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Part 1: BASIC FOUNDATIONS OF CARDIOLOGY Chapter 8:

CARDIOVASCULAR TISSUE MODIFICATION BY GENETIC APPROACHES Authors: Elizabeth G. Nabel, Victor J. Dzau

The field of cardiovascular gene therapy had its origins in the mid-1980s as a result of rapid advances in the molecular genetics of the cardiovascular system. The cloning of genes important for the development and function of the cardiovascular system increased our understanding of the normal biology and pathology of cardiac diseases. In turn, this genetic information provided new opportunities for novel therapeutics using gene-transfer approaches.

Somatic gene transfer is the introduction of recombinant genetic material (DNA or RNA) into host cells such that gene expression within the host cell is altered to achieve a therapeutic effect. The genetic material includes eukaryotic genes (often with transcriptional regulatory elements) and RNA that encodes intracellular or secreted gene products. Vectors are used commonly to introduce the genetic material into cells (Table 8-1). These vectors include replication-incompetent viruses and biochemical substances. The genetic material can be delivered directly into vascular or myocardial cells in vivo, referred to as direct gene transfer, or into tissues, such as a venous bypass graft ex vivo that in turn is returned to the host. This latter approach is termed indirect gene transfer. Local delivery catheters are required for the introduction of vectors and cells (Fig. 8-1).

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Hydrogel Gel

Cardiovascular Gene

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Figure 8-1: Catheters for cardiovascular gene therapy. (From Nabel,95 with permission.) Table 8-1: Gene Transfer Vectors

Viral vectors Nonviral vectors

Retrovirus

Cationic liposomes

Adenovirus

Fusigenic liposomes

Adeno-associated virus

DNA plasmid vectors

This chapter reviews our current understanding of genetic therapies, including stem cell biology, for cardiovascular diseases. This discussion will examine vector systems for delivering genes, disease targets and preclinical animal models, recent results of clinical trials, and new, emerging opportunities for cell transplantation with pluripotent stem cells.

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