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Gene transfer has been carried out in more than 700 patients as part of over 200 registered protocols in the United States and Europe since 1989. Although success rates vary and many efficacy and safety issues remain unsolved, the potential of this alternative therapeutic method is well accepted. The lack of success of many pharmaceutical agents in reducing restenosis rates after angioplasty shown in dozens of clinical trials has encouraged the development of gene therapy as a further treatment. The introduction of special catheters for local drug delivery allows high efficacy combined with maximum safety.
Pathophysiology of restenosis
Four overlapping stages occur in the development of restenosis as described in animal models. The inflammatory and thrombotic phases begin at the time of injury and are maximal hours later. These are followed by a proliferative phase, with the highest division activity of smooth muscle cells about seven days after injury. Finally, there is matrix formation from one week onwards.1 As part of these processes, extracellular growth factors bind to cell surface receptors and can initiate the cascade required for signal transduction that leads eventually to cell division. Proto-oncogenes in the normal growth–regulatory pathway are stimulated by these factors, are transiently switched on, and, together with other cell cycle related genes, regulate cell division. Cell proliferation in restenosis may also result from a reduction in inhibitory cell cycle controlling factors.
Methods of gene transfer
PHYSICAL MEANS
Local drug delivery devices have been developed to achieve increased regional concentrations of transferred agents, including genes. The arterial wall is easily accessible with a percutaneous transluminal approach and this facilitates local therapy. If suitable drug application is performed at the time of angioplasty, no further intervention may be necessary.
MOLECULAR MEANS
The goal of gene modification in restenosis is to produce a transient and localised specific effect on certain cells and thus reduce cell proliferation …