Abstract
BackgroundCardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.MethodsVascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).ResultsCompared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.ConclusionsWe have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.
Highlights
Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies
Havenga et al have previously demonstrated that Adenovirus serotype 5 (Ad5) vectors pseudotyped with the fiber from several subgroup B viruses show enhanced transduction of human vascular cells compared to Ad5 [16] and the Ad subgroup B receptor CD46 has been shown to be relatively highly expressed by vascular cells [12]
In vitro binding and transduction profiles of a CD46 binding Ad vector in human vascular cells Surface plasmon resonance has previously demonstrated that mutations in the hexon protein of the virus Ad5T* prevent binding to factor X (FX), and following systemic delivery in mice, this ablation of FX binding causes a significant reduction in liver tropism [26]
Summary
Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Pre-clinical studies indicate that gene delivery to the vasculature could potentially be utilised to treat a range of cardiovascular diseases such as vein graft failure [1], instent restenosis [2] and peripheral vascular disease [3]. ATPase gene (SERCA2a) in patients with advanced heart failure [8] This treatment significantly improved several cardiovascular parameters [8] and demonstrates the future potential of gene therapy treatments targeting the cardiovascular system. Critical to realising this potential is the development of more efficient gene delivery systems to generate sufficient levels of therapeutic transgene expression, at the target site without causing any adverse effects. To maximise uptake into the vessel we have focused on developing a vector which utilises CD46 and not CAR as the principal receptor for binding to the cell surface
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