Gene Therapy For Cardiovascular Disease Research Articles

Oligonucleotide-based gene therapy for 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, transplant coronary vasculopathy, homozygous familial hypercholesterolemia and cystic fibrosis, for which no known effective therapy exists. Gene therapy requires efficient in vivo gene transfer technology. During the past decade, many gene transfer methods including viral transfer techniques have been developed, and some are being applied clinically in human gene therapy studies. Molecular biology and pathophysiology of the cardiovascular system have started to emerge, and the time is ripe for the introduction of gene therapy to the management of cardiovascular disorders. In this review, we have focused on the future potential of oligonucleotide-based gene therapy for the treatment of cardiovascular disease.

Transfer and expression of recombinant nitric oxide synthase genes in the cardiovascular system.

Gene therapy involves the transfer of a functional gene into host cells to correct the malfunction of a specific gene or to alleviate the symptoms of a disease. For gene transfer to the cardiovascular system, adenoviral vectors are the most efficient means of transfer. Recently, transfer and functional expression of recombinant nitrio oxide synthase (NOS) genes to cerebral and cardiovascular beds have been demonstrated both ex vivo and in vivo. Here, Alex Chen and colleagues review current progress in the field of vascular NOS gene transfer and the potential use of NOS gene therapy for a number of cardiovascular diseases. Although the feasibility of the NOS gene transfer approach has been demonstrated in animal models, currently available vectors have a number of technical and safety limitations that have to be solved before human NOS gene therapy for cardiovascular disease can be attempted.

Guidelines for Trials of Gene Therapy and Somatic Gene Therapy in Cardiovascular Disease

Use of the techniques of molecular and cellular biology to treat diseases has begun. More than 222 clinical trials have been initiated in humans1,2; many of these represent preliminary gene-marking trials and Phase I gene-replacement studies in rare and lethal diseases. The application of new somatic cell therapy and gene therapy products to various diseases, including cardiovascular disease, presents many familiar as well as some unique issues that must be addressed. There have been guidelines such as the 1991 Points to Consider for Human Somatic Cell Therapy and Gene Therapy3 as well as the establishment of statutory authority within the United States.4 However, guidelines for extending clinical trials beyond Phase I have not been developed.

Present and Future of Gene Therapy in Cardiovascular Disease

Present and Future of Gene Therapy in Cardiovascular Disease

Vascular gene transfer.

Vascular gene transfer may be useful for the treatment of several cardiovascular diseases. It can also be used as an experimental tool to test the effects of various genes in a local vascular compartment. Promising therapeutic effects have been obtained in animal models of restenosis with the transfer of vascular endothelial growth factor, nitric oxide synthase, thymidine kinase, retinoblastoma, growth arrest homeobox gene, cyclin/cyclin-dependent kinase inhibitor (p21), and hirudin genes, and antisense oligonucleotides against transcription factors or cell cycle regulatory proteins. Vascular endothelial growth factor and fibroblast growth factor gene transfers have improved blood flow and capillary development in models of ischaemic limb and myocardium. First experiences of vascular endothelial growth factor gene transfer to human peripheral arteries have also been reported. However, further developments in gene delivery techniques and gene transfer vectors will be required before a full therapeutic potential of gene therapy in cardiovascular diseases can be evaluated.

Transgenic animal models: new avenues in cardiovascular physiology.

