Targeting Transforming Growth Factor-beta signalling in the vasculature: a novel gene therapy approach

Coronary heart disease (CHD) is a leading cause of death in the UK, incurring an annual cost of £9bn to the economy. People suffering from CHD can be treated using heart bypass surgery, which relieves blockages in their coronary arteries. Approximately 90% of bypass surgeries involve the use of the patient’s own saphenous veins (in excess of 1 million operations worldwide/annum). However almost half of these vein grafts fail in the long term, resulting in risky and costly repeat interventions. The main cause of saphenous vein graft failure is the development of an occlusive neointima, which leads to blockage of the bypass graft.

Transforming growth factor-beta (TGFß) drives neointima formation and represents a promising target for gene therapy. However, TGFß regulates many important processes in the body by activating several signalling pathways, which means that a selective approach to modulate TGFß is essential. Gene therapy involves the delivery of therapeutic genes to diseased cells and tissues, primarily using modified viruses as delivery vehicles. This proposal will use a novel adenoviral gene therapy vector platform to identify exactly how TGFß drives neointima formation, by altering TGFß signalling specifically in vascular smooth muscle cells. This strategy could be used to treat many vascular pathologies driven by TGFß, including heart bypass graft failure.