Forced myofiber regeneration promotes dystrophin gene transfer and improved muscle function despite advanced disease in old dystrophic mice

Ghiabe H. Guibinga, Satoru Ebihara, Josephine Nalbantoglu, Paul Holland, George Karpati, Basil J. Petrof

    Research output: Contribution to journalArticlepeer-review

    14 Citations (Scopus)

    Abstract

    Duchenne muscular dystrophy (DMD) is caused by defects in the dystrophin gene. In young dystrophic mdx mice, immature regenerating myofibers represent the principal substrate for adenovirus vector (AdV)-mediated dystrophin gene transfer. However, in DMD patients immature regenerating myofibers are generally sparse. Such a situation also exists in old mdx mice, which may represent a more realistic model. Therefore, here we have used old mdx mice (of 14- to 17 months of age) to test the hypothesis that one-time administration of a myonecrotic agent can transiently re-establish a population of immature myofibers susceptible to AdV-mediated dystrophin gene transfer. This strategy led to upregulation of the coxsackie/adenovirus attachment receptor by means of induction of regenerating myofibers, significantly augmented AdV-mediated dystrophin gene expression, and enhanced force-generating capacity. In addition, it led to an increased resistance to contraction-induced injury compared with untreated controls. The latter protective effect was positively correlated with the number of dystrophin-expressing myofibers (r = 0.83, P < 0.05). Accordingly, the risk:benefit ratio associated with the sequential use of forced myofiber regeneration and AdV-mediated dystrophin gene transfer was favorable in old mdx mice despite advanced disease. These findings have implications for the potential applicability of AdV-mediated gene therapy to DMD and other muscle diseases in which immature regenerating myofibers are lacking.

    Original languageEnglish
    Pages (from-to)499-507
    Number of pages9
    JournalMolecular Therapy
    Volume4
    Issue number5
    DOIs
    Publication statusPublished - 2001

    Keywords

    • Adenovirus
    • Coxsackie and adenovirus receptor
    • Duchenne muscular dystrophy
    • Gene therapy
    • Muscle function
    • Muscle repair
    • Notexin

    ASJC Scopus subject areas

    • Molecular Medicine
    • Molecular Biology
    • Genetics
    • Pharmacology
    • Drug Discovery

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