A study of intracoronary gene transfer using stents coated with plasmid vectors

Percutaneous coronary intervention with stent deployment is the dominant form of revascularisation for patients with coronary artery disease. Although drug-eluting stents have reduced the incidence of instent restenosis, they are associated with late problems related to delayed vascular healing including late stent thrombosis. The use of gene-eluting stents offers the potential to deliver localised gene therapy to the vascular wall with the aim of both reducing restenosis and promoting endothelialisation. Two candidate genes were investigated. Connective tissue growth factor (CTGF) promotes smooth muscle cell apoptosis and stimulates endothelial growth in vitro, and has an integral role in wound healing. Fibromodulin (FMOD) is involved in collagen metabolism and is a key mediator of scarless wound healing. Both genes have previously been shown to suppress restenosis in an ex vivo vein graft model. Plasmids containing these two genes were constructed with an expression cassette specially designed to maximise transgene expression in vascular smooth muscle cells. These plasmids were coated onto coronary stents with a polymer and the effects of these gene-eluting stents were investigated in an in vivo pig coronary artery model. Previous work by our group has suggested that systemic -blockade can affect the degree of transgene expression from viral vectors, and experiments were also performed to investigate the effect of β-blockers on plasmid-mediated gene expression. At 28 days there was no significant difference in angiographic late loss or neointimal hyperplasia between the groups treated with stents coated with FMOD or CTGF and the group treated with stents coated with the marker gene lacZ. This lack of efficacy appeared to be as a result of extremely poor transgene expression rather than due to a genuine failure of the transgenes to elicit a relevant biological effect. There was no difference in in vivo gene expression demonstrated as a result of β-blockade, but again this result was probably due to limited transgene expression. The potential causes of poor transgene expression in this study are reviewed and future directions for research on plasmid-mediated gene therapy are considered.EThOS - Electronic Theses Online ServiceBritish Heart FoundationGBUnited Kingdo