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Human Molecular Genetics Advance Access published online on April 4, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl082
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received February 16, 2006
Revised March 25, 2006
Accepted March 25, 2006

Article

A highly functional mini-dystrophin/GFP fusion gene for cell and gene therapy studies of Duchenne muscular dystrophy

Sheng Li 1, En Kimura 1, Rainer Ng 2, Brent M. Fall 1, Leonard Meuse 1, Morayma Reyes 1, John A. Faulkner 3, and Jeffrey S. Chamberlain 4 *

1 Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195-7720, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington School of Medicine, Seattle, WA 98195-7720, USA
2 Departments of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109-2007, USA
3 Departments of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109-2007, USA; Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-2007, USA
4 Department of Neurology, K243b HSB, University of Washington School of Medicine, 1959 NE Pacific St., Seattle, WA 98195-7720, USA; Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Washington School of Medicine, Seattle, WA 98195-7720, USA

* To whom correspondence should be addressed.
Jeffrey S. Chamberlain, E-mail: jsc5{at}u.washington.edu


  Abstract

A promising approach for treating Duchenne muscular dystrophy (DMD) is by autologous cell transplantation of myogenic stem cells transduced with a therapeutic expression cassette. Development of this method has been hampered by a low frequency of cellular engraftment, the difficulty of tracing transplanted cells, the rapid loss of autologous cells carrying marker genes that are unable to halt muscle necrosis, and the difficulty of stable transfer of a large dystrophin gene into myogenic stem cells. We engineered a 5.7-kb miniDys-GFP fusion gene by replacing the dystrophin C-terminal domain ({Delta}CT) with an eGFP coding sequence and removing much of the dystrophin central rod domain ({Delta}H2-R19). In a transgenic mdx4Cv mouse expressing the miniDys-GFP fusion protein under the control of a skeletal muscle-specific promoter, the green fusion protein localized on the sarcolemma, where it assembled the dystrophin-glycoprotein complex and completely prevented the development of dystrophy in transgenic mdx4Cv muscles. When myogenic and other stem cells from these mice were transplanted into mdx4Cv recipients, donor cells can be readily identified in skeletal muscle by direct green fluorescence or by using antibodies against GFP or dystrophin. In mdx4Cv mice reconstituted with bone marrow cells from the transgenic mice, we monitored engraftment in various muscle groups and found the number of miniDys-GFP+ fibers increased with time. We suggest that these transgenic mdx4Cv mice are highly useful for developing autologous cell therapies for DMD.


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