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Development and Use of Gene Transfer for Treatment of Cardiovascular Disease

Abstract Gene therapy holds promise for the treatment of cardiovascular diseases for which effective pharmacological therapies are insufficient or unavailable. Recent studies have suggested that modification of current gene delivery systems combined with the use of efficacious therapeutic genes may ultimately be successful for clinical vascular gene therapy. Although certain applications such as vein‐graft failure may be best suited for short‐term transient overexpression of therapeutic genes, other disorders including human essential hypertension and atherosclerosis require sustained overexpression of genes. Hence, design and use of vector systems for delivery of genes to the required site in vivo requires careful consideration. Both viral and nonviral gene therapy vectors show low efficiency for gene transfer into vascular cells and demonstrate a lack of selectivity, as vectors have natural tropism for other cells and tissues. Recent work has focused on the design, development, and utility of vascular cell‐selective gene therapy vectors for use in distinct and diverse vascular gene therapy scenarios. Using phage display technology we have isolated small peptide ligands that mediate selective binding to either vascular endothelial cells or vascular smooth muscle cells. When engineered into either adenoviral (Ad) or adeno‐associated viral (AAV) vectors, candidate peptides enabled the virus to selectively bind to the desired cell type thus generating novel vascular cell‐selective gene transfer. As preclinical studies have highlighted both the potential for vascular gene therapy as well as defining the potential pitfalls, the development of disease‐selective gene therapeutics will increase safety and efficiency of gene therapy for future clinical use.