title: The mouse dystrophin muscle promoter/enhancer drives expression of mini-dystrophin in transgenic mdx mice and rescues the dystrophy in these mice.
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.
authors.affiliation: Ottawa Health Research Institute, Ottawa, ON, Canada K1H 8L6.
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Anderson
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifelli
authors.forename: Philip
authors.initials: P
authors.lastname: Marshall
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Renaud
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Worton
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000818:Animals; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism*; D049029:Dystrophin-Associated Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009928:Organ Specificity; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding
chemical_list: D016189:Dystrophin; D049029:Dystrophin-Associated Proteins