential cure but are limited by the availability of a matched donor, carry significant risks of serious complications and have a reported mortality as high as 50%. Currently they are not recommended for those patients who have advanced disease. The research team at St. George's, University of London are world leaders in developing the red blood cell (erythrocyte) as a vehicle for carrying (i.e. encapsulating) therapeutic proteins in the blood. In the current study they are investigating the effectiveness of using the 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 damaging effects. Data obtained from the compassionate use of erythrocyte encapsulated thymidine phosphorylase (EE-TP) in two patients with MNGIE shows that a reduction in plasma thymidine and deoxyuridine concentrations can be causally linked to clinical benefit. The aim of this project is to confirm the safety and clinical effectiveness of EE-TP in a European-wide clinical study in ten patients with MNGIE. Successful results from this study will support applications to the regulatory authorities for a marketing license for EE-TP and ensuring patients globally have equitable access.