Sustained Improvement of Muscle Function One Year After Full-Length Dystrophin Gene Transfer into mdx Mice by a Gutted Helper-Dependent Adenoviral Vector

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DOIResolve DOI: http://doi.org/10.1089/104303404772679959
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TypeArticle
Journal titleHuman Gene Therapy
Volume15
Issue2
Pages145156; # of pages: 12
AbstractDystrophin gene transfer using helper-dependent adenoviral vectors (HDAd) deleted of all viral genes is a promising option to treat muscles in Duchenne muscular dystrophy (DMD). Previously, we reported high-level dystrophin expression and functional correction of dystrophin-deficient (mdx) mouse muscle 60 days after gene transfer with an HDAd encoding two full-length murine dystrophin cDNAs (referred to as HDCBDysM). In the present study, we tested the long-term efficacy of HDCBDysM by examining muscle contractility parameters and the stability of dystrophin expression 1 year after injection into neonatal mdx muscles. At this point, HDCBDysM-treated muscles averaged 52% dystrophin-positive fibers. Treated muscles also displayed significantly greater isometric force production as well as greater resistance to the force deficits and damage caused by eccentric contractions. The level of protection against eccentric contraction-induced force deficits correlated with the percentage of dystrophin-positive fibers. Furthermore, HDCBDysM treatment restored the dystrophin-glycoprotein complex (DGC) to the sarcolemma and improved other aspects of mdx muscle histopathology examined (central nucleation, muscle hypertrophy, and mononuclear [phagocytic] cell infiltration). These improvements occurred despite the induction of a humoral response against murine dystrophin. Our results indicate that major therapeutic benefits of HDCBDysM are maintained for a long period of the animals' lifespan and suggest that HDCBDys holds promise for treating DMD by gene therapy.
Publication date
AffiliationNational Research Council Canada; NRC Biotechnology Research Institute
Peer reviewedNo
NPARC number12327034
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Record identifier15c380c0-31db-4b18-aaca-57b2f802d8b6
Record created2009-09-10
Record modified2016-05-09
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