Improved Performance of a Fully Gutted Adenovirus Vector Containing Two Full-Length Dystrophin cDNAs Regulated by a Strong Promoter

From National Research Council Canada

DOI	Resolve DOI: https://doi.org/10.1006/mthe.2002.0689
Author	Search for: Gilbert, Rénald; Search for: Liu, An-Bang; Search for: Petrof, Basil J.; Search for: Nalbantoglu, Josephine; Search for: Karpati, George
Format	Text, Article
Abstract	Dystrophin gene transfer using gutted or helper-dependent adenoviruses (HDAd), which have most of their genes deleted, is a promising approach to treat Duchenne muscular dystrophy. In an attempt to boost the amount of dystrophin produced after gene transfer, we have constructed a fully deleted HDAd (HDCBDys2x) containing two human dystrophin cDNAs controlled by the powerful hybrid cytomegalovirus enhancer/beta-actin promoter. We demonstrated high dystrophin expression after infection of muscle cultures with HDCBDys2x. Similarly, high (mean=583) and moderate (mean=124) numbers of muscle fibers were transduced in anterior tibialis muscle after intramuscular injection of HDCBDys2x in neonate and adult dystrophindeficient (mdx) mice 10 days postinjection. In fact, in the neonatally injected mdx mice, the transferred dystrophin was five times more abundant than in normal human muscle. However, the high early transduction level was transient in both animal groups, and we observed a humoral response against the human dystrophin. In contrast, we demonstrated sustained dystrophin expression in immunodeficient mouse muscles. Dystrophin expression of HDCBDys2x could be further increased in the presence of an E1/E3-deleted (first-generation) adenovirus, thus demonstrating that the latter vector synthesizes trans-acting enhancing factors. We have achieved abundant dystrophin expression with our new, improved HDAd. It is anticipated that high longterm transgene expression will be possible by employing weaker immunogenic transgenes.
Publication date	2002-10
In	Molecular Therapy 6, no. 4 (October 2002): 501–509.
NRC publication	This is a non-NRC publication "Non-NRC publications" are publications authored by NRC employees prior to their employment by NRC.
NPARC number	12338565
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Record identifier	c3a7ce10-174a-48e7-aea3-53c5c693516c
Record created	2009-09-10
Record modified	2020-03-30

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