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ABSTRACT: Adenovirus (Ad)-mediated gene delivery is a promising approach for genetic manipulation of the vasculature and is being used in both preclinical models and clinical trials. However, safety concerns relating to infection of nontarget tissue and the poor infectivity of vascular cells compared to other cell types necessitates Ad vector refinement. Here, we combine a transductional targeting approach to improve vascular cell infectivity through RGD peptide insertion into adenovirus fibers, combined with transcriptional targeting to endothelial cells using a approximately 1 kb fragment of the fms-like tyrosine kinase receptor-1 (FLT-1) promoter. Single- and double-modified vectors were characterized in human cell lines that either support or have silenced FLT-1 expression. In rat hepatocytes and endothelial cells, the double modification substantially shifted transduction profiles toward vascular endothelial cells. Furthermore, in intact aortae derived from spontaneously hypertensive rats that display enhanced alphav integrin expression on dysfunctional endothelium, enhanced levels of transduction were observed using the double-modified vector but not in aortae derived from normotensive control rats. Our data indicate that Ad-mediated transduction can be beneficially modified in vitro and in vivo by combining fiber modification and a cell-selective promoter within a single-component vector system.
Gene Therapy 09/2004; 11(16):1296-300. · 3.71 Impact Factor
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ABSTRACT: A sustained-release multi-trace element/vitamin bolus has been devised for administration to ewes in advance of mating. Each bolus contained 5.3g Cu, 50mg Se, 90mg Co, 100mg I, 3.2g Mn and 4.7g Zn with 268x10(3) IU Vitamin A, 54x10(3) IU Vitamin D and 800 IU Vitamin E. About 50% of each nutrient is released during the first 6 weeks. Thereafter the release rate slows and over the remaining life of the bolus (about 6 months extending to lambing time) the daily release rates are about 15mg Cu, 0.1mg Se, 0.2mg Co, 0.3mg I, 9.4mg Mn and 13mg Zn with 775 IU Vitamin A, 156 IU Vitamin D and 2 IU Vitamin E. In one study the proportion of twins born to ewes given the bolus was very significantly (P<0.001) higher than for the untreated ewes and greater than for those given a copper injection or copper oxide needles. In a second study the proportion of ewes given a bolus and having twin lambs was significantly (P<0.01) greater than for untreated ewes and significantly (P<0.05) fewer ewes were non-pregnant. In a third study, giving a bolus to shearling ewes tended (P=0.06) to result in fewer non-pregnant animals than for those untreated. Blood copper and Vitamin B(12) concentrations and glutathione peroxidase activities were above normal values throughout.
Small Ruminant Research 01/2001; 39(1):25-30. · 1.29 Impact Factor
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Canadian Medical Association Journal 12/2000; 163(10):1239; author reply 1239, 1242. · 8.22 Impact Factor