Application of molecular genetic tools to inherited cardiovascular disorders has provided important insights into the molecular mechanisms underlying cardiomyopathies, arrhythmias, blood pressure regulation, and atherosclerosis. In addition, alteration of gene expression has been observed under common cardiovascular conditions such as cardiac hypertrophy and heart failure. Recent advances in transgenic and gene-targeting approaches allow a sophisticated manipulation of the mouse genome by gene addition, gene deletion, or gene modifications. These transgenic models enable the dissection of in vivo pathways responsible for these complex disease phenotypes. This review describes tissue-specific promoters suitable for targeting candidate genes to the cardiovascular system as well as a number of valuable transgenic animal models of blood pressure regulation, atherogenesis, defects in the coagulation system, cardiac hypertrophy, myocarditis, cardiomyopathies, and heart failure. Limitations and difficulties associated with these transgenic approaches are discussed. Animal models which may provide a basis for future gene therapy of cardiovascular diseases are introduced. Finally, methods are described to regulate the spatial and temporal expression level of a transgene, to inactivate a target gene in a tissue-specific manner, and to introduce specific mutations into the genome. These recent advances in transgenic technology are expected to have a considerable impact on cardiovascular research in the near future.

Therapeutic targets in cardiovascular disorders

The feasibility of gene therapy for cardiovascular diseases related to atherosclerosis is a topic that needs to be addressed. Most recent papers have dealt with technical aspects and feasibility and most of the genes transferred were reporter genes like those for β-galactosidase or luciferase. This may mean that the ideal vector, one that is not pathogenic or immunotolerant but is still efficient, is still not available. The results of these studies are ambiguous and it has been doubted whether the genes targeted really affect the disease. Further efforts are therefore needed to elucidate the underlying pathophysiology.

Fusigenic viral liposome for gene therapy in cardiovascular diseases.

To improve the efficiency of liposome-mediated DNA transfer as a tool for gene therapy, we have developed a fusigenic liposome vector based on principles of viral cell fusion. The fusion proteins of hemagglutinating virus of Japan (HVJ; also Sendai virus) are complexed with liposomes that encapsulate oligodeoxynucleotide or plasmid DNA. Subsequent fusion of HVJ-liposomes with plasma membranes introduces the DNA directly into the cytoplasm. In addition, a DNA-binding nuclear protein is incorporated into the HVJ-liposome particle to enhance plasmid transgene expression. The fusigenic viral liposome vector has proven to be efficient for the intracellular introduction of oligodeoxynucleotide, as well as intact genes up to 100 kbp, both in vitro and in vivo. Many animal tissues have been found to be suitable targets for fusigenic viral liposome DNA transfer. In the cardiovascular system, we have documented successful cytostatic gene therapy in models of vascular proliferative disease using antisense oligodeoxynucleotides against cell cycle genes, double-stranded oligodeoxynucleotides as "decoys" to trap the transcription factor E2F, and expression of a transgene encoding the constitutive endothelial cell form of nitric oxide synthase. Similar strategies are also effective for the genetic engineering of vein grafts and for the treatment of a mouse model of immune-mediated glomerular disease.

A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo.

An important goal of gene therapy for cardiovascular diseases and cancer is the development of effective vectors for catheter-based gene delivery. Although adenoviral vectors have proven effective for this purpose in animal models, the ability to achieve comparable gene transfer with nonviral vectors would provide potentially desirable safety and toxicity features for clinical studies. In this report, we describe the use of a new cationic DNA-liposome complex using an improved expression vector and lipid, N-(3-aminopropyl)-N, N-dimethyl-2,3-bis(dodecyloxy)-1-propaniminium bromide/dioleyl phosphatidylethanolamine (GAP-DL-RIE/DOPE) to optimize catheter-mediated gene transfer in porcine arteries. The efficiency of this vector was compared to DNA alone, DNA with a previously described cationic liposome complex, (+/-)-N-(2-hydroxyethyl)-N, N-dimethyl-2,3-bis(tetradecyloxy)-1-propanaminium bromide (DMRIE/DOPE), and a replication-defective adenoviral vector in a porcine artery gene transfer model. When used in optimal ratios, GAP-DL-RIE/DOPE liposomes provided a 15-fold higher level of gene expression in arteries compared to DNA alone or DMRIE/DOPE. Gene expression was observed in intimal and medial cells. However, when compared to adenoviral vectors (10(10) pfu/ml), gene expression following GAP-DLRIE/DOPE transfection was approximately 20-fold lower. Following intravenous injection of GAP-DLRIE/DOPE in mice, biochemical, hematological, and histopathological abnormalities were not observed. Significant improvements in the efficacy of arterial gene expression can be achieved by optimization of transfection condition with DNA-liposome complexes in vivo that may prove useful for arterial gene delivery in cardiovascular diseases and cancer.

