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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2563.)
© 2007 American Heart Association, Inc.

Vascular Biology

Local Delivery of Anti-Monocyte Chemoattractant Protein-1 by Gene-Eluting Stents Attenuates In-Stent Stenosis in Rabbits and Monkeys

Kensuke Egashira; Kaku Nakano; Kisho Ohtani; Kouta Funakoshi; Gang Zhao; Yoshiko Ihara; Jun-ichiro Koga; Satoshi Kimura; Ryuji Tominaga; Kenji Sunagawa

From the Department of Cardiovascular Medicine (K.E., K.N., K.O., K.F., Y.I., J.K., K.S.) and Surgery (S.K., R.T.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and the Department of Cardiovascular Medicine (G.Z.), Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China.

Correspondence to Kensuke Egashira, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Objective— We have previously shown that the intramuscular transfer of the anti–monocyte chemoattractant protein-1 (MCP-1) gene (called 7ND) is able to prevent experimental restenosis. The aim of this study was to determine the in vivo efficacy and safety of local delivery of 7ND gene via the gene-eluting stent in reducing in-stent neointima formation in rabbits and in cynomolgus monkeys.

Methods and Results— We here found that in vitro, 7ND effectively inhibited the chemotaxis of mononuclear leukocytes and also inhibited the proliferation/migration of vascular smooth muscle cells. We then coated stents with a biocompatible polymer containing a plasmid bearing the 7ND gene, and deployed these stents in the iliac arteries of rabbits and monkeys. 7ND gene-eluting stents attenuated stent-associated monocyte infiltration and neointima formation after one month in rabbits, and showed long-term inhibitory effects on neointima formation when assessments were carried out at 1, 3, and 6 months in monkeys.

Conclusions— Strategy of inhibiting the action of MCP-1 with a 7ND gene-eluting stent reduced in-stent neointima formation with no evidence of adverse effects in rabbits and monkeys. The 7ND gene-eluting stent could be a promising therapy for treatment of restenosis in humans.

We created stents coated with 7ND gene, which attenuated stent-associated monocyte infiltration and neointima formation in rabbits, and showed long-term inhibitory effects on neointima formation in monkeys. No adverse effects of 7ND-eluting stent were noted. Therefore, 7ND gene-eluting stent might be useful for treatment of restenosis in humans.

Key Words: restenosis • inflammation • leukocytes • stents • smooth muscle cells

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