GENE THERAPY OF CORONARY ARTERY DISEASE

基因治疗可能是一种新的治疗方法， 心肌缺血 该研究项目旨在开发 腺病毒载体转移内皮细胞生长的cDNA 进入心脏细胞。 将使用相同的腺病毒载体 两个不同的研究：（1）血管生成和改善 冠状动脉侧支循环：预计新血管形成 改善心肌缺血区域的血流。 本研究 腺病毒载体将被注射到冠状循环中 或直接进入心肌。 (2)血管成形术后恢复： 快速再内皮化的一段冠状动脉， 在血管成形术期间经历内皮剥脱的患者， 降低再狭窄和内膜增生的严重程度。 为此 研究腺病毒载体将被递送到局部区域 冠状动脉球囊扩张术后 我们有 构建了携带以下cDNA的腺病毒载体 血管生成生长因子(1)血管内皮生长因子 （VEGF）。 (2)酸性成纤维细胞生长因子（aFGF）。 (3)的重组 aFGF的一种形式，其已通过添加分泌型 FGF-4信号序列（sp-aFGF）。 与aFGF的天然形式不同， 这种重组形式的aFGF被分泌到细胞外空间中。 我们的初步研究表明，所有三种腺病毒载体都产生一种 能够诱导内皮细胞生长的功能性蛋白质， 体外分化。 在另外的研究中， 携带报告基因lacZ的cDNA的载体（AdRSV.lacZ） 我们已经研究了腺病毒载体是否能使心肌细胞增殖， 在小型猪身上。 我们发现，冠状动脉内注射Ad RSV.lacZ转导内皮细胞、血管平滑肌细胞和 心肌细胞 心肌内注射AdRSV.lacZ 主要转导心肌细胞。 目前正在进行研究， 进一步表征携带cDNA的载体的性质， 对于血管生成因子，在其用于体内模型之前， 心肌缺血和血管成形术后再狭窄。

Gene therapy may represent a novel approach for the treatment of myocardial ischemia. This research project aims at developing adenoviral vectors to transfer the cDNA for endothelial cell growth factors into cardiac cells. The same adenoviral vectors will be used for two different studies: (1) Angiogenesis and improvement of coronary collateral circulation: Neovascularization is expected to improve blood flow to ischemic areas of the myocardium. For this study the adenoviral vectors will be injected into the coronary circulation or directly into the myocardium. (2) Restenosis after angioplasty: Rapid reendothelialization of a segment of coronary artery which has undergone endothelial denudation during angioplasty may be expected to decrease the severity of restenosis and intimal hyperplasia. For this study the adenoviral vectors will be delivered to the localized area of the coronary artery which has undergone balloon dilatation. We have constructed adenoviral vectors which carry the cDNA for the following angiogenic growth factors. (1) Vascular endothelial growth factor (VEGF). (2) Acidic fibroblast growth factor (aFGF). (3) A recombinant form of aFGF which has been modified with the addition of the secretory signal sequence from FGF-4 (sp-aFGF). Unlike the natural form of aFGF this recombinant form of aFGF is secreted into the extracellular space. Our initial studies show all three adenoviral vectors produce a functional protein capable of inducing endothelial cell growth and differentiation in vitro. In additional studies with an adenoviral vector which carries the cDNA for the reporter gene lacZ (AdRSV.lacZ) we have examined whether adenoviral vectors can transduce cardiac cells in the minipigs. We have found that intracoronary injection of Ad RSV.lacZ transduces endothelial cells, vascular smooth muscle cells and myocardial cells. In contrast, intramyocardial injection of AdRSV.lacZ transduces mostly myocardial cells. Studies are now in progress to further characterize the properties of the vectors which carry the cDNA for the angiogenic factors prior to their use in in vivo models of myocardial ischemia and restenosis after angioplasty.