(Circulation. 1995;92:1981-1993.)
© 1995 American Heart Association, Inc.
Articles |
Antisense Therapy for Angioplasty Restenosis
Some Critical Considerations
From the Department of Pathology, University of Washington, Seattle.
Correspondence to Dr M.R. Bennett, Unit of Cardiovascular Medicine, University of Cambridge School of Clinical Medicine, Department of Medicine, Level 5, Addenbrooke's Hospital, Hills Rd, Cambridge CB2 2QQ, UK. E-mail mrb@mole.bio.cam.ac.uk.
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Introduction |
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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
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