The mouse dystrophin muscle promoter/enhancer drives expression of mini-dystrophin in transgenic mdx mice and rescues the dystrophy in these mice

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.