Preface [Hot Topic: Recent Progress in Cardiovascular Gene Therapy;Emerging to Real Drug? (Guest Editor: Ryuichi Morishita)]

Recent progress in molecular and cellular biology has developed numerous effective cardiovascular drugs. However, there are still number of diseases for which no known effective therapy exists, such as peripheral arterial disease, ischemic heart disease, restenosis after angioplasty, vascular bypass graft occlusion and transplant coronary vasculopathy. Currently, gene therapy is emerging as a potential strategy for the cardiovascular disease to treat such diseases despite of its limitation. The first human trial in cardiovascular disease has started in 1994 to treat peripheral vascular disease using vascular endothelial growth factor (VEGF). In addition, therapeutic angiogenesis using VEGF gene was applied to treat ischemic heart disease from 1997. The results from these clinical trials seem to exceed expectation. Improvement of clinical symptoms in peripheral arterial disease and ischemic heart disease has been reported. Many different potent angiogenic growth factors have been tested in clinical trials to treat peripheral arterial disease or ischemic heart disease. Somatic gene therapy consists of the introduction of normal genes into the somatic cells of patients to correct an inherited or acquired disorder through the synthesis of specific gene products in vivo. In general, there are three methods of gene modification: 1) gene replacement, 2) gene correction, and 3) gene augmentation. Gene augmentation is the most promising technique for the modification of targeted cells in therapy for cardiovascular disease. For this purpose, many in vivo gene transfer methods have been developed. In vivo gene transfer techniques for cardiovascular applications include 1) viral gene transfer: retrovirus, adenovirus, or adeno-associated virus (AAV) etc., 2) non-viral gene transfer: cationic liposomes or HVJ (Hemagglutinating Virus of Japan: Sendai virus)-liposome etc., and 3) naked plasmid DNA transfer. These in vivo gene transfer techniques have different advantages and disadvantages. Although current in vivo methods for cardiovascular gene transfer are still limited by the lack of efficiency and potential toxicity, recent advances in in vivo gene transfer may provide the opportunity to treat cardiovascular diseases such as peripheral arterial disease by manipulating angiogenic growth factor genes. Although gene therapy drug has not yet been used in clinical pharmaceutical, comparison of gene therapy versus pharmacotherapy might be considered. The present promising gene therapy is mainly local administrated agents, while most of the pharmacotherapy is based on oral drugs. To consider the advantage of gene therapy, one might compare the recombinant therapy, since both concepts are relatively closed. The advantages of gene therapy are several lines as followed: 1) It has the potential to maintain an optimally high and local concentration over time. This issue may be critical in the case of arterial gene therapy. However, on the case of therapeutic angiogenesis as discussed in this special issue, it may be preferable to deliver a lower dose over a period of several days or more from an actively expressed transgene in the iliac artery, rather than a single or multiple bolus doses of recombinant protein, to avoid side effect. 2) Regarding economics, which therapy would ultimately cost more to develop, implement, and reimburse, particularly for those indications requiring multiple or even protracted treatment, needs to be considered. 3) The feasibility of a clinical trial of recombinant protein is currently limited by the lack of approved or available quantities of human quality grade of recombinant protein, due in large part to the nearly prohibitive cost of scaling up from research grade to human quality recombinant protein. In contrast, gene therapy also has the disadvantages such as safety aspects, and local and limited effects. This special issue of Current Gene Therapy has been conceived to cover recent and successful cardiovascular gene therapy as well as more recent developed gene transfer methodologies. Its aim is not to exhaustively review the past, but rather to present the present and future state of cardiovascular gene therapy in order to open new horizons and help research to successfully achieve real pharmaceutical drugs. Hopefully, the first gene therapy drug in cardiovascular field will be launched until 2006.