NFκB Decoy Oligodeoxynucleotide-Based Therapy in Cardiovascular Diseases

Abstract

Gene therapy based on oligodeoxynucleotides (ODNs) offers a novel approach for the prevention and treatment of cardiovascular diseases. We focused on the regulation of powerful transcriptional factors which could be mainly involved in the process of atherosclerosis, myocardial infarction, and vascular remodeling, etc. The transcription factor nuclear factor-kappa B (NF-κB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes such as tumor necrosis factor (TNF)-α, inlerleukin-6, and ICAM-1, and we utilized ODNs as “decoy” cis-elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation. Transfection of NF-κB decoy ODNs into coronary artery effectively prevented transactivation of essential cytokine and adhesion molecule protein expression. In the myocardial infarction model of rat, transfection of NF-κB decoy decreased the infarction size induced by reperfusion injury. Transfection of NF-κB decoy ODNs into balloon-injured carotid artery or porcine coronary artery also markedly reduced neointimal formation. For the next generation of OSN-based gene therapy, we designed chimeric decoy ODNs, containing the consensus sequences 300 of both the NF-κB- and ets-binding sites, to inhibit both the transcription factors simultaneously. The covalently modified ODNs were developed by enzymatically ligating two identical molecules, thereby preventing their degradation by exonucleases. Although there are still unresolved issues, decoy ODN drugs should become a reality in the near future.