title: Thymidine phosphorylase is both a therapeutic and a suicide gene in a murine model of mitochondrial neurogastrointestinal encephalomyopathy.
abstract: Suicide gene therapy (SGT) is a promising strategy for treating cancer. In this work, we show that thymidine phosphorylase (TP) deficiency, the underlying genetic defect in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), presents an opportunity to apply SGT using capecitabine, a commonly used prodrug that is converted into 5-fluorouracil by TP. Using an immortalised B-lymphoblastoid cell line from a patient with MNGIE, the tumourigenic EL-4 cell line, lentiviral vectors encoding TP and a double knockout (Tymp(-/-)Upp1(-/-)) murine model, we found that EL-4 cell-derived TP(+) tumours were exquisitely sensitive to capecitabine and generated a significant local bystander effect. In addition, we detected a spontaneous cytolytic immune response in a significant fraction of the animals surviving more than 20 days after termination of the therapy. These data indicate that, in individuals lacking TP expression, TP is a highly specific suicide gene, which can be used to treat tumours that could hypothetically arise in MNGIE patients undergoing gene therapy, as these tumours will likely originate from the gene-modified cells and will be selectively targeted by capecitabine. These observations have important implications for gene therapy for MNGIE.
authors.affiliation: Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute (VHIR)/Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: López-Estévez
authors.affiliation: Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute (VHIR)/Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Ferrer
authors.affiliation: 1] Mitochondrial Pathology Unit, VHIR/Universitat Autònoma de Barcelona, Barcelona, Spain [2] Biomedical Network Research, Centre on Rare Diseases (CIBERER) ISCIII, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Torres-Torronteras
authors.affiliation: Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute (VHIR)/Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Mansilla
authors.affiliation: Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute (VHIR)/Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Casacuberta-Serra
authors.affiliation: Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute (VHIR)/Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Martorell
authors.affiliation: Department of Neurology, Columbia University, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hirano
authors.affiliation: 1] Mitochondrial Pathology Unit, VHIR/Universitat Autònoma de Barcelona, Barcelona, Spain [2] Biomedical Network Research, Centre on Rare Diseases (CIBERER) ISCIII, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Martí
authors.affiliation: Gene and Cell Therapy Laboratory, Vall d'Hebron Research Institute (VHIR)/Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Barquinero
mesh_terms: D000818:Animals; D000069287:Capecitabine; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D055786:Gene Knockout Techniques; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D039141:Muscular Dystrophy, Oculopharyngeal; D009886:Ophthalmoplegia / Q000151:congenital; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D028361:Mitochondrial Diseases
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; D013939:Thymidine Phosphorylase; D005472:Fluorouracil