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

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.

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Preclinical Toxicity Evaluation of Erythrocyte-Encapsulated Thymidine Phosphorylase in BALB/c Mice and Beagle Dogs: An Enzyme-Replacement Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy

Toxicological Sciences ◽

10.1093/toxsci/kfs278 ◽

2012 ◽

Vol 131 (1) ◽

pp. 311-324 ◽

Cited By ~ 22

Author(s):

Michelle Levene ◽

David G. Coleman ◽

Hugh C. Kilpatrick ◽

Lynette D. Fairbanks ◽

Babunilayam Gangadharan ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Thymidine Phosphorylase ◽

Beagle Dogs ◽

Toxicity Evaluation ◽

Mitochondrial Neurogastrointestinal Encephalomyopathy ◽

Enzyme Replacement

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Validation of an Immunoassay for Anti-thymidine Phosphorylase Antibodies in Patients with MNGIE Treated with Enzyme Replacement Therapy

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2018.08.007 ◽

2018 ◽

Vol 11 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Michelle Levene ◽

Dario Pacitti ◽

Charlotte Gasson ◽

Jamie Hall ◽

Marcia Sellos-Moura ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Thymidine Phosphorylase ◽

Enzyme Replacement

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Erythrocyte Encapsulated Thymidine Phosphorylase for the Treatment of Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy: Study Protocol for a Multi-Centre, Multiple Dose, Open Label Trial

Journal of Clinical Medicine ◽

10.3390/jcm8081096 ◽

2019 ◽

Vol 8 (8) ◽

pp. 1096 ◽

Cited By ~ 15

Author(s):

Bax ◽

Levene ◽

Bain ◽

Fairbanks ◽

Filosto ◽

...

Keyword(s):

Multiple Dose ◽

Thymidine Phosphorylase ◽

Autosomal Recessive Disorder ◽

Open Label ◽

Post Dose ◽

Mitochondrial Neurogastrointestinal Encephalomyopathy ◽

Clinical Assessments ◽

Enzyme Replacement ◽

Normal Metabolism ◽

Open Label Trial

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.

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Delivery and postpartum management of a patient with Pompe disease: Case report and review of the literature

Obstetric Medicine ◽

10.1177/1753495x16688601 ◽

2017 ◽

Vol 10 (3) ◽

pp. 150-151 ◽

Cited By ~ 1

Author(s):

Kazibe Koyuncu ◽

Batuhan Turgay ◽

Rusen Aytac ◽

Feride Soylemez

Keyword(s):

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Pompe Disease ◽

Autosomal Recessive ◽

Late Onset ◽

Autosomal Recessive Disorder ◽

Enzyme Replacement ◽

Disease Case ◽

Alpha Glucosidase ◽

Gaa Gene

Pompe disease is an autosomal-recessive disorder caused by acid alpha-glucosidase deficiency due to mutations in the GAA gene. There are two forms of the disease: infantile-onset Pompe disease and late-onset Pompe disease. The worldwide incidence of both forms of the disease is commonly reported to be 1 in 40,000. Adult patients are affected by limb-girdle muscular weakness and respiratory insufficiency. Enzyme replacement therapy with alglucosidase-alpha is available since 2006. There is little knowledge about pregnant woman with Pompe disease. These women should be considered as high-risk pregnant women. Here, we aim to present Cesarean delivery and postpartum management of a case with an interrupted enzyme replacement therapy during pregnancy.

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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

Journal of Clinical Medicine ◽

10.3390/jcm9030788 ◽

2020 ◽

Vol 9 (3) ◽

pp. 788 ◽

Cited By ~ 1

Author(s):

Karin Kipper ◽

Max Hecht ◽

Natalicia J. Antunes ◽

Lynette D. Fairbanks ◽

Michelle Levene ◽

...

Keyword(s):

Formic Acid ◽

Thymidine Phosphorylase ◽

Plasma Metabolites ◽

Mitochondrial Neurogastrointestinal Encephalomyopathy ◽

Enzyme Replacement ◽

Water Detection ◽

Mobile Phases ◽

Regulatory Guidelines ◽

Liquid Chromatography Tandem Mass ◽

Positive Mode

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disorder caused by mutations in TYMP, leading to a deficiency in thymidine phosphorylase and a subsequent systemic accumulation of thymidine and 2’-deoxyuridine. Erythrocyte-encapsulated thymidine phosphorylase (EE-TP) is under clinical development as an enzyme replacement therapy for MNGIE. Bioanalytical methods were developed according to regulatory guidelines for the quantification of thymidine and 2’-deoxyuridine in plasma and urine using liquid chromatography-tandem mass spectrometry (LC–MS/MS) for supporting the pharmacodynamic evaluation of EE-TP. Samples were deproteinized with 5% perchloric acid (v/v) and the supernatants analyzed using a Hypercarb column (30 × 2.1 mm, 3 µm), with mobile phases of 0.1% formic acid in methanol and 0.1% formic acid in deionized water. Detection was conducted using an ion-spray interface running in positive mode. Isotopically labelled thymidine and 2’-deoxyuridine were used as internal standards. Calibration curves for both metabolites showed linearity (r > 0.99) in the concentration ranges of 10–10,000 ng/mL for plasma, and 1–50 µg/mL for urine, with method analytical performances within the acceptable criteria for quality control samples. The plasma method was successfully applied to the diagnosis of two patients with MNGIE and the quantification of plasma metabolites in three patients treated with EE-TP.

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Management of Fabry Disease with Agalsidase Treatment

Clinical Medicine Insights Therapeutics ◽

10.4137/cmt.s6104 ◽

2010 ◽

Vol 2 ◽

pp. CMT.S6104

Author(s):

Guillem Pintos-Morell ◽

Olivier Lidove ◽

Atul Mehta

Keyword(s):

Quality Of Life ◽

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Clinical Safety ◽

Enzyme Preparations ◽

Enzyme Replacement

Fabry disease is an X-linked lysosomal storage disorder that is caused by a deficiency in the enzyme α-galactosidase A. It results in a progressive multi systemic disorder with major organ involvement (principally renal, cardiac and cerebrovascular) as well as peripheral and autonomic nervous system leading to a poor quality of life, and early death. Enzyme replacement therapy with α-galactosidase A has been used to treat Fabry disease since 2001. Two preparations of the enzyme are available: agalsidase alfa, produced in a human cell line, and agalsidase beta, produced in Chinese hamster ovary cells. Both products have a similar composition, mechanism of action and pharmacokinetic profile however major differences exist in the recommended dose, immunogenicity and rate of adverse reactions. Several clinical trials with the two enzyme preparations have assessed clinical efficacy with respect to impact of treatment on kidney function, cardiomyopathy, pain control and quality of life. Both preparations appear to be broadly equivalent. It has not yet been established that early initiation of enzyme replacement therapy (ERT) can prevent the emergence of disease manifestations. This review will cover the main aspects of clinical safety and efficacy of ERT for Fabry disease.

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