Local delivery of anti-monocyte chemoattractant protein-1 by gene-eluting stents attenuates in-stent stenosis in rabbits and monkeys.
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.


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.
Egashira
Kensuke
K
Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. egashira@cardiol.med.kyushu-u.ac.jp
Nakano
Kaku
K
Ohtani
Kisho
K
Funakoshi
Kouta
K
Zhao
Gang
G
Ihara
Yoshiko
Y
Koga
Jun-Ichiro
J
Kimura
Satoshi
S
Tominaga
Ryuji
R
Sunagawa
Kenji
K
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001672:Biocompatible Materials; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D003251:Constriction, Pathologic / Q000517:prevention & control; D004195:Disease Models, Animal; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007083:Iliac Artery / Q000473:pathology / Q000601:surgery*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008252:Macaca fascicularis; D008264:Macrophages / Q000473:pathology; D008297:Male; D008670:Metals; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011474:Prosthesis Design; D011817:Rabbits; D015607:Stents; D013997:Time Factors; D017539:Tunica Intima / Q000473:pathology; D014656:Vascular Surgical Procedures / Q000009:adverse effects / Q000295:instrumentation*
D001672:Biocompatible Materials; D018932:Chemokine CCL2; D008670:Metals