Lessons from human arteries: how to design a gene therapy strategy for treatment of cardiovascular disease.

Gene therapy is emerging as a potential strategy for the treatment of cardiovascular disease, such as restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy, for which no known effective therapy exists. The first federally approved human gene therapy protocol started on September 14, 1990, in adenosine deaminase–deficienct patients. Eight years since the commencement of the first trial, .250 clinical studies of gene therapy are under investigation. In the cardiovascular field, .5 protocols have been approved. More recently, Isner and colleagues have demonstrated the utility of gene therapy using an angiogenic growth factor (vascular endothelial growth factor [VEGF]) for the treatment of critical limb ischemia in human patients. A reendothelialization strategy using the VEGF gene has also been tested in a clinical trial for the treatment of restenosis after angioplasty. The objectives were generally to evaluate (1) the in vivo efficacy of the gene transfer method, (2) the safety of the gene transfer method, and (3) the possible therapeutic efficacy. Although there are still many unresolved issues, human gene therapy for cardiovascular disease is now becoming a reality. Nevertheless, gene therapy still requires efficient in vivo gene transfer technology to achieve the final goal. During the past decade, many gene transfer methods, including viral transfer techniques such as the adenoviral method, have been developed, and some are being applied clinically in human gene therapy studies. In addition to these issues, it is time to take a hard look at practical issues that will determine the real clinical potential. These include (1) further innovations in gene transfer methods, (2) well-defined disease targets, (3) cell-specific targeting strategies, and (4) effective and safe delivery systems. However, it is difficult to address these issues in regard to human blood vessels despite its necessity. Thus, investigators have used animal models to test their hypotheses in relation to human clinical therapy. Although there are numerous reports of successful treatment of cardiovascular disease using gene therapy strategies in animal models, possible differences between animal experiments and real therapy in human subjects still exist as follows: (1) Can significant gene transfer be accomplished with human blood vessels? (2) Is there a difference between normal and atherosclerotic vessels in susceptibility to gene transfer? (3) What cell types can be readily infected in normal versus atherosclerotic vessels? (4) Do anatomic barriers (eg, endothelial cells and extracellular matrix) influence the transfection efficiency in atherosclerotic plaques?