Pre-clinical safety studies of erythrocyte encapsulated thymidine phosphorylase

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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.