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

被引:55
作者
Nalbantoglu, J
Larochelle, N
Wolf, E
Karpati, G
Lochmuller, H
Holland, PC
机构
[1] McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2B4, Canada
[2] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ H3A 2B4, Canada
[3] Univ Munich, Genzentrum, Munich, Germany
关键词
D O I
10.1128/JVI.75.9.4276-4282.2001
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Significant levels of adenovirus (Ad)-mediated gene transfer occur only in immature muscle or in regenerating muscle, indicating that a developmentally regulated event plays a major role in limiting transgene expression in mature skeletal muscle. We have previously shown that in developing mouse muscle, expression of the primary Ad receptor CAR is severely downregulated during 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 control of the muscle-specific creatine kinase promoter. Five-month-old transgenic mice were compared to their nontransgenic littermates for their susceptibility 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 cytomegalovirus enhancer-thicken beta -actin gene promoter), differential transducibility was still evident (893 +/- 149 versus 153 +/- 30 fibers; P < 0,001), Furthermore, a tivefofd decrease in the titer of injected AdV still resulted in significant transduction of muscle (253 <plus/minus> 130 versus 14 +/- 4 fibers). The dramatic enhancement in AdV-mediated gene transfer to mature 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.
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页码:4276 / 4282
页数:7
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