Developmental Clinical Studies - Gene Therapy For Vein Graft Failure

Failure rates for heart bypass grafts using veins remain very high and represent a major clinical problem that lacks a drug-based treatment. Our prior studies have demonstrated the unique ability of gene therapy (the use of a patient s genes to treat the disease) to prevent the vein getting blocked which is associated with graft failure. We wish to perform a clinical trial in patients undergoing bypass grafting and assess the safety and beneficial effect of gene therapy.

Our clinical trial application is based on a gene therapy approach for prevention of vein graft failure. The long term failure of bypass grafting using autologous saphenous vein remains a major clinical burden on the NHS. Preventing neointima formation in the immediate time points post-grafting is likely to have a major impact on the frequency of long term graft failure. We have developed a gene therapy approach using a replication-defective adenovirus vector that overexpresses the therapeutic gene ?tissue inhibitor of metalloproteinases-3 (TIMP-3)? that significantly attenuates neointima formation in human saphenous vein ex vivo and pig vein grafts in vivo. We propose a phase I/II clinical trial to assess the safety and efficacy of this approach in patients undergoing elective coronary bypass graft surgery. This first-in-man ex vivo approach maximises target vascular gene transfer while minimising systemic vector dissemination post-grafting. Our trial is designed with key milestones with firm efficacy endpoints.