Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE

Javier Torres-Torronteras, Carlo Viscomi, Raquel Cabrera-Pérez, Yolanda Cámara, Ivano Di Meo, Jordi Barquinero, Alberto Auricchio, Giuseppe Pizzorno, Michio Hirano, Massimo Zeviani, Ramon Martí

    Research output: Contribution to journalArticleResearchpeer-review

    38 Citations (Scopus)

    Abstract

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in TYMP, enconding thymidine phosphorylase (TP). TP deficiency results in systemic accumulation of thymidine and deoxyuridine, which interferes with mitochondrial DNA (mtDNA) replication and leads to mitochondrial dysfunction. To date, the only treatment available for MNGIE patients is allogeneic hematopoietic stem cell transplantation, which is associated with high morbidity and mortality. Here, we report that AAV2/8-mediated transfer of the human TYMP coding sequence (hcTYMP) under the control of a liver-specific promoter prevents the biochemical imbalances in a murine model of MNGIE. hcTYMP expression was restricted to liver, and a dose as low as 2 × 10 11 genome copies/kg led to a permanent reduction in systemic nucleoside levels to normal values in about 50% of treated mice. Higher doses resulted in reductions to normal or slightly below normal levels in virtually all mice treated. The nucleoside reduction achieved by this treatment prevented deoxycytidine triphosphate (dCTP) depletion, which is the limiting factor affecting mtDNA replication in this disease. These results demonstrate that the use of AAV to direct TYMP expression in liver is feasible as a potentially safe gene therapy strategy for MNGIE. © 2014 The American Society of Gene and Cell Therapy.
    Original languageEnglish
    Pages (from-to)901-907
    JournalMolecular Therapy
    Volume22
    Issue number5
    DOIs
    Publication statusPublished - 1 Jan 2014

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