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dc.contributor.authorYadak, Rana
dc.contributor.authorCabrera-Pérez, Raquel
dc.contributor.authorTorres-Torronteras, Javier
dc.contributor.authorBugiani, Marianna
dc.contributor.authorHaeck, Joost C
dc.contributor.authorHuston, Marshall W
dc.contributor.authorBogaerts, Elly
dc.contributor.authorGoffart, Steffi
dc.contributor.authorJacobs, Edwin H
dc.contributor.authorStok, Merel
dc.contributor.authorLeonardelli, Lorena
dc.contributor.authorBiasco, Luca
dc.contributor.authorVerdijk, Robert M
dc.contributor.authorBernsen, Monique R;, Ruijter, George
dc.contributor.authorMartí, Ramon
dc.contributor.authorWagemaker, Gerard
dc.contributor.authorvan Til, Niek P
dc.contributor.authorde Coo, Irenaeus F M
dc.date.accessioned2018-04-16T08:17:12Z
dc.date.available2018-04-16T08:17:12Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6325
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.
dc.language.isoEN
dc.publisherElsevier BV
dc.relation.ispartofseriesMolecular therapy : methods & clinical development
dc.relation.urihttp://dx.doi.org/10.1016/j.omtm.2018.01.001
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMNGIE
dc.subjectthymidine phosphorylase
dc.subjecthematopoietic stem cells
dc.subjectlentiviral vectors
dc.subjectgene therapy
dc.titlePreclinical Efficacy and Safety Evaluation of Hematopoietic Stem Cell Gene Therapy in a Mouse Model of MNGIE
dc.description.versionpublished version
dc.contributor.departmentYmpäristö- ja biotieteiden laitos / Toiminta
uef.solecris.id53818386en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© Authors
dc.relation.doi10.1016/j.omtm.2018.01.001
dc.description.reviewstatuspeerReviewed
dc.format.pagerange152-165
dc.relation.volume8
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessOpen access -julkaisukanavassa ilmestynyt julkaisu


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