Angiogenic gene therapy
Angiogenic gene therapy
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DOI：
10.1358/dot.2002.38.12.820100
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发表时间：
2002-12-01
期刊：
影响因子：
1.8
通讯作者：
Sylvén, C
中科院分区：
文献类型：
--
作者：
Sylvén, C
血管生成被定义为营养血管从局部预先存在的血管中生长出来，主要基于局部存在的内皮细胞的生长，暗示着一种微妙的平衡，其中刺激和抑制因素都可以影响结果。启动这一过程的主要因素是刺激内皮细胞生长的血管内皮生长因子(VEGFs)，尽管其他一些关键因素，如成纤维细胞生长因子(FGFs)、胎盘生长因子(PIGF)、血小板衍生生长因子(PDGFs)和血管生成素(Angiopoietins)必须发挥作用，使血管成熟而不恶化。就局部传递血管生成蛋白而言，存在两种可能性。一种是以缓释配方传递蛋白质。植入纤维蛋白或藻酸盐制剂，心外膜下释放成纤维细胞生长因子。另一种在一段时间内获得局部递送的方法是基因治疗，方法是局部递送携带治疗性基因的载体，或者开发仅在感兴趣器官中使用和表达的载体。利用腺病毒载体或裸质粒可获得短暂性过表达，可用于治疗缺血性心脏病。通过血管内皮生长因子基因的转染，在动物心肌缺血模型上证实了血管生成和再内皮化，为心脏治疗的原理提供了证据，并为临床试验铺平了道路。目前，约有200名患者因周围动脉闭塞性疾病或心肌缺血而接受心肌内血管内皮生长因子基因治疗。报道的不良事件很少，也没有观察到治疗后动脉粥样硬化的恶化。
Angiogenesis, which is defined as the outgrowth of nutritive vessels from locally preexisting ones, is primarily based on the outgrowth of locally present endothelial cells and implies a delicate balance where both stimulating and inhibitory factors can influence the outcome. The primary players starting the process are the vascular endothelial growth factors (VEGFs), which stimulate endothelial cell growth, although some other key factors such as fibroblast growth factors (FGFs), placental growth factors (PIGFs), platelet-derived growth factors (PDGFs) and angiopoietins must come into play for vessels to mature and not deteriorate.Two possibilities exist in terms of local delivery of the angiogenic proteins. One is the delivery of the protein in a slow-release formulation. Fibrin or alginate formulations have been implanted, subepicardially releasing FGF. Another approach to get a local delivery over a period of time is gene therapy by local delivery of the vector carrying the therapeutic gene or with the development of vectors that are taken up and expressed only in the organ of interest. A transient overexpression, desirable for the treatment of ischemic heart disease, can be achieved with adenoviral vectors or naked plasmid.With VEGF gene transfection, angiogenesis and reendothelialization were demonstrated in animal cardiac ischemia models showing proof of principle for cardiac therapy and paving the way for clinical trials. Currently, about 200 patients have been treated with intramyocardial VEGF gene therapy for peripheral occlusive artery disease or for myocardial ischemia. Reported adverse events have been few and no worsening of atherosclerosis following treatment has been observed.