Safety and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase in Mitochondrial Neurogastrointestinal Encephalomyopathy.

Michelle Levene,Niranjanan Nirmalananthan,Dario Pacitti,Massimiliano Filosto,Andrew Mackinnon,Bridget Bax,Nicholas Moran,Mauro Scarpelli,Joanna Poulton,Murray Bain,Hanna Mandel,Lynette Fairbanks

doi:10.3390/jcm8040457

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive disorder of nucleoside metabolism that is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) gene, encoding for the enzyme thymidine phosphorylase. There are currently no approved treatments for MNGIE. The aim of this study was to investigate the safety, tolerability, and efficacy of an enzyme replacement therapy for the treatment of MNGIE. In this single centre study, three adult patients with MNGIE received intravenous escalating doses of erythrocyte encapsulated thymidine phosphorylase (EE-TP; dose range: 4 to 108 U/kg/4 weeks). EE-TP was well tolerated and reductions in the disease-associated plasma metabolites, thymidine, and deoxyuridine were observed in all three patients. Clinical improvements, including weight gain and improved disease scores, were observed in two patients, suggesting that EE-TP is able to reverse some aspects of the disease pathology. Transient, non-serious adverse events were observed in two of the three patients; these did not lead to therapy discontinuation and they were managed with pre-medication prior to infusion of EE-TP. To conclude, enzyme replacement therapy with EE-TP demonstrated biochemical and clinical therapeutic efficacy with an acceptable clinical safety profile.

Highlights

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive metabolic disorder (Online Mendelian inheritance in Man #603041, Genome Database accession #9835128) that is almost universally fatal [1]
MNGIE is caused by mutations in the nuclear thymidine phosphorylase gene (TYMP) and a subsequent deficiency in thymidine phosphorylase activity (EC 2.4.2.4) [3,4]
There is a systemic accumulation of thymidine and deoxyuridine in the absence of thymidine phosphorylase activity, which generates imbalances within the mitochondrial deoxyribonucleotide pools, causing mitochondrial DNA point mutations, depletion and deletion abnormalities, and mitochondrial dysfunction [5,6,7,8,9]

Summary

Introduction

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare autosomal recessive metabolic disorder (Online Mendelian inheritance in Man #603041, Genome Database accession #9835128) that is almost universally fatal [1]. It causes relentless and progressive morbidity, followed by premature death at an average age of 37.6 years [2]. There is a systemic accumulation of thymidine and deoxyuridine in the absence of thymidine phosphorylase activity, which generates imbalances within the mitochondrial deoxyribonucleotide pools, causing mitochondrial DNA (mtDNA) point mutations, depletion and deletion abnormalities, and mitochondrial dysfunction [5,6,7,8,9]. Gastrointestinal dysfunction with frequent intestinal sub-occlusive episodes, malnutrition, cachexia and neurological involvement, including ptosis and ophthalmoparesis, peripheral neuropathy, myopathy, symmetric distal weakness, which prominently affects the inferior extremities, and leukoencephalopathy mainly typify the clinical picture of MNGIE [3,5,10]

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