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

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.

Erythrocytes as Carriers: From Drug Delivery to Biosensors

“…β-Galactosidase - [21] β-Glucocerebrosidase (β-glucosidase) Gaucher disease [21,37,38,[44][45][46]250] β-Glucuronidase Syndrome Slaya [251] l-Phenylalanine ammonia lyase Phenylketonuria [48,252,253] Phenylalanine hydroxylase [50,254] Uricase (uratoxidase) Uric acid removal [255,256] Urease, urease + alanine dehydrogenase Urea utilization [257][258][259] Adenosine deaminase Severe combined immunodeficiency caused by deaminase deficiency [27,[55][56][57][58]260] Thymidine phosphorylase Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) [56,246,261,262] Glutamate dehydrogenase Hyperammonemia [59,60,72] Glutamine synthetase [73,74] Glutamate dehydrogenase + alanine aminotransferase [11,63] Arginase Hyperammonemia due to arginase deficiency [263] Alcohol dehydrogenase…”

Quantification of Plasma and Urine Thymidine and 2’-Deoxyuridine by LC-MS/MS for the Pharmacodynamic Evaluation of Erythrocyte Encapsulated Thymidine Phosphorylase in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy

“…Microbial contamination is likely to be responsible for analyte degradation and this is therefore not an unexpected finding. Other studies report the immediate storage of collected urine at −20 • C to avoid analyte degradation [4]. To improve analyte stability, the addition of 5% PCA (v/v) to the urine samples was investigated.…”

“…During a clinical assessment by his neurologist specialist, improvements in the patient's swallowing and dysgeusia were noted and his tongue looked less glossitic. Changes recorded for Patients 1 and 3 included decreased nausea and vomiting, increased walking distance, increases in the physical and mental components of the SF36 health and well-being survey, and improved sensory ataxia, balance and gait and fine finger movements [4,13].…”

“…However, to confirm the stability of analytes during the clinical trial sample storage period we are conducting a partial long-term stability validation. We have no reason to believe that there will be a deterioration in metabolite concentrations under the intended storage conditions and for the duration of the clinical trial, as plasma samples for patients 1 and 3 were analyzed after a storage period of over three years at −80 • C and provided measurements that were equivalent to those that had been measured by a UPLC we previously employed [4,13].…”

“…Currently there are no licensed therapies available for patients with MNGIE, although a number of experimental therapeutic approaches have been investigated. The therapeutic approaches have the common aim of normalizing or reducing the systemic accumulations of the deoxyribonucleosides, and thereby prevent further mitochondrial damage and slow disease progression [2][3][4][5][6][7][8][9][10][11][12][13]. We have regulatory approval in the United Kingdom for a trial of erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement therapy for the treatment of MNGIE.…”