Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia.

Newman, Kurt D.; Dunn, Peter F.; Owens, J W; Schulick, Andrew H.; Virmani, Renu; Sukhova, Galina K.; Libby, Peter; Dichek, David A.

doi:10.1172/jci118367

Cited by 290 publications

(185 citation statements)

References 43 publications

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“…Additionally, the immunogenicity of the vector can produce local and systemic adverse reactions. [23][24][25] Therefore, we have examined the use of polymer carriers to facilitate gene delivery using plasmid DNA. The release of genetic material from intravascular stents could represent a new therapeutic modality 14 since, unlike balloon catheters, the stent remains within the vessel, avoiding the limitations associated with the delivery of large quantities of genetic material within a few minutes.…”

Section: Discussionmentioning

confidence: 99%

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

Takahashi

Palmer-Opolski²,

Smith

et al. 2003

Gene Ther

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Metallic stents coated with a polyurethane emulsion containing plasmid DNA were implanted in rabbit iliac arteries to evaluate transgene delivery and expression in the vessel wall. The expression of the plasmid-encoded marker genes, b-galactosidase, luciferase and green fluorescence protein (GFP), were evaluated at 7 days after implantation. In all cases, plasmid transfer was confined to the vessel wall at the site of stent implantation, plasmid DNA was not observed in vessel segments immediately proximal or distal to the stent and dissemination of plasmid DNA to lung, liver or spleen was not observed. Expression of transgenes occurred only in vessel segments in contact with the stent and analysis of the GFP expression pattern revealed a high frequency of marker protein-positive cells occurring at or near the luminal surface. The extent of transgene expression was dependent upon the quantity of DNA loaded onto the stent and no signal was detected in vessel segments that received polymer-coated stents lacking plasmid DNA. Of significance, colocalization studies identified transgene expression not only in vascular smooth muscle cells but also in macrophages. Hence, polymer-coated stents provide a new capability for transgene delivery to immune cells that are believed to contribute to the development of in-stent restenosis.

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Section: Discussionmentioning

confidence: 99%

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

Takahashi

Palmer-Opolski²,

Smith

et al. 2003

Gene Ther

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show abstract

“…To investigate the function of the transgene it is crucial that the vector itself does not alter the biological process being studied. It has recently been reported that the high adenoviral loads needed to achieve transgene expression have been associated with local inflammation after delivery into rabbit arteries 1 and the respiratory epithelium of both primates 2 and humans. 3 However, the precise mechanism underlying this inflammatory response remains obscure.…”

Section: Introductionmentioning

confidence: 99%

High adenoviral loads stimulate NFκB-dependent gene expression in human vascular smooth muscle cells

et al. 1998

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“…However, this is not without the complications of toxicity and immunogenicity and mediates a purely transient transgene expression when first-generation vectors are utilized. 7 Adeno-associated viruses (AAV) have been suggested as potential alternative vectors for vascular gene therapy due to their longevity of transgene expression and relatively favourable safety profile. AAV serotype-2 (AAV-2)-based vectors have been used for cardiovascular gene delivery locally into blood vessels 8,9 and by direct intra-myocardial injection, 10 the latter showing success therapeutically when delivered prior to surgical intervention, thereby allowing sufficient transgene to be expressed in the heart.…”

mentioning

confidence: 99%

Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation

2005

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Transduction of the vascular endothelium by adeno-associated virus (AAV) vectors would have broad appeal for gene therapy. However, levels of transduction by AAV serotype-2 are low, an observation linked to deficiencies in endothelial cell binding, sequestration of virions in the extracellular matrix and/or virion degradation by the proteasome. Strategies to improve transduction of endothelial cells include AAV-2 capsid targeting using small peptides isolated by phage display or the use of alternate serotypes. Previously, we have shown that AAV serotypes-3 through -6 transduce endothelial cells with poor efficiency. Recently, AAV serotypes-7 and -8 have been shown to mediate efficient transduction of the skeletal muscle and liver, respectively, although their infectivity profile for vascular cells has not been addressed. Here, we show that AAV-7 and -8 also transduce endothelial cells with poor efficiency and the levels of transgene expression are markedly enhanced by inhibition of the proteasome. In both cases proteasome blockade enhances the nuclear translocation of virions. We further show that this is vascular cell-type selective since transduction of smooth muscle cells is not sensitive to proteasome inhibition. Analysis in intact blood vessels corroborated these findings and suggests that proteasome degradation is a common limiting factor for endothelial cell transduction by AAV vectors. Gene Therapy (2005) 12, 1534-1538.

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Adenovirus-mediated gene transfer into normal rabbit arteries results in prolonged vascular cell activation, inflammation, and neointimal hyperplasia.

Cited by 290 publications

References 43 publications

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

Transgene delivery of plasmid DNA to smooth muscle cells and macrophages from a biostable polymer-coated stent

High adenoviral loads stimulate NFκB-dependent gene expression in human vascular smooth muscle cells

Adeno-associated virus (AAV)-7 and -8 poorly transduce vascular endothelial cells and are sensitive to proteasomal degradation

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