Long-Term Sustained Effect of Liver-Targeted Adeno-Associated Virus Gene Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy

Javier Torres-Torronteras, Raquel Cabrera-Pérez, Ferran Vila-Julià, Carlo Viscomi, Yolanda Cámara, Michio Hirano, Massimo Zeviani, Ramon Martí

    Research output: Contribution to journalArticleResearchpeer-review

    12 Citations (Scopus)

    Abstract

    © Copyright 2018, Mary Ann Liebert, Inc. 2018. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in TYMP, the gene encoding the enzyme thymidine phosphorylase (TP). TP dysfunction results in systemic accumulation of the noxious TP substrates thymidine and deoxyuridine. Gene therapy using either a lentiviral vector or adeno-associated vector (AAV) has proven to be a feasible strategy, as both vectors restore biochemical homeostasis in a murine model of the disease. This study shows that the effect of an AAV containing the TYMP coding sequence transcriptionally targeted to the liver persists long term in mice. Although the vector copy number was diluted and AAV-mediated liver TP activity eventually reduced or lost after 21 months at the lowest vector doses, the effect was sustained (with a negligible decrease in TP activity) and fully effective on nucleoside homeostasis for at least 21 months at a dose of 2 × 10 12 vg/kg. Macroscopic visual inspection of the animals' organs at completion of the study showed no adverse effects associated with the treatment. These results further support the feasibility of gene therapy for MNGIE.
    Original languageEnglish
    Pages (from-to)708-718
    JournalHuman Gene Therapy
    Volume29
    Issue number6
    DOIs
    Publication statusPublished - 1 Jun 2018

    Keywords

    • AAV, liver/metabolic, MNGIE, thymidine phosphorylase, mitochondria

    Fingerprint Dive into the research topics of 'Long-Term Sustained Effect of Liver-Targeted Adeno-Associated Virus Gene Therapy for Mitochondrial Neurogastrointestinal Encephalomyopathy'. Together they form a unique fingerprint.

    Cite this