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dc.contributor.authorYadak, Rana
dc.contributor.authorCabrera-Pérez, Raquel
dc.contributor.authorTorres-Torronteras, Javier
dc.contributor.authorWagemaker, Gerard
dc.date.accessioned2020-02-11T11:23:08Z
dc.date.available2020-02-11T11:23:08Z
dc.date.issued2018
dc.identifier.issn2329-0501
dc.identifier.urihttps://doi.org/10.1016/j.omtm.2018.01.001
dc.identifier.urihttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908387/
dc.identifier.urihttp://hdl.handle.net/11655/22035
dc.description.abstractMitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by thymidine phosphorylase (TP) deficiency resulting in systemic accumulation of thymidine (d-Thd) and deoxyuridine (d-Urd) and characterized by early-onset neurological and gastrointestinal symptoms. Long-term effective and safe treatment is not available. Allogeneic bone marrow transplantation may improve clinical manifestations but carries disease and transplant-related risks. In this study, lentiviral vector-based hematopoietic stem cell gene therapy (HSCGT) was performed in Tymp−/−Upp1−/− mice with the human phosphoglycerate kinase (PGK) promoter driving TYMP. Supranormal blood TP activity reduced intestinal nucleoside levels significantly at low vector copy number (median, 1.3; range, 0.2–3.6). Furthermore, we covered two major issues not addressed before. First, we demonstrate aberrant morphology of brain astrocytes in areas of spongy degeneration, which was reversed by HSCGT. Second, long-term follow-up and vector integration site analysis were performed to assess safety of the therapeutic LV vectors in depth. This report confirms and supplements previous work on the efficacy of HSCGT in reducing the toxic metabolites in Tymp−/−Upp1−/− mice, using a clinically applicable gene transfer vector and a highly efficient gene transfer method, and importantly demonstrates phenotypic correction with a favorable risk profile, warranting further development toward clinical implementation.tr_TR
dc.language.isoengtr_TR
dc.publisherElseviertr_TR
dc.relation.isversionof10.1016/j.omtm.2018.01.001tr_TR
dc.rightsinfo:eu-repo/semantics/openAccesstr_TR
dc.subjectMNGIEtr_TR
dc.subjectGene therapytr_TR
dc.subjectHematopoietic stem cellstr_TR
dc.subjectLentiviral vectorstr_TR
dc.subjectThymidine phosphorylasetr_TR
dc.subject.lcshTıptr_TR
dc.titlePreclinical Efficacy and Safety Evaluation of Hematopoietic Stem Cell Gene Therapy in a Mouse Model of Mngietr_TR
dc.typeinfo:eu-repo/semantics/articletr_TR
dc.typeinfo:eu-repo/semantics/publishedVersion
dc.relation.journalMolecular Therapy. Methods & Clinical Developmenttr_TR
dc.contributor.departmentKök Hücretr_TR
dc.identifier.volume8tr_TR
dc.identifier.startpage152tr_TR
dc.identifier.endpage165tr_TR
dc.indexingWoStr_TR
dc.indexingScopustr_TR
dc.indexingPubMedtr_TR
dc.fundingYoktr_TR


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