Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice (original) (raw)

Gene Therapy volume 5, pages 369–379 (1998) Cite this article

Abstract

Duchenne muscular dystrophy (DMD) and murine X-linked muscular dystrophy (mdx) are both due to absence of the subsarcolemmal protein dystrophin. Recombinant adenovirus vectors (AdV) are considered a promising means for delivering a functional dystrophin gene to muscle. However, the usefulness of AdV for this purpose is limited by vector toxicity as well as immune-mediated elimination of infected fibers. In addition, studies to date of AdV-mediated dystrophin gene transfer have either failed to examine effects on muscle strength or been performed in immunologically immature neonatal animals with little baseline abnormality of force-generating capacity. In the present study, AdV-mediated dystrophin gene transfer was perfor-med in adult mdx mice with pre-existent dystrophic patho- logy and muscle weakness. The main findings are as follows: (1) acute myofiber toxicity and gene transfer efficiency are both AdV dose-dependent, such that the therapeutic margin of safety is fairly narrow; (2) immunosuppressive therapy (FK506) prevents immune-mediated elimination of dystrophin-positive fibers but not the dose-dependent toxic effects; (3) at the optimal vector dosage and with effective immunosuppression, AdV-mediated dystrophin minigene transfer is capable of alleviating the loss of force-generating capacity as well as histopathological evidence of disease progression normally seen in adult mdx muscles over a 2-month period. These findings have important implications for the eventual application of AdV-mediated dystrophin gene transfer in DMD patients.

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Authors and Affiliations

  1. Respiratory Division, Royal Victoria Hospital, and Meakins-Christie Laboratories, McGill University, Montreal, Quebec, Canada
    L Yang, J Luo & BJ Petrof
  2. Neuromuscular Research Group, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
    H Lochmuller, J Nalbantoglu & G Karpati
  3. Genzentrum and Friedrich-Baur-Institut, Munich, Germany
    H Lochmuller
  4. Biotechnology Research Institute, National Research Council of Canada, Montreal, Quebec, Canada
    B Massie

Authors

  1. L Yang
  2. H Lochmuller
  3. J Luo
  4. B Massie
  5. J Nalbantoglu
  6. G Karpati
  7. BJ Petrof

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Yang, L., Lochmuller, H., Luo, J. et al. Adenovirus-mediated dystrophin minigene transfer improves muscle strength in adult dystrophic (MDX) mice.Gene Ther 5, 369–379 (1998). https://doi.org/10.1038/sj.gt.3300600

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