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Improvement of the mdx mouse dystrophic phenotype by systemic in utero AAV8 delivery of a minidystrophin gene

Gene Therapy volume 17, pages 1355–1362 (2010)Cite this article

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Abstract

Duchenne muscular dystrophy (DMD) is a devastating primary muscle disease with pathological changes in skeletal muscle that are ongoing at the time of birth. Progressive deterioration in striated muscle function in affected individuals ultimately results in early death due to cardio-pulmonary failure. As affected individuals can be identified before birth by prenatal genetic testing for DMD, gene replacement treatment can be started in utero. This approach offers the possibility of preventing pathological changes in muscle that begin early in life. To test in utero gene transfer in the mdx mouse model of DMD, a minidystrophin gene driven by the human cytomegalovirus promoter was delivered systemically by an intraperitoneal injection to the fetus at embryonic day 16. Treated mdx mice studied at 9 weeks after birth showed widespread expression of recombinant dystrophin in skeletal muscle, restoration of the dystrophin-associated glycoprotein complex in dystrophin-expressing muscle fibers, improved muscle pathology, and functional benefit to the transduced diaphragm compared with untreated littermate controls. These results support the potential of the AAV8 vector to efficiently cross the blood vessel barrier to achieve systemic gene transfer to skeletal muscle in utero in a mouse model of muscular dystrophy, to significantly improve the dystrophic phenotype and to ameliorate the processes that lead to exhaustion of the skeletal muscle regenerative capacity.

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Acknowledgements

This work was supported by Grant R01 AR050565 (PRC) and R01 AR45967 (XX) from the NIH. The authors take full responsibility for the contents of this paper, which do not represent the views of the Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    B M Koppanati, D P Reay, H Zheng & P R Clemens

  2. Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    J Li & X Xiao

  3. Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    B Wang

  4. Department of Pediatrics, Magee-Women's Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    M Daood & J F Watchko

  5. Department of Veterans Affairs Medical Center, Neurology Service, Pittsburgh, PA, USA

    P R Clemens

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  1. B M Koppanati
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Correspondence to P R Clemens.

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Koppanati, B., Li, J., Reay, D. et al. Improvement of the mdx mouse dystrophic phenotype by systemic in utero AAV8 delivery of a minidystrophin gene. Gene Ther 17, 1355–1362 (2010). https://doi.org/10.1038/gt.2010.84

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  • DOI: https://doi.org/10.1038/gt.2010.84

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