Antisense Therapy for Restenosis Following Percutaneous Coronary Interventions

Abstract

Antisense refers to a gene inactivating technology which blocks the “sense” of the genetic code (hence antisense) and prevents the normal wound healing responses that can lead to vessel obstruction or restenosis following injury.

Recent studies have focused on the use of antisense compounds to prevent recurrent vessel obstruction or restenosis following PTCA. Some antisense compounds can inhibit the cell cycle response to injury in the G-1 by blocking c-myc, a regulatory gene that is the key factor in the cascade of effects that leads to restenosis in many angioplasty patients.

Until recently, the clinical applicability of antisense technology to the problem of restenosis has been limited due to a relative lack of target specificity, slow uptake across the cell membranes, and rapid intracellular degradation of the antisense oligonucleotides. 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.

However, the recently introduced AVI-4126 (Resten-NG) belongs to a new family of molecules known as the phosphorodiamidate morpholino oligomers (PMO). These oligomers are comprised of 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, PMO are capable of binding to ribonucleic acid (RNA) in a sequence-specific fashion with sufficient avidity to be useful for the inhibition of the translation of mRNA into protein in vivo, a result commonly referred to as an antisense effect.

The most robust of the observations to date include the fact that AVI-4126 is safe and effective in reduction of restenosis in multiple species and conducted by multiple investigators. Three different methods for local and systemic delivery have been described, each with advantages and limitations. Efficacy in animal models is encouraging. Further, clinical trials with AVI-4126 indicate that the agent is very safe. The last remaining question: Will AVI-4126 find a place in the future therapeutic regimen for the prevention of restenosis remains unanswered.