Perspectives on antisense therapy for the prevention of restenosis

One of the potential clinical applications of antisense therapy is the prevention or treatment of restenosis following coronary interventions. Inhibition of several cellular proto-oncogenes have been shown to inhibit smooth muscle cell proliferation in vitro and to reduce neointimal thickening in vivo. The clinical applicability of antisense technology, however, remains limited due to a relative lack of specificity, slow uptake across the cell membrane and rapid intracellular degradation of the oligonucleotide. The one study in humans with c-myc antisense yielded a negative result with respect to restenosis after stent implantation. Recent studies have introduced phosphorothioate morpholino oligomers (PMO), which represent an unusual DNA chemistry with a six-membered morpholino ring instead of a deoxyribose sugar. In addition, the charged phosphodiester internucleotide linkage is replaced by an uncharged phosphorothioate. The PMOs are resistant to serum nucleases found in serum and exhibit a high degree of specificity and efficacy in both in vitro and cell-free translation studies. In vivo studies in four different animal models of restenosis demonstrated significant reduction of myointimal response. The combination of enhanced efficacy and greater specificity introduced by the PMO chemistry led us to re-examine the potential efficacy of a neutrally charged c-myc antisense approach for the prevention of restenosis. Clinical studies are underway to investigate safety and efficacy of local delivery of this latest generation of antisense to reduce restenosis after coronary stenting.