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Human Molecular Genetics Advance Access originally published online on June 9, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 15 1669-1675
DOI: 10.1093/hmg/ddh174
Human Molecular Genetics, Vol. 13, No. 15 © Oxford University Press 2004; all rights reserved

Full-length dystrophin expression in half of the heart cells ameliorates ß-isoproterenol-induced cardiomyopathy in mdx mice

Yongping Yue1, Jeffrey W. Skimming2, Mingju Liu1, Tammy Strawn2 and Dongsheng Duan1,*

1Department of Molecular Microbiology and Immunology and 2Department of Child Health and Department of Medical Pharmacology and Physiology, The University of Missouri, School of Medicine, Columbia, MO 65212, USA

Received April 12, 2004; Accepted May 26, 2004

Gene therapy holds great promise for curing Duchenne muscular dystrophy (DMD), the most common fatal inherited childhood muscle disease. Success of DMD gene therapy depends upon functional improvement in both skeletal and cardiac muscle. Numerous gene transfer studies have been performed to correct skeletal muscle pathology, yet little is known about cardiomyopathy gene therapy. Since complete transduction of the entire heart is an impractical goal, it becomes critical to determine the minimal level of correction needed for successful DMD cardiomyopathy gene therapy. To address this question, we generated heterozygous mice that persistently expressed the full-length dystrophin gene in 50% of the cardiomyocytes of mdx mice, a model for DMD. We questioned whether dystrophin expression in half of the heart cells was sufficient to prevent stress-induced cardiomyopathy. Heart function of mdx mouse is normal in the absence of external stress. To determine the therapeutic effect, we challenged 3-month-old mice with ß-isoproterenol. Cardiomyocyte sarcolemma integrity was significantly impaired in mdx but not in heterozygous and C57Bl/10 mice. Importantly, in vivo closed-chest hemodynamic assays revealed normal left ventricular function in ß-isoproterenol-stimulated heterozygous mice. Since the expression profile in the heterozygous mice mimicked viral transduction, we conclude that gene therapy correction in 50% of the heart cells may be sufficient to treat cardiomyopathy in mdx mice. This finding may also apply to the gene therapy of other inherited cardiomyopathies.

* To whom correspondence should be addressed at: Department of Molecular Microbiology and Immunology, The University of Missouri, School of Medicine, One Hospital Drive, Room M610G, MSB, Columbia, MO 65212, USA. Tel: +1 5738849584; Fax: +1 5738824287; Email: duand{at}missouri.edu


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