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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

Levene, M; Coleman, DG; Kilpatrick, HC; Fairbanks, LD; Gangadharan, B; Gasson, C; Bax, BE (2013) 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, 131 (1). 311 - 324 . ISSN 1096-6080 https://doi.org/10.1093/toxsci/kfs278
SGUL Authors: Bax, Bridget Elizabeth

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Abstract

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.

Item Type: Article
Additional Information: This is a pre-copyedited, author-produced PDF of an article accepted for publication in TOXICOLOGICAL SCIENCES following peer review. The version of record Michelle Levene, David G. Coleman, Hugh C. Kilpatrick, Lynette D. Fairbanks, Babunilayam Gangadharan, Charlotte Gasson,and Bridget E. Bax. Preclinical Toxicity Evaluation of Erythrocyte-Encapsulated Thymidine Phosphorylase in BALB/c Mice and Beagle Dogs: An Enzyme-Replacement Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy Toxicol. Sci. (2013) 131 (1): 311-324 first published online September 12, 2012 doi:10.1093/toxsci/kfs278 is available online at: http://dx.doi.org/10.1093/toxsci/kfs278
Keywords: Animals, Blood Transfusion, Autologous, Dogs, Drug Carriers, Drug Evaluation, Preclinical, Enzyme Replacement Therapy, Erythrocyte Transfusion, Erythrocytes, Intestinal Pseudo-Obstruction, Mice, Mice, Inbred BALB C, Mitochondrial Encephalomyopathies, Thymidine Phosphorylase, Toxicity Tests, Science & Technology, Life Sciences & Biomedicine, Toxicology, TOXICOLOGY, enzyme replacement, erythrocyte carriers, mitochondrial neurogastrointestinal encephalomyopathy, thymidine phosphorylase, toxicity, ADENOSINE-DEAMINASE, IN-VIVO, MNGIE, DEOXYURIDINE, DEFICIENCY, METABOLISM, DRUGS, CELLS, enzyme replacement, erythrocyte carriers, mitochondrial neurogastrointestinal encephalomyopathy, thymidine phosphorylase, toxicity, Toxicology, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: TOXICOLOGICAL SCIENCES
ISSN: 1096-6080
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Dates:
DateEvent
1 January 2013Published
Web of Science ID: WOS:000313652900029
URI: http://openaccess.sgul.ac.uk/id/eprint/107123
Publisher's version: https://doi.org/10.1093/toxsci/kfs278

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