Development of targeted gene delivery vectors to assess cardiac overexpresion of ACE2 in vivo

摘要

The renin angiotensin system is often maninpulated clinically for the treatment of hypertension and heart failure. This pathway is of major clinical importance and it is thus a major target for therapy. The incidence of cardiovascular diseases continues to increase worldwide, highlighting the need for new therapies to treat these conditions. Gene therapy for the treatment of cardiovascular diseases is currently being developed. Gene therapy is by definition the treatment or prevention of disease by means of gene transfer. The efficiency of gene transfer will determine how successful the gene therapy application will be. Before the full potential of gene therapy can be reached, many limitations common to all methods of gene delivery must be overcome. The current lack of suitable vectors capable of transducing cells of the vasculature or of the myocardium is a major rate-limiting step, but may be overcome by increasing the specifity of gene therapy vectors. This may be achieved through the isolation of new viral serotypes that can be developed into vectors, or the creation of new vectors by the alteration of the tropism of existing ones. This thesis aimed to assess the effect of ACE2 overexpression in vivo on heart function and blood pressure. In order to achieve cardiac gene transfer, we first had to identify an efficient cardiac gene delivery vector. This was approached by the application of the two main techniques; (1) the use of phage-display identified peptides to retarget viral vectors and (2) the comparison and optimisation of rAAV6 and rAAV9 mediated gene delivery to myocardium in vivo in a rat disease model.