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William H. Miller, PhD, Stuart A. Nicklin, PhD, Andrew H. Baker, PhD, and Anna F. Dominiczak, PhD



Modes of Transgene Delivery

Vectors for Cardiovascular Gene Therapy

Targeted Gene Transfer

Application of Gene Transfer to Cardiovascular Disease




The cardiovascular application of gene transfer and therapy has three overlapping goals. First, it can be seen as a molecular tool to probe pathways and mechanisms that are difficult to elucidate by other means. Second, it is widely used in preclinical studies and a variety of cardiovascular disease models to find the most efficient and safe clinical applications. Lastly, it is increasingly being used in clinical trial settings, for example to attenuate restenosis and vascular graft failure in coronary and peripheral vascular disease. We provide a critical overview of all three spheres of gene therapy-related strategies in cardiovascular disease research.

Key Words: Cardiovascular disease; gene therapy; adenovirus; AAV; targeting; vascular; tropism.


A wide variety of cardiovascular pathologies are potentially amenable to treatment using gene therapy. Examples include myocardial ischemia, vein graft failure, atherosclerosis, hypercholesterolemia, peripheral ischemia, and hypertension. Gene transfer offers the potential for overexpression of candidate therapeutic genes in these conditions, with the ultimate aim of prevention, improvement, or regression of the condition.

From: Contemporary Cardiology: Cardiovascular Genomics Edited by: M. K. Raizada, et al. © Humana Press Inc., Totowa, NJ

Gene therapy has two distinct modes of use. In monogenic disorders, in which a single mutated or absent gene has been identified as being causal, the aim of gene therapy would be to insert the corrected form of the gene into the appropriate target cell type to restore normal function. A number of monogenic cardiovascular diseases have been well documented, for example, in conditions such as hypertension (1) or hypercholesterolemia (2). However, the majority of cardiovascular conditions are complex, polygenic disorders, in which environmental factors, such as diet, lifestyle, smoking, exercise, and so on also play a highly important role. In such conditions, elucidating causative genes is difficult. Therefore, the potential for gene therapy is not so much to replace malfunctioning genes in these disorders, but to offer an alternative or adjunct to conventional pharmacological approaches. Thus gene therapy may be aimed at manipulating molecular pathways that have been identified as being crucial in the pathogenesis of a disease—for example, the overexpression of antioxidant genes to combat vascular oxidative stress in hypertension.

Rapid progress has been made in gene therapy research in a number of fields, including cardiovascular disease, to the extent that a number of potential therapies are now undergoing extensive clinical trials. This has led to greater understanding of the requirements for optimal gene transfer, and it has become apparent that an idealized gene delivery system should meet a number of criteria. These include provision of efficient gene delivery, selectivity for the target tissue or cell type, nontoxicity and nonimmunogenicity, in vivo stability, and appropriate regulation of transgene expression in vivo, which may be inducible under pathophysiological conditions. Moreover, the desired vector system should be economical to construct and propagate to high titers, and possess targeting capabilities, thus allowing systemic administration directed at target tissues or show minimal dissemination after local application.

Although it is highly unlikely that any vector will ever meet all of these idealized criteria, a great deal of progress has been made toward attaining many of them. This chapter discusses the current strategies and vectors utilized for gene transfer studies and outlines the techniques used to tailor and specifically target these vectors for cardiovascular use, before describing some key cardiovascular disorders in which gene therapy research is becoming increasingly well characterized.

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