Therapeutic gene transfer to dystrophic diaphragm by an adenoviral vector deleted of all viral genes

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DOIResolve DOI: http://doi.org/10.1152/ajplung.00117.2004
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TypeArticle
Journal titleAmerican Journal of Physiology: Lung Cellular and Molecular Physiology
ISSN1040-0605
Volume287
Issue3
PagesL569L576; # of pages: 8
Subjectbio; Duchenne muscular dystrophy; gene therapy; dystrophin deficiency; viral vectors; mdx mouse; adenoviridae; animals; CD4-positive T-lymphocytes; CD8-positive T-lymphocytes; diaphragm; dystrophin; gene expression; gene transfer techniques; mice; mice, inbred C57BL; mice, inbred mdx; muscular dystrophy, animal; muscular dystrophy, duchenne
AbstractDuchenne muscular dystrophy is caused by defects in the dystrophin gene, and the mdx mouse is the most frequently employed genetic model of this disease. It is well known that different muscle groups do not respond in the same way to dystrophin deficiency. In particular, the mdx mouse diaphragm exhibits severe morphological and functional changes not found in other mdx muscles. Use of early generation adenoviral vectors to deliver genes to the diaphragm in immunocompetent mdx mice has been associated with substantial functional toxicity and a rapid loss of transgene expression. Here we determined the response to dystrophin gene replacement in the mdx diaphragm using a “gutted” adenoviral vector that contains the coding sequence of two full-length dystrophin genes and is deleted of most viral DNA sequences. At 1 wk postdelivery of the vector, 23.6 ± 4% of total fibers in the injected diaphragm bundle expressed dystrophin at the sarcolemma, which remained stable over the study duration of 30 days without the need for continuous immunosuppression. Treated diaphragms showed a significantly improved resistance to the abnormal force deficits induced by high-stress muscle contractions, the latter being a functional hallmark of dystrophin-deficient muscle. This functional amelioration was achieved despite the presence of mildly increased inflammation (CD4+ and CD8+ lymphocytes) within the vector-treated diaphragms. To our knowledge, this is the first demonstration that a viral vector can achieve reversal of functional abnormalities in the dystrophic diaphragm via therapeutic dystrophin gene transfer without the need for sustained immunosuppressive therapy.
Publication date
LanguageEnglish
AffiliationNRC Biotechnology Research Institute; National Research Council Canada
Peer reviewedNo
Identifier10462983
NRC number37733
NPARC number3539975
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Record identifierf76b6963-7dc0-45ff-9d55-662ddf4f6c14
Record created2009-03-01
Record modified2016-05-09
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