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Human Molecular Genetics, 2003, Vol. 12, No. 11 1287-1299
DOI: 10.1093/hmg/ddg141
© 2003 Oxford University Press

Prolonged dystrophin expression and functional correction of mdx mouse muscle following gene transfer with a helper-dependent (gutted) adenovirus-encoding murine dystrophin

Rénald Gilbert1,{dagger}, Roy W. R. Dudley2, An-Bang Liu1,{ddagger}, Basil J. Petrof2, Josephine Nalbantoglu1 and George Karpati1,*

1Neuromuscular Research Group, Montreal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4 and 2Respiratory Division, McGill University Health Center and Meakins-Christie Laboratories, McGill University, Montréal, Québec, Canada H3A 1A1

Received January 17, 2003; Accepted March 30, 2003

Dystrophin gene transfer using helper-dependent adenoviruses (HDAd), which are deleted of all viral genes, is a promising option to treat muscles in Duchenne muscular dystrophy. We investigated the benefits of this approach by injecting the tibialis anterior (TA) muscle of neonatal and juvenile (4–6-week-old) dystrophin-deficient (mdx) mice with a fully deleted HDAd (HDCBDysM). This vector encoded two full-length murine dystrophin cDNAs regulated by the powerful cytomegalovirus enhancer/ß-actin promoter. At 10 days post-injection of neonatal muscles, 712 fibers (42% of the total number of TA fibers) were dystrophin-positive (dys+), a value that did not decrease for 6 months (the study duration). In treated juveniles, maximal transduction occurred at 30 days post-injection (414 dys+ fibers, 24% of the total number of TA fibers), but decreased by 51% after 6 months. All studied aspects of the pathology were improved in neonatally treated muscles: the percentage of dys+ fibers with centrally localized myonuclei remained low, localization of the dystrophin associated protein complex was restored at the plasma membrane, muscle hypertrophy was reduced, and maximal force-generating capacity and resistance to contraction-induced injuries were increased. The same pathological aspects were improved in the treated juveniles, except for reduction of muscle hypertrophy and maximal force-generating capacity. We demonstrated a strong humoral response against murine dystrophin in both animal groups, but mild inflammatory response occurred only in the treated juveniles. HDCBDysM is thus one of the most promising and efficient vectors for treating DMD by gene therapy.

* To whom correspondence should be addressed at: Montreal Neurological Institute, 3801 University Street, Montréal, Québec, Canada H3A 2B4. Tel: +1 5143988528; Fax: +1 5143988310; Email: george.karpati{at}mcgill.ca

{dagger} Present address: Biotechnology Research Institute, NRC, 6100 Royalmount Ave, Montréal, Québec, Canada H4P 2R2.

{ddagger} Present address: Department of Neurology, Tzu Chi Medical Center, Hualien, Taiwan.


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