Antisense therapy for restenosis following percutaneous coronary intervention

Abstract

Recent advances in vascular gene transfer have shown potential new treatment modalities for cardiovascular disease, particularly in the treatment of vascular restenosis. The antisense approach to inhibiting gene expression involves introducing oligonucleotides complementary to mRNA into cells in order to block any one of the following processes: uncoiling of DNA, transcription of DNA, export of RNA, DNA splicing, RNA stability, or RNA translation involved in the synthesis of proteins in cellular proliferation. The approach includes the use of antisense oligonucleotides, antisense mRNA, autocatalytic ribozymes, and the insertion of a section of DNA to form a triple helix. Proof of principle has been established that inhibition of several cellular proto-oncogenes, including DNA binding protein c-myb, non-muscle myosin heavy chain, PCNA proliferating-cell nuclear antigen, platelet-derived growth factor, basic fibroblast growth factor and c-myc, inhibits smooth muscle cell proliferation in vitro and in several animal models. The first clinical study demonstrated the safety and feasibility of local delivery of antisense in the treatment and prevention of restenosis; another randomised clinical trial (AVAIL) with local delivery of c-myc morpholino compound in patients with coronary artery disease demonstrated its long-term effect on reducing neointimal formation, as well as its safety. These preliminary findings from the small cohort of patients require confirmation in a larger trial utilising more sophisticated drug-eluting technologies.