The development of molecular therapy using decoy oligonucleotides : for clinical applications.

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In this program, we developed a newly system, chimeric decoy strategy which regulate the activity of two transcription factors, and evaluated the possibility of novel molecular therapies for cardiovascular diseases based on atherosclerosis.1) Abdominal aortic aneurysm (AAA) is a common degenerative condition associated with aging and atherosclerosis. To develop a novel therapeutic approach, we examined the simultaneous inhibition of the transcription factors NFkB and ets, which regulate inflammation and matrix degradation, in a rabbit AAA model. Ultrasound and angiographic analysis demonstrated that treatment with chimeric decoy oligodeoxynucleotides significantly prevented the progression of elastase-induced aortic dilatation. Transfection of chimeric decoy oligodeoxynucleotides reduced the activities of MMP-2 and MMP-9 as compared to scrambled decoy oligodeoxynucleotides. Treatment with chimeric decoy oligodeoxynucleotides markedly inhibited the proteolysis of elastin as compared to … More scrambled decoy oligodeoxynucleotides. Interestingly, immunohistochemical study demonstrated that macrophage infiltration of mainly the adventitia and media was significantly inhibited by transfection of chimeric decoy oligodeoxynucleotides.2) Although autologous vein remains the commonly used conduit for bypass grafts, neointimal hyperplasia is known to be one of the major disease processes in vein graft failure. We investigated the inhibitory effect of NFkB decoy oligodeoxynucleotides (ODN) on prevention of vein graft failure in a rabbit hypercholesterolemic model. Four weeks after vein implantation, the treatment with NFkB decoy ODN significantly suppressed intimal hyperplasia. Treatment of NFkB decoy ODN significantly inhibited the recruitment of macrophages and the proliferation of vascular smooth muscle cells (VSMC), while the apoptosis in VSMC was significantly increased by NFkB decoy ODN. Moreover, transfection of chimeric decoy ODN against E2F and NFkB resulted in significantly inhibition of anastomotic intimal hyperplasia. Immunohistochemical staining revealed that chimera decoy ODN inhibited DNA synthesis and the migration of macrophages, followed by the inhibition of inflammatory changes. These findings raised the possibility of novel strategy for prevention of graft failure. Less