Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice.
Limb-girdle muscular dystrophy type 2D (LGMD 2D) is the most common cause of LGMD with a sarcoglycan defect. We recently engineered a murine model for this progressive disease and we investigated the possibility of preventing the development of muscular dystrophy in these animals by adenovirus-mediated gene transfer of human alpha-sarcoglycan. Here we report that a single intramuscular injection of a first generation adenovirus into the skeletal muscle of neonate mice led to sustained expression of alpha-sarcoglycan at the sarcolemma of transduced myofibers for at least 7 months. The morphology of transduced muscles was consequently preserved. In addition, we have used contrast agent-enhanced magnetic resonance imaging (MRI) to investigate sarcolemmal integrity in adenovirus-injected animals and have thereby demonstrated maintenance of sarcolemmal function. In conclusion, we provide evidence that early virus-mediated gene transfer of a sarcoglycan protein constitutes a promising therapeutic strategy for LGMDs and that the benefits of this approach can easily and effectively be monitored by noninvasive methodologies such as MRI.
Allamand
V
V
Howard Hughes Medical Institute, Department of Physiology and Biophysics, University of Iowa College of Medicine, Iowa City 52242, USA.
Donahue
K M
KM
Straub
V
V
Davisson
R L
RL
Davidson
B L
BL
Campbell
K P
KP
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008562:Membrane Glycoproteins / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000737:chemistry / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000175:diagnosis / Q000378:metabolism / Q000628:therapy*; D049031:Sarcoglycans
D003598:Cytoskeletal Proteins; D008562:Membrane Glycoproteins; D049031:Sarcoglycans