Local application of antisense for prevention of restenosis

In 1977, percutaneous transluminal coronary angioplasty (PTCA) was first introduced, and it has become an effective treatment for limited coronary artery disease. PTCA treatment has since become more extensive and gained favor as an alternative treatment for coronary artery bypass grafting. The artery is injured at the site of PTCA, leading to wound healing responses including thrombosis, smooth muscle proliferation and migration, elastic recoil, and vascular remodeling. Each of these responses may contribute to recurrent obstruction or vessel narrowing, referred to as restenosis.The clinical applicability of antisense technology, however, has been limited due to a relative lack of target specificity, slow uptake across the cell membranes, and rapid intracellular degradation of the oligonucleotide. The only randomized study in humans with c-myc antisense demonstrated no reduction in restenosis after stent implantation when arteries were pretreated with the drug. Recently introduced, AVI-4126 belongs to a family of molecules known as the phosphorodiamidate morpholino oligomers (PMOs). These oligomers comprise (dimethylamino) phosphinylideneoxy-linked morpholino subunits. The morpholino subunits contain a heterocyclic base recognition moiety of DNA (A, C, G, T) attached to a substituted morpholine ring system. In general, PMOs are capable of binding to RNA in a sequence-specific fashion with sufficient avidity to be useful for inhibition of the translation of mRNA into protein in vivo, a result commonly referred to as an \"antisense\" effect. Although PMOs share many similarities with other substances capable of producing antisense effects, such as DNA, RNA, and their analogous oligonucleotide analogs such as the phosphorothioates, there are important differences. Most important, PMOs are uncharged and resistant to degradation under biological conditions. The combination of efficacy, potency, and lack of nonspecific activities of the PMO chemistry compelled us to reexamine the approach to antisense to c-myc for the prevention of restenosis following balloon angioplasty.