1. ¹Ottawa Health Research Institute, Ottawa, ON, Canada K1H 8L6
2. ²Center for Neuromuscular Disease, University of Ottawa, Ottawa, ON, Canada K1H 8M5
3. ³Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5
4. ⁴Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON, Canada K1H 8M5
5. ⁵Department of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5

Correspondence: Rashmi Kothary, Ottawa Health Research Institute, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6. Fax: +1 613 737 8803. E-mail: rkothary@ohri.ca

Received 8 June 2005; Revised 15 March 2006; Accepted 16 April 2006.

Abstract

Successful gene therapy for Duchenne muscular dystrophy (DMD) requires the restoration of dystrophin protein in skeletal muscles. To achieve this goal, appropriate regulatory elements that impart tissue-specific transgene expression need to be identified. Currently, most muscle-directed gene therapy studies utilize the muscle creatine kinase promoter. We have previously described a muscle enhancer element (mDME-1) derived from the mouse dystrophin gene that increases transcription from the mouse dystrophin muscle promoter. Here, we explore the use of this native mouse dystrophin muscle promoter/enhancer to drive expression of a human dystrophin minigene in transgenic mice. We show that the dystrophin promoter can provide tissue-specific transgene expression and that the mini-dystrophin protein is expressed at the sarcolemma of skeletal muscles from mdx mice, where it restores the dystrophin-associated glycoprotein complex. The level of transgene expression obtained is sufficient to protect mdx muscles from the morphological and physiological symptoms of muscular dystrophy, as well as from exercise-induced damage. Therefore, the dystrophin muscle promoter/enhancer sequence represents an alternative for use in gene therapy vectors for the treatment of DMD.