Muscle-specific overexpression of the adenovirus primary receptor CAR overcomes low efficiency of gene transfer to mature skeletal muscle

Citation
J. Nalbantoglu et al., Muscle-specific overexpression of the adenovirus primary receptor CAR overcomes low efficiency of gene transfer to mature skeletal muscle, J VIROLOGY, 75(9), 2001, pp. 4276-4282
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Microbiology
Journal title
JOURNAL OF VIROLOGY
ISSN journal
0022-538X → ACNP
Volume
75
Issue
9
Year of publication
2001
Pages
4276 - 4282
Database
ISI
SICI code
0022-538X(200105)75:9<4276:MOOTAP>2.0.ZU;2-N
Abstract
Significant levels of adenovirus (Ad)-mediated gene transfer occur only in immature muscle or in regenerating muscle, indicating that a developmentall y regulated event plays a major role in limiting transgene expression in ma ture skeletal muscle. We have previously shown that in developing mouse mus cle, expression of the primary Ad receptor CAR is severely downregulated du ring muscle maturation. To evaluate how global expression of CAR throughout muscle affects Ad vector (AdV)-mediated gene transfer into mature skeletal muscle, we produced transgenic mice that express the CAR cDNA under the co ntrol of the muscle-specific creatine kinase promoter. Five-month-old trans genic mice were compared to their nontransgenic littermates for their susce ptibility to AdV transduction. In CAR transgenics that had been injected in the tibialis anterior muscle with AdVCMVIacZ, increased gene transfer was demonstrated by the increase in the number of transduced muscle fibers (433 +/- 121 in transgenic mice versus 8 +/- 4 in nontransgenic littermates) as well as the 25-fold increase in overall beta -galactosidase activity, Even when the reporter gene was driven by a more efficient promoter (the cytome galovirus enhancer-thicken beta -actin gene promoter), differential transdu cibility was still evident (893 +/- 149 versus 153 +/- 30 fibers; P < 0,001 ), Furthermore, a tivefofd decrease in the titer of injected AdV still resu lted in significant transduction of muscle (253 <plus/minus> 130 versus 14 +/- 4 fibers). The dramatic enhancement in AdV-mediated gene transfer to ma ture skeletal muscle that is observed in the CAR transgenics indicates that prior modulation of the level of CAR expression can overcome the poor AdV transducibility of mature skeletal muscle and significant transduction can be obtained at tow titers of AdV.