Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys
Catheter-based adenovirus-mediated anti-monocyte chemoattractant gene therapy attenuates in-stent neointima formation in cynomolgus monkeys
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DOI：
10.1016/j.atherosclerosis.2006.10.029
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发表时间：
2007-10-01
期刊：
影响因子：
5.3
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Nakano, Kaku;Egashira, Kensuke;Sunagawa, Kenji
我们以前已经证明了抗单核细胞趋化蛋白-1（MCP- 1）基因治疗的巨大益处，即通过将人MCP-1基因的N-末端缺失突变体（称为7 ND）“全身性”转移到骨骼肌中来治疗再狭窄和动脉粥样硬化。然而，最近的证据表明，“局部”基因转移可能是一种临床相关的方法。因此，我们测试了基于导管的腺病毒介导的抗MCP-1基因治疗减弱支架相关的新生内膜形成的假设。裸金属支架植入高胆固醇饮食的食蟹猴髂动脉。在支架植入术后，立即通过Remedy通道递送导管将生理盐水或含有LacZ或7 ND基因的重组腺病毒载体局部施用到支架植入部位。与生理盐水灌注或LacZ基因转移相比，7 ND基因转移在早期阶段显著减少炎症变化，并在4周后减弱新生内膜形成。这种策略也减少了促炎和促生长因子如血小板衍生生长因子的产生。未检测到7 ND基因转移的全身不良反应。三组间血清胆固醇水平无显著差异，提示导管介导的抗MCP-1基因治疗可能是治疗支架内再狭窄的临床相关和可行的策略。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
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-infiammatory 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. (c) 2006 Elsevier Ireland Ltd. All rights reserved.