The development of viral vectors for targeted gene delivery to atherosclerotic plaques

QR355 Virology;R Medicine (General)

White, Katie ; Baker, Andrew H.

University:University of Glasgow

关键词: QR355 Virology;    R Medicine (General);   

Others  :  http://theses.gla.ac.uk/30729/1/2007WhitePhD.pdf

来源: University of Glasgow

【 摘 要 】

Cardiovascular disease is one of the leading causes of death in the Western world. One of the most common causes is the rupture of unstable atherosclerotic plaques, which can lead to thrombus formation, occlusion of the artery and myocardial infarction. Therefore there is a need for treatments that stabilise vulnerable plaques. Gene therapy has the potential to provide a novel treatment for this. To maximise therapeutic gene expression and minimize any potential adverse effects due to unwanted transgene expression in non-target tissues, a gene delivery vector specifically targeted to areas of atherosclerotic vasculature is required. The vector is also required to efficiently infect cells to produce relatively long term transgene expression, be stable in blood, non-toxic, non-immunogenic and producible at high titres. Viral vectors, particularly those based on adenovirus (Ad) and adeno-associated virus (AAV) have many of the desired features, but transduce vascular cells relatively inefficiently and in a non-selective manner. Methods of altering their tropism have been established and could be utilised to develop vectors with a high degree of selectivity for atherosclerotic plaques. Detargeting of vectors can be achieved by mutating regions of the virus capsid that are thought to bind the native cellular receptors and retargeting to novel cell types is achieved by inserting peptide ligands into the virus capsid. The aim of this study was to develop atherosclerotic plaque targeted vectors and to characterise Ad and AAV vector platforms in this regard. Two approaches were taken. In the first approach three previously identified plaque targeting peptides were tested for their ability to target viral vectors to atherosclerotic plaques. The second approach involved performing phage display in a mouse model of plaque rupture to identify novel peptides that specifically target unstable plaques. Further work was carried out to characterise and develop methods for using an AAV2 based peptide library as a novel tool for biopanning. This work has provided further characterisation of Ad and AAV platform vectors that may be utilised in the development of vectors with a highly selective tropism. (Abstract shortened by ProQuest.)