Molecular Immunology Unit, UCL Institute of Child Health, University College London, London, UK.
Gene Ther. 2013 Oct;20(10):979-86. doi: 10.1038/gt.2013.20. Epub 2013 May 2.
Vein graft failure caused by neointimal hyperplasia (IH) after coronary artery bypass grafting with saphenous veins is a major clinical problem. The lack of safe and efficient vectors for vascular gene transfer has significantly hindered progress in this field. We have developed a Receptor-Targeted Nanocomplex (RTN) vector system for this purpose and assessed its therapeutic efficacy in a rabbit vein graft model of bypass grafting. Adventitial delivery of β-Galactosidase showed widespread transfection throughout the vein wall on day 7, estimated at about 10% of cells in the adventitia and media. Vein grafts were then transfected with a plasmid encoding inducible nitric oxide synthase (iNOS) and engrafted into the carotid artery. Fluorescent immunohistochemistry analysis of samples from rabbits killed at 7 days after surgery showed that mostly endothelial cells and macrophages were transfected. Morphometric analysis of vein graft samples from the 28-day groups showed approximately a 50% reduction of neointimal thickness and 64% reduction of neointimal area in the iNOS-treated group compared with the surgery control groups. This study demonstrates efficacy of iNOS gene delivery by the RTN formulation in reducing IH in the rabbit model of vein graft disease.
静脉移植物失败导致的血管内再狭窄（IH）是冠状动脉旁路移植术后的主要临床问题。由于缺乏安全有效的血管基因转移载体，这一领域的进展受到了显著阻碍。我们为此开发了一种受体靶向纳米复合物（RTN）载体系统，并在兔静脉旁路移植模型中评估了其治疗效果。β-半乳糖苷酶的外膜给药在第 7 天显示出整个静脉壁的广泛转染，估计外膜和中膜的细胞约占 10%。然后，用编码诱导型一氧化氮合酶（iNOS）的质粒转染静脉移植物，并移植到颈动脉中。手术后 7 天处死的兔子样本的荧光免疫组织化学分析显示，大多数转染的是内皮细胞和巨噬细胞。28 天组的静脉移植物样本的形态计量学分析显示，与手术对照组相比，iNOS 治疗组的新生内膜厚度减少约 50%，新生内膜面积减少 64%。这项研究证明了 RTN 制剂在减少兔静脉移植物疾病模型中 IH 方面的 iNOS 基因传递的有效性。
