Percutaneous transluminal angioplasty is now a well-established and frequently performed procedure that has an initial success rate in reestablishing arterial patency of> 95%. 1 2 Although good symptomatic improvement occurs in the majority of cases, the procedure is complicated by restenosis in> 30% of cases. 3 4 Despite the apparent success of several therapeutic modalities in animal models, attempts to use pharmacological therapy to prevent restenosis in the clinical setting have not been successful. This failure has prompted research into alternative forms of intervention, including the use of antisense oligonucleotides therapeutically targeted to genes believed to be critical for the pathogenesis of restenosis.

The rationale for the use of antisense oligonucleotides to prevent restenosis is twofold. First, the prevailing view is that restenosis is the end result of a reactive proliferation of cells of the vessel wall after angioplasty. Thus, it follows that an agent that suppresses cell proliferation may suppress restenosis. Second, antisense agents have been used extensively to analyze genetic events associated with cell proliferation and the cell cycle (review in References 5 and 6). When any cell replicates, there is a characteristic sequential activation of a cascade of genes. 7 8 This cascade of gene activation is also seen as cells are induced to proliferate after arterial injury. 9 10 11 12 Because antisense agents can suppress the expression of genes associated with cell replication, the use of these agents to block cell proliferation after angioplasty is an attractive concept. Several studies have attested to the efficacy of antisense oligonucleotides directed at cell-cycle proteins in preventing neointimal formation after injury in animal models. The success of these animal studies has spawned widespread interest and enthusiasm for the use of antisense agents to prevent human restenosis. With that in mind, we review the critical issues that may determine whether or not an antisense strategy is likely to be successful in preventing human restenosis. The issues to be considered are as follows.(1) Is replication a critical step in restenosis?(2) Are antisense agents truly specific for their putative targets?(3) What factors determine the specificity and efficacy of an antisense agent?(4) Are side effects likely to be manifested as problems in clinical toxicology?