title: Long-Term Restoration of Thymidine Phosphorylase Function and Nucleoside Homeostasis Using Hematopoietic Gene Therapy in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy.
abstract: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a metabolic disorder caused by mutations in TYMP, encoding thymidine phosphorylase (TP). In MNGIE patients, TP dysfunction produces systemic thymidine and deoxyuridine accumulation, which ultimately impairs mitochondrial DNA replication and results in mitochondrial dysfunction. To date, only allogeneic hematopoietic stem cell transplantation has demonstrated long-term clinical efficacy, but high morbidity and mortality associated with this procedure necessitate the search for safer alternatives. In a previous study, we demonstrated that hematopoietic stem cell gene therapy using a lentiviral vector containing the coding sequence of TYMP restored the biochemical homeostasis in an animal model of MNGIE. In the present follow-up study, we show that ectopic expression of TP in the hematopoietic system restores normal nucleoside levels in plasma, as well as in tissues affected in MNGIE such as small intestine, skeletal muscle, brain, and liver. Mitochondrial dNTP pool imbalances observed in liver of the animal model were also corrected by the treatment. The biochemical effects were maintained at least 20 months even with low levels of chimerism. No alterations in the blood cell counts or other toxic effects were observed in association with the lentiviral transduction or TP overexpression. These results further support the notion that gene therapy is a feasible treatment option for MNGIE.
authors.affiliation: 1 Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.|2 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain .
authors.forename: Javier
authors.initials: J
authors.lastname: Torres-Torronteras
authors.affiliation: 1 Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.|2 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain .
authors.forename: Raquel
authors.initials: R
authors.lastname: Cabrera-Pérez
authors.affiliation: 3 Research Group on Cardiocirculatory Pathology, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Barba
authors.affiliation: 4 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Costa
authors.affiliation: 1 Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.|2 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain .
authors.forename: Noemí
authors.initials: N
authors.lastname: de Luna
authors.affiliation: 1 Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.|2 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain .
authors.forename: Antoni L
authors.initials: AL
authors.lastname: Andreu
authors.affiliation: 5 Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Barquinero
authors.affiliation: 6 Department of Neurology, H. Houston Merritt Center, Columbia University Medical Center , New York, New York.
authors.forename: Michio
authors.initials: M
authors.lastname: Hirano
authors.affiliation: 1 Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.|2 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain .
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Cámara
authors.affiliation: 1 Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona , Barcelona, Spain.|2 Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain .
authors.forename: Ramon
authors.initials: R
authors.lastname: Martí
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D018380:Hematopoietic Stem Cell Transplantation; D006706:Homeostasis; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics / Q000628:therapy*; D039141:Muscular Dystrophy, Oculopharyngeal; D009705:Nucleosides / Q000378:metabolism*; D009886:Ophthalmoplegia / Q000151:congenital; D013939:Thymidine Phosphorylase / Q000235:genetics*; D028361:Mitochondrial Diseases
chemical_list: D009705:Nucleosides; D013939:Thymidine Phosphorylase