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

周围动脉疾病基因治疗新策略

• 批准号: 15390375
• 负责人: KOMORI Kimihiro
• 金额: $ 9.47万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390375/
• 关键词: Midkine; Vein graft; intimal hyperplasia; gene therapy; siRNA; 血管内膜肥厚

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

血管成形术后再狭窄和静脉搭桥术后内膜增生导致的晚期移植物失败是血管成形术的主要临床问题。我们之前已经证明，在midkini缺乏的小鼠中，新内膜的形成明显受到抑制。如果给予midkine蛋白，新生内膜的形成可以恢复。Midkine（MK）是一种肝素结合生长因子，与炎症细胞和血管平滑肌细胞的迁移有关。在这里，我们评估了MK反义寡脱氧核糖核苷酸（ODN）预防再狭窄的潜力。此外，我们评估了siRNA靶向MK策略作为静脉移植失败的治疗方法。反义寡脱氧核糖核苷酸对生长因子MK抑制球囊损伤新生内膜形成的作用：克隆了兔MKe的cDNA。球囊损伤诱导兔颈动脉中MKe的表达，在血管成形术后7-14天达到最高水平。在体内，反义ODN抑制了更多的MK诱导，从而抑制了新生内膜的形成，其水平为对照组的60%。siRNA对MKe的控释减轻静脉移植物内膜增生：术后7天诱导MK表达达到最高水平。通过将siRNA应用于血管周围胶原蛋白，可以抑制逐渐增加的siRNA表达。与对照组相比，移植后28天的内膜/中膜比和内膜厚度都减少了90%以上。结论：这些结果提示MK是血管再狭窄治疗的候选分子靶点。此外，MKe是预防静脉移植失败的候选分子靶点。此外，对于siRNA的临床应用，术中单一的基于软骨组织的非病毒递送方法可能是实现siRNA在体内最大功能的可靠途径。这种策略可能是一种有用的和实用的基因治疗形式，以防止人类静脉移植失败。少

项目成果

Shoji T, Yonemitsu Y, Komori K, Tani M, Itoh H, Sata S, Shimokawa H, Hasegawa M, Sueishi K, Maehara Y: "Intramuscular Gene Transfer of FGF-2 Attenuates Regenerative Endothelial Dysfunction and Inhibits Neointimal Hyperplasia of Autologous Femoral Vein Gra

Shoji T、Yonemitsu Y、Komori K、Tani M、Itoh H、Sata S、Shimokawa H、Hasekawa M、Sueishi K、Maehara Y：“肌肉内 FGF-2 基因转移可减轻再生内皮功能障碍并抑制自体股静脉的新生内膜增生

Komori K.: "Mechanisms and Prevention of Intimal Thickening of the Autogenous Vein Grafts - Possible Involvement of Nitric oxide -"Aichi Jounal. 66. 9-19 (2003)

小森 K.：“自体静脉移植物内膜增厚的机制和预防 - 一氧化氮的可能参与 -”爱知杂志。

Hydrophilic statin suppresses vein graft intimal hyperplasia via endothelial cell-tropic Rho-kinase inhibition

• DOI: 10.1016/j.jvs.2005.05.041
• 发表时间: 2005-10-01
• 期刊: JOURNAL OF VASCULAR SURGERY
• 影响因子: 4.3
• 作者: Yamanouchi, D;Banno, H;Komori, K
• 通讯作者: Komori, K

External iliac venous aneurysm in a pregnant woman.

孕妇的髂外静脉动脉瘤。

• 发表时间: 2004
• 期刊: J Vasc Surg 40
• 作者: Banno H;Kobayashi M;Matsushita M;Nagata J;Yamanouchi D;Fujita H;Nishikimi N;Komori k
• 通讯作者: Komori k

Ex vivo electroporation as a potent new strategy for nonviral gene transfer into autologous vein grafts

离体电穿孔作为非病毒基因转移至自体静脉移植物的有效新策略

• 发表时间: 2005
• 期刊: Am J Physiol 289
• 作者: 松浦成昭;横山雄起;他;門田守人;Kajiguchi M;Fujishiro K;Takeda H;Kobayashi K;Furuyama T;Bannno H;Hayashi K;Yamaoka T
• 通讯作者: Yamaoka T