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Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

White, Katie M, Alba, Raul, Parker, Alan L., Wright, Audrey F, Bradshaw, Angela C, Delles, Christian, McDonald, Robert A and Baker, Andrew H 2013. Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile. Journal of Cardiothoracic Surgery 8 (1) , 183. 10.1186/1749-8090-8-183

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Abstract

Background 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. 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. Methods Vascular 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). Results Compared 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. Conclusions We 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Adenovirus; Vascular gene therapy; TIMP-3; Vein graft failure
Publisher: BioMed Central
ISSN: 1749-8090
Date of Acceptance: 1 August 2013
Last Modified: 20 Sep 2017 09:22
URI: http://orca.cf.ac.uk/id/eprint/85111

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