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

Par Conseil national de recherches du Canada

DOI	Trouver le DOI : https://doi.org/10.1006/mthe.2002.0689
Auteur	Rechercher : Gilbert, Rénald; Rechercher : Liu, An-Bang; Rechercher : Petrof, Basil J.; Rechercher : Nalbantoglu, Josephine; Rechercher : Karpati, George
Format	Texte, Article
Résumé	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.
Date de publication	2002-10
Dans	Molecular Therapy 6, nº 4 (octobre 2002) : 501–509.
Publication du CNRC	Cette publication n’est pas du CNRC Ce sont des publications qui ont été rédigées par un auteur du CNRC, mais avant que celui-ci soit employé du CNRC.
Numéro NPARC	12338565
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Identificateur de l’enregistrement	c3a7ce10-174a-48e7-aea3-53c5c693516c
Enregistrement créé	2009-09-10
Enregistrement modifié	2020-03-30

Date de modification :: 2024-04-20