Preclinical Efficacy and Safety Evaluation of Hematopoietic Stem Cell Gene Therapy in a Mouse Model of MNGIE

Rana Yadak, Raquel Cabrera-Pérez, Javier Torres-Torronteras, Marianna Bugiani, Joost C. Haeck, Marshall W. Huston, Elly Bogaerts, Steffi Goffart, Edwin H. Jacobs, Merel Stok, Lorena Leonardelli, Luca Biasco, Robert M. Verdijk, Monique R. Bernsen, George Ruijter, Ramon Martí, Gerard Wagemaker, Niek P. van Til, Irenaeus F.M. de Coo

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    11 Citations (Scopus)


    © 2018 The Authors Mitochondrial 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.
    Original languageEnglish
    Pages (from-to)152-165
    JournalMolecular Therapy - Methods and Clinical Development
    Publication statusPublished - 16 Mar 2018


    • MNGIE
    • gene therapy
    • hematopoietic stem cells
    • lentiviral vectors
    • thymidine phosphorylase


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