Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

Mitochondrialneurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterised by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder which primarily affects the gastrointestinal and nervous systems. This disease is caused by mutations in the nuclear TYMP gene, which encodes for thymidine phosphorylase, an enzyme required for the normal metabolism of deoxynucleosides, thymidine, and deoxyuridine. The subsequent elevated systemic concentrations of deoxynucleosides lead to increased intracellular concentrations of their corresponding triphosphates, and ultimately mitochondrial failure due to progressive accumulation of mitochondrial DNA (mtDNA) defects and mtDNA depletion. Currently, there are no treatments for MNGIE where effectiveness has been evidenced in clinical trials. This Phase 2, multi-centre, multiple dose, open label trial without a control will investigate the application of erythrocyte-encapsulated thymidine phosphorylase (EE-TP) as an enzyme replacement therapy for MNGIE. Three EE-TP dose levels are planned with patients receiving the dose level that achieves metabolic correction. The study duration is 31 months, comprising 28 days of screening, 90 days of run-in, 24 months of treatment and 90 days of post-dose follow-up. The primary objectives are to determine the safety, tolerability, pharmacodynamics, and efficacy of multiple doses of EE-TP. The secondary objectives are to assess EE-TP immunogenicity after multiple dose administrations and changes in clinical assessments, and the pharmacodynamics effect of EE-TP on clinical assessments.

Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is currently under development as an enzyme replacement therapy for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder caused by a deficiency of thymidine phosphorylase. The rationale for the development of EE-TP is based on the pathologically elevated metabolites (thymidine and deoxyuridine) being able to freely diffuse across the erythrocyte membrane where the encapsulated enzyme catalyses their metabolism to the normal products. The systemic toxic potential of EE-TP was assessed when administered intermittently by iv bolus injection to BALB/c mice and Beagle dogs for 4 weeks. The studies consisted of one control group receiving sham-loaded erythrocytes twice weekly and two treated groups, one dosed once every 2 weeks and the other dosed twice per week. The administration of EE-TP to BALB/c mice resulted in thrombi/emboli in the lungs and spleen enlargement. These findings were also seen in the control group, and there was no relationship to the number of doses administered. In the dog, transient clinical signs were associated with EE-TP administration, suggestive of an immune-based reaction. Specific antithymidine phosphorylase antibodies were detected in two dogs and in a greater proportion of mice treated once every 2 weeks. Nonspecific antibodies were detected in all EE-TP-treated animals. In conclusion, these studies do not reveal serious toxicities that would preclude a clinical trial of EE-TP in patients with MNGIE, but caution should be taken for infusion-related reactions that may be related to the production of nonspecific antibodies or a cell-based immune response.