Anti-oxidant gene therapy by NF kappa B decoy oligodeoxynucleotide

Oxidative stress to cardiovascular cells induced by an interaction of multiple cytokines and adhesion molecules has been postulated to be responsible for cardiovascular disease. Since nuclear factor-kappaB (NFkappaB) also plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes, we utilized oligodeoxynucleotides (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. Indeed, transfection of NFkappaB decoy ODNs into coronary artery effectively prevented transactivation of essential cytokine and adhesion molecule protein expression, and thereby protected the myocardium from infarction. Transfection of NFkappaB decoy ODNs into balloon-injured carotid artery or porcine coronary artery markedly reduced neointimal formation. Thus, a clinical trial using NFkappaB decoy ODNs to treat restenosis was started in 2002. Recently, the therapeutic target utilizing NFkappaB decoy has been expanded to glomerulonephritis, rheumatoid arthritis, atopic dermatitis and osteoporosis. Moreover, the clinical trials to treat RA patients were initiated in 2003 and a Phase I/IIa human clinical trial using NFkappaB decoy ODNs to treat atopic dermatitis was initiated in December 2001. Topical application of NFkappaB decoy ODNs exhibited marked therapeutic effects on the facial skin condition of patients with atopic dermatitis. The covalently modified ODNs were developed by enzymatically ligating two identical molecules, thereby preventing their degradation by exonucleases. Indeed, the modified decoy ODNs possess increased nuclease resistance and are transported more efficiently into cells. Although there are still unresolved issues, decoy ODN drugs should become a reality.