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The role of receptors in the maturation-dependent adenoviral transduction of myofibers

Gene Therapy volume 8, pages 627–637 (2001)Cite this article

Abstract

One of the major hurdles facing the application of adenoviral gene transfer to skeletal muscle is the maturation-dependent transduction of muscle myofibers. It was recently proposed that the viral receptors (Coxsackie and adenovirus receptor (CAR) and the integrins αvβ3/β5) play a major role in the poor adenoviral transduction of mature myofibers. Here we report the findings of morphological studies designed to determine experimentally the role of receptors in the adenoviral transduction of mature myofibers. First, we observed that the expression of both attachment and internalization receptors did not change significantly during muscle development. Second, when an extended tropism adenoviral vector (AdPK) that attaches to heparan sulfate proteoglycan (HSP) is used, a significant reduction of adenoviral transduction still occurs in mature myofibers despite HSP's high expression in mature skeletal muscle fibers. Third, when the adeno-associated virus (AAV) is used, which also utilizes HSP as a viral receptor, muscle fibers at different maturities can be highly transduced. Fourth, the pre-irradiation of the skeletal muscle of newborn mice to inactivate myoblasts dramatically decreased the transduction level of Ad and AdPK, but had no effect on AAV-mediated viral transduction of immature myofibers. These results taken together suggest that the viral receptor(s) is not a major determinant in maturation-dependent adenoviral transduction of myofibers.

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Acknowledgements

This work was supported by the Parent Project (USA), the Muscular Dystrophy Association (USA), the National Institutes of Health (NIH PO1 AR 45925–01), and the William F and Jean W Donaldson Chair at Children's Hospital of Pittsburgh. The authors thank Jim Cummins, Marcelle Pellerin and Arvydas Usas for technical contributions and Lauren Rudick, Dana Och and Megan Mowry for assistance with the manuscript. We thank Dr JM Bergelson of Children's Hospital of Philadelphia for kindly providing the CAR antibody.

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Authors and Affiliations

  1. Department of Orthopaedic Surgery, Growth and Development Laboratory, Children's Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, PA, USA

    B Cao, R Pruchnic, M Ikezawa & J Huard

  2. Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA

    X Xiao, J Li & J Huard

  3. Genvec, Inc., Gaithersburg, MD, USA

    T J Wickham & I Kovesdi

  4. Department of Immunogenetics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA

    W A Rudert

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  1. B Cao
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Cao, B., Pruchnic, R., Ikezawa, M. et al. The role of receptors in the maturation-dependent adenoviral transduction of myofibers. Gene Ther 8, 627–637 (2001). https://doi.org/10.1038/sj.gt.3301425

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