Prospects for gene therapy in cardiovascular disease.

Prospects for gene therapy in cardiovascular disease.

Gene therapy for cardiovascular diseases.

Gene therapy offers a promising alternative for the treatment of various cardiovascular diseases. Blood vessels are among the easiest targets for gene therapy and in some pathological conditions only a temporary expression of the transfected gene will be required to achieve a beneficial biological effect. These conditions include the prevention of postangioplasty restenosis, postbypass atherosclerosis, peripheral atherosclerotic vascular disease and thrombus formation. Further developments in gene transfer vectors and gene delivery techniques are required before a full therapeutic potential or gene therapy in cardiovascular diseases can be evaluated.

Novel strategy of gene therapy in cardiovascular disease with HVJ-liposome method.

Novel strategy of gene therapy in cardiovascular disease with HVJ-liposome method.

Gene therapy for cardiovascular diseases.

Gene therapy for cardiovascular diseases.

Somatic gene therapy for cardiovascular disease: Recent advances

The recent development of several novel approaches for in vivo gene transfer into the coronary arteries and myocardium has led to new possibilities for the treatment of both acquired and inherited cardiovascular diseases. This review summarizes the current state of the art of in vivo gene transfer into the heart and coronary arteries with particular emphasis on antisense oligonucleotide-mediated suppression of gene expression in vascular smooth muscle cells, liposome-mediated gene transfer into the vasculature, and percutaneous transluminal gene transfer (PTGT) into the heart with the use of replication-defective adenoviruses.

The advent of adenovirus. Gene therapy for cardiovascular disease.

The advent of adenovirus. Gene therapy for cardiovascular disease.

Gene therapy for cardiovascular disease

Gene therapy for cardiovascular disease

Tomorrow's Gene Therapy Suggests Plenteous, Patent Cardiac Vessels

CLEARING a blocked coronary artery, ensuring that it doesn't clog up again, and engendering collateral blood vessels for extra circulatory protection may all become one simple procedure when gene therapy is applied to the human heart. This is one near-future possibility sketched by Jeffrey M. Leiden, MD, PhD, chief of cardiology, University of Chicago (Ill) Pritzker School of Medicine, at the 65th annual scientific sessions of the American Heart Association, in New Orleans, La. Somatic Gene Therapy Leiden, who is also professor of medicine and pathology, and his colleagues are among the pioneers of somatic gene therapy for cardiovascular disease. Somatic gene therapy, in which normal copies of genes are introduced into the appropriate cells of an individual to treat a specific disorder by replacing abnormal genes, can be thought of as just a new type of pharmacologic treatment. It carries none of the ethical burden of germ-line gene therapy,

Tomorrow's gene therapy suggests plenteous, patent cardiac vessels

CLEARING a blocked coronary artery, ensuring that it doesn't clog up again, and engendering collateral blood vessels for extra circulatory protection may all become one simple procedure when gene therapy is applied to the human heart. This is one near-future possibility sketched by Jeffrey M. Leiden, MD, PhD, chief of cardiology, University of Chicago (Ill) Pritzker School of Medicine, at the 65th annual scientific sessions of the American Heart Association, in New Orleans, La. <h3>Somatic Gene Therapy</h3> Leiden, who is also professor of medicine and pathology, and his colleagues are among the pioneers of somatic gene therapy for cardiovascular disease. Somatic gene therapy, in which normal copies of genes are introduced into the appropriate cells of an individual to treat a specific disorder by replacing abnormal genes, can be thought of as just a new type of pharmacologic treatment. It carries none of the ethical burden of germ-line gene therapy,