Current Gene Therapy - Volume 4, Issue 2, 2004

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.

Acute cardiac allograft rejection is still a major complication after heart transplantation. Acute rejection usually responds to conventional immunosuppressions, however, the nonspecific nature of the immunosuppression and the toxicities of the drugs can be life threatening and may compromise the recipient's quality of life. In addition, cardiac allograft arteriosclerosis or chronic rejection limits the long-term survival of recipients. Such conditions cannot be prevented with conventional therapies. To overcome acute and chronic rejection of cardiac allograft as well as ischemia / reperfusion injury associated with organ preservation many novel approaches have been proposed. Gene transfection of the donor organ during organ preservation is an attractive method, because the transfected genes would not affect recipients and treatment could be delivered specifically to the site of inflammation. This method could be useful to prevent graft failure without systemic adverse effects. Here we shall review current advances in gene therapies to prevent and treat organ failure of transplanted allografts.

Late luminal loss after coronary angioplasty has resisted pharmacological and physical attempts at prevention for over twenty years. As a consequence of the resistance of restenosis to traditional therapeutic approaches it has become a popular target for DNA-based treatment modalities. In this review we consider what is currently known of the basic pathophysiology of restenosis and briefly outline the previous attempts to influence the long-term outcome after coronary intervention. We then discuss the animal models of vascular injury that have been used for studies of gene therapy and the vectors that have been applied to the setting of vascular gene transfer before considering the many studies in which the effects of specific gene transfer have been studied in the setting of vascular injury. These transgenes are considered in four broad groupings: those that act by the suppression of cellular proliferation in the vessel wall; those that inhibit cell migration; anti-thrombotic transgenes; and transgenes that have multiple effects within the vessel. We finally consider why, although more than eight years have passed since publication of the first studies of gene transfer to inhibit the vascular responses to endoluminal injury, little progress has been made in translating gene therapy for restenosis into the human setting. Principle reasons for the disappointingly slow clinical implementation of gene therapy for restenosis are an incomplete understanding of the vascular biology of restenosis, the difficulty of translating findings in animal models into the human setting and the technical difficulties incumbent upon localised gene delivery into coronary arteries.

Recently promising results of gene therapy clinical trials have been reported for treatment of peripheral vascular and cardiovascular diseases using various angiogenic growth factors and other therapeutic genes. Viral vector and non-viral vector systems were employed in preclinical studies and clinical trials. Adenoviral vector and naked plasmid have been used most in the clinical studies. HVJ (hemagglutinating virus of Japan or Sendai virus)-liposome vector, a hybrid non-viral vector system with fusion of inactivated HVJ virus particle and liposome, has developed and demonstrated high transfection efficiency in preclinical studies of many different disease models, including a wide range of cardiovascular disease models. However, some limitations exist in the HVJ-liposome technology, especially in the scalability of its production. Recently an innovative vector technology, HVJ envelope (HVJ-E) has been developed as a non-viral vector, consisting of HVJ envelope without its viral genome, which is eliminated by a combination of inactivation and purification steps. HVJ-E is able to enclose various molecule entities, including DNA, oligonucleotides, proteins, as single or multiple therapeutic remedies. The therapeutic molecule-included HVJ-E vector can transfect various cell types in animals and humans with high efficiency. In this review, vector technology for cardiovascular disease and the biology of HVJ-E vector technology is discussed.

Muscular dystrophies are broadly classed as skeletal muscle disease entities of genetic origin. Accordingly, the development and application of gene therapy treatment modalities has focused on skeletal muscle gene replacement. Irrespective of this generalization, most forms of dystrophy are accompanied by progressive cardiomyopathy and cardiac involvement in muscular dystrophies is now recognized as an independent risk for patient morbidity. In this review, we summarize the available murine strains most suitable for modeling the dystrophic myocardium and discuss the use of adenoviral based vector systems as the preferred gene delivery vehicle for modulating dystrophic cardiomyopathy.

HGF is a mesenchyme-derived pleiotropic factor, which regulates cell growth, cell motility, and morphogenesis of various types of cells and is thus considered a humoral mediator of epithelial-mesenchymal interactions responsible for morphogenic tissue interactions during embryonic development and organogenesis. Although HGF was originally identified as a potent mitogen for hepatocytes, it has also been identified as a member of angiogenic growth factors. Interestingly, the presence of its specific receptor, c-met, is observed in vascular cells and cardiac myocytes. In addition, among growth factors, the mitogenic action of HGF on human endothelial cells was most potent. Recent studies have demonstrated the potential application of HGF to treat cardiovascular diseases such as peripheral vascular disease, myocardial infarction and cerebrovascular disease. In this review, we will discuss a potential therapeutic strategy using HGF in cardiovascular disease.

Cardiovascular diseases are one of the main causes of mortality in Western countries. Gene therapy is emerging as a potential strategy for the treatment of cardiovascular diseases, such as peripheral arterial disease, ischemic heart disease, restenosis after angioplasty, vascular bypass graft occlusion and transplant-associated coronary artery disease. Since the initial experiments more than one decade ago, remarkable progress has been made in the field of gene transfer and human clinical trials are underway. In here we give an overview of available gene transfer strategies describing several delivery routes and currently used vectors in animal studies and clinical trials. Hereby we want to focus on new approaches including the potential combination of gene therapy with cell therapy and tissue engineering, gene silencing and recently developed techniques for targeting genes to the vascular wall and the myocardium.

Anginal symptoms due to myocardial ischemia continue to affect millions of patients despite ongoing improvements in the diagnosis and treatment of coronary artery disease. Revascularization therapy with percutaneous coronary interventions and coronary artery bypass graft surgery can be highly effective in eligible subjects, but many patients are suboptimal candidates due to various factors, which include diffuse vascular disease, poor ventricular function and failure of prior procedures. Introduction of vascular growth factors to the heart to promote angiogenesis and collateral vessel formation has emerged as an alternative strategy for the relief of myocardial ischemia in these patients. Early preclinical work demonstrated that gene transfer of fibroblast growth factor using an E1-deleted adenovirus vector via intracoronary injection could safely reverse stress-induced ischemic ventricular dysfunction with no discernible evidence of inflammatory response. The AGENT trial established that intracoronary administration of Ad5FGF-4 could be performed with reasonable safety to patients with coronary artery disease, and that a one-time dose could provide an anti-ischemic effect out to 12 weeks of evaluation. Further evaluation of the efficacy and safety of Ad5FGF-4 is now being conducted in two simultaneous multicenter, randomized, double-blind, placebo-controlled pivotal trials in the United States and the European Union, with planned enrollment of ∼1000 treated subjects. The primary efficacy variable in the trial will be changed in treadmill exercise duration at 12 weeks compared to baseline. Secondary efficacy variables include the rate of all-cause mortality and coronary events (non-fatal myocardial infarction, and unplanned hospitalization and revascularization due to myocardial ischemia) up to 1 year.