Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys.
We have previously demonstrated great benefit from anti-monocyte chemoattractant protein-1 (MCP-1) gene therapy by "systemic" transfer of an N-terminal deletion mutant of human MCP-1 (called 7ND) gene into skeletal muscle for treatment of restenosis and atherosclerosis. However, recent evidence suggests that "local" gene transfer may be a clinically relevant approach. We therefore tested the hypothesis that catheter-based adenovirus-mediated anti-MCP-1 gene therapy attenuates stent-associated neointima formation. Bare metal stents were implanted in iliac arteries of cynomolgus monkeys fed a high cholesterol diet. Immediately after the stenting procedure, normal saline or recombinant adenoviral vector containing LacZ or the 7ND gene was administered locally into the stenting site through a Remedy channel-delivery catheter. Compared to saline infusion or LacZ gene transfer, 7ND gene transfer markedly reduced inflammatory changes at an early stage and attenuated neointima formation after 4 weeks. This strategy also reduced the increased production of pro-inflammatory and growth-promoting factors such platelet-derived growth factor. No systemic adverse effects of 7ND gene transfer were detected. There were no significant differences in serum cholesterol levels among the three groups. These data suggest that catheter-based adenovirus-mediated anti-MCP-1 gene therapy may be a clinically relevant and feasible strategy for treatment of in-stent restenosis.
Nakano
Kaku
K
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, Japan.
Egashira
Kensuke
K
Ohtani
Kisho
K
Zhao
Gang
G
Funakoshi
Kota
K
Ihara
Yoshiko
Y
Sunagawa
Kenji
K
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000917:Antibody Formation; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics*; D023903:Coronary Restenosis / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D008252:Macaca fascicularis; D008297:Male; D011817:Rabbits; D015607:Stents / Q000009:adverse effects*; D014162:Transfection; D017539:Tunica Intima / Q000473:pathology
C111835:CCL2 protein, human; D018932:Chemokine CCL2