Defining gene transfer before expecting gene therapy: putting the horse before the cart.

The remarkable advances in our understanding of the molecular and biochemical bases for disease during the past decade, in conjunction with the “genomic revolution,” have generated understandable enthusiasm for the development of genetic therapies. Whereas the initial hope was that gene therapy would aid in the treatment of patients with primary genetic disorders, applications have now been expanded to populations with diseases in which acquired environmental and other factors play a major pathogenic role. Research into gene transfer techniques as potential therapeutic strategies for cardiovascular disease began in the early 1980s and has been translated into phase I and, more recently, phase II and III clinical trials. Currently, 46 of 509 ongoing clinical gene transfer trials are investigating cardiovascular diseases.1 The majority of gene therapy trials and studies in cardiovascular disease are aimed at testing the safety and efficacy of therapeutic angiogenesis, and to a lesser extent, examining restenosis after vascular intervention. At this juncture, at a time of justifiable excitement and intense interest in the role of gene therapy in cardiovascular disease, it is perhaps opportune to critically review what we have learned and to discuss what directions should be taken in the near future. Gene transfer is, after all, a system of drug delivery that uses complex and potentially toxic biochemicals. Nonetheless, the emphasis of current clinical trials has been on developing individual gene transfer “products” as therapeutic agents, as opposed to focusing on the core components of gene therapy—namely, gene transfer and transgene expression. Although these clinical studies are generating important data on the feasibility and safety of individual gene transfer products, there needs to be a redirection toward the growing need to enhance our understanding of the underpinnings of human gene transfer. Even though defining vector distribution and transgene expression and function have been essential parts of preclinical studies, these same parameters have not been adequately addressed in current clinical studies. Thus, the lack of human pharmacokinetic and pharmacodynamic data will eventually limit the effective application of gene transfer in the treatment of cardiovascular disease. Opportunities to obtain the necessary data will require cooperation, perseverance, and imagination within the cardiovascular gene transfer community. Nonetheless, the acquisition of such data is the foundation on which future clinical studies could flourish or flounder.