The New Strategy of Gene Therapy for the Patients with Pheripheral Arterial Disease

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Restenosis after angioplasty and late graft failure due to intimal hyperplasia after vein bypass surgery are the major clinical problem of angioplasty. We have previously shown that neointima formation is strikingly suppressed in midkine-deficient mice. Neointima formation is restored if midkine protein is administrated to the deficient mice. Midkine(MK) is a heparin-binding growth factor, and implicated in the migration of inflammatory cells and vascular smooth muscle cells. Here, we evaluated the potential of MK antisense oligodeoxyribonucleotide (ODN) for the prevention of restenosis. In addition, we evaluated the siRNA targeting MK strategy as a therapy for vein graft failure.1.Antisense Oligodeoxyribonucleotide as to the Growth Factor MK Suppresses Neointima Formation Induced by Balloon Injury : We cloned the cDNA of rabbit MKe. The balloon injury induced MKe expression, the maximum level occurring 7-14 days after angioplasty, in the rabbit carotid artery. The antisense ODN suppre … More ssed MK induction in vivo, and consequently suppressed neointima formation to 60% of the control level.2.Controlled Release of siRNA as to MKe Attenuates Intimal Hyperplasia in Vein Grafts : MK expression was induced and reached the maximum level 7 days afteroperation. Knockdown of the gradually increasing expression was achieved by perivascular application of siRNA using atelocollagen. Both the intima/media ratio and the intima thickness at 28 days after grafting were reduced by more than 90% by this treatment as compared with in controls. Conclusions : These results suggest that MK is a candidate molecular target for the therapy for vascular restenosis. In addition, MKe is a candidate molecular target for preventing vein graft failure.Furthermore, for clinical applications of siRNA, a single intraoperative atelocollagen-based non viral delivery method could be a reliable approach to achieve maximal function of siRNA in vivo. This strategy may be a useful and practical form of gene therapy against human vein graft failure. Less