明胶蛋白涂层支架携载治疗性质粒抑制小型猪冠状动脉支架置入术后再狭窄的系列研究
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摘要
经皮冠状动脉腔内成形术(PTCA)及支架置入术作为冠心病血管重建的有效方法之一，已在世界范围内得到广泛应用，但其面临的最主要问题——再狭窄并未得到完全解决。近年来药物洗脱支架在降低再狭窄方面取得了显著进展，但预测在广泛应用以后仍会有10％左右的再狭窄，基因治疗仍然可能是最终解决再狭窄的途径之一。
基因治疗再狭窄涉及到三个方面的研究：筛选有效的治疗基因：构建及改进可介导基因高效转染细胞的载体；选择安全的可精确定位于冠状动脉病变局部血管壁的机械运载系统。目前国内外的研究结果都未能达到临床应用阶段。
本课题组在基因治疗再狭窄领域的实验研究已历时八年，建立了可靠的置入过大的冠状动脉支架导致再狭窄的小型猪模型，初步筛选了人诱导型一氧化氮合酶(iNOS)基因作为治疗性基因片段，以明胶蛋白涂层支架转基因技术作为冠状动脉局部转基因治疗的载药平台并已获得美国和中国专利。本课题研究是该系列性研究的第三阶段，共包括两部分的研究内容：
第一部分 改进后的明胶蛋白涂层支架携载新构建的治疗性一氧化氮合酶质粒效能的体外量化评估研究
包括以下三个方面的研究内容：
第一节 明胶蛋白涂层支架的制备及改进
在以往已获得的技术专利基础上，我课题组分别与上海华东理工大学、上海微创公司两家单位协作，对支架明胶蛋白涂层的制备工艺、质量控制和稳定性进行改进研究，采用电脑控制的喷涂工艺以及改进交联剂的使用条件，基本解决了明胶蛋白涂层支架浸泡后、随球囊加压扩张时发生涂层脱落或撕裂的技术难题，最终可以按照标准化工艺制备Ⅰ型(华东理工大学)200ug～400ug、Ⅱ型(微创公司)200ug～800ug不同涂层厚度组的明胶蛋白涂层支架，支架涂层表面的均匀度、光洁度、顺应性、耐扩张性能均能满足临床应用的要求，为其后项目的顺利进行奠定了物质基础。
第二节 pcDNA3.1／iNOS质粒的构建、鉴定、制备
在以往的工作基础上，为开发能拥有完全自主知识产权的治疗性基因药物，我课题组采用了新的pcDNA3.1(+)哺乳动物表达载体，对治疗性iNOS(L24553)基因片
Part 1. In vitro quantitative study of absorption of pcDNA3.1/iNOS plasmid by improved gelatin-coated stent
&
Part 2. Feasibility study of tissue-membrane-covered stent as a new type of drug eluting platform in treatment of coronary restenosis
Percutaneous transluminal coronary angioplasty (PTCA) and stent implantation, as one of effective methods for coronary revascularization, has been used world wide. But the main problem of restenosis has not been fully resolved. Recently,drug eluting stent has made distinct progress in treatment of coronary restenosis, but scholars still believe that there will be 10% of restenosis remained in the future clinical practice, so gene therary may play a certain role in finally resolving the problem.
Gene therapy for preventing restenosis involves three aspects of studies: screening effective therapeutic gene, construction and improvement of vectors for mediating highly efficient transfection, and selection of mechanical local
基因治疗再狭窄涉及到三个方面的研究：筛选有效的治疗基因：构建及改进可介导基因高效转染细胞的载体；选择安全的可精确定位于冠状动脉病变局部血管壁的机械运载系统。目前国内外的研究结果都未能达到临床应用阶段。
本课题组在基因治疗再狭窄领域的实验研究已历时八年，建立了可靠的置入过大的冠状动脉支架导致再狭窄的小型猪模型，初步筛选了人诱导型一氧化氮合酶(iNOS)基因作为治疗性基因片段，以明胶蛋白涂层支架转基因技术作为冠状动脉局部转基因治疗的载药平台并已获得美国和中国专利。本课题研究是该系列性研究的第三阶段，共包括两部分的研究内容：
第一部分 改进后的明胶蛋白涂层支架携载新构建的治疗性一氧化氮合酶质粒效能的体外量化评估研究
包括以下三个方面的研究内容：
第一节 明胶蛋白涂层支架的制备及改进
在以往已获得的技术专利基础上，我课题组分别与上海华东理工大学、上海微创公司两家单位协作，对支架明胶蛋白涂层的制备工艺、质量控制和稳定性进行改进研究，采用电脑控制的喷涂工艺以及改进交联剂的使用条件，基本解决了明胶蛋白涂层支架浸泡后、随球囊加压扩张时发生涂层脱落或撕裂的技术难题，最终可以按照标准化工艺制备Ⅰ型(华东理工大学)200ug～400ug、Ⅱ型(微创公司)200ug～800ug不同涂层厚度组的明胶蛋白涂层支架，支架涂层表面的均匀度、光洁度、顺应性、耐扩张性能均能满足临床应用的要求，为其后项目的顺利进行奠定了物质基础。
第二节 pcDNA3.1／iNOS质粒的构建、鉴定、制备
在以往的工作基础上，为开发能拥有完全自主知识产权的治疗性基因药物，我课题组采用了新的pcDNA3.1(+)哺乳动物表达载体，对治疗性iNOS(L24553)基因片
Part 1. In vitro quantitative study of absorption of pcDNA3.1/iNOS plasmid by improved gelatin-coated stent
&
Part 2. Feasibility study of tissue-membrane-covered stent as a new type of drug eluting platform in treatment of coronary restenosis
Percutaneous transluminal coronary angioplasty (PTCA) and stent implantation, as one of effective methods for coronary revascularization, has been used world wide. But the main problem of restenosis has not been fully resolved. Recently,drug eluting stent has made distinct progress in treatment of coronary restenosis, but scholars still believe that there will be 10% of restenosis remained in the future clinical practice, so gene therary may play a certain role in finally resolving the problem.
Gene therapy for preventing restenosis involves three aspects of studies: screening effective therapeutic gene, construction and improvement of vectors for mediating highly efficient transfection, and selection of mechanical local
引文
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8．Genebank L09210检索结果见附录．
9．Genebank L24553检索结果见附录．
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21．袁晋青，高润霖，史瑞文，等．金属支架蛋白涂层介导血管内局部转基因．中国循环杂志．1997；12：330-333．
22．袁晋青，高润霖，史瑞文，等．猪冠状动脉腔内金属支架蛋白涂层的生物相容性研究．中国循环杂志．1998；13：271-273．
23. R Gao, J yuan, J Tang, et al. Intravascular local gene transfer mediated by??protein-coated metallic stent. JACC.1988;abstract 203c.
24. R Gao, J Yuan, R Shi, et al. Intracoronary prourokinase gene transfer with protein-coated stent decreased platelet deposition and smooth muscle cell proliferation in mini-pig. JACC. 1998; abstract 257c.
25．祁哲，高润霖，钱杰，等．外源性基因在血管球囊损伤后新生内膜中的表达．中国循环杂志．1999；14：50-51．
26．钱杰，高润霖，史瑞文，等．金属蛋白涂层支架用于小型猪冠状动脉质粒介导下转基因研究．中国循环杂志．1999；14：152-154．
27．袁晋青，高润霖，史瑞文，等．在小型猪模型由蛋白涂层支架局部转染尿激酶前体基因对冠状动脉再狭窄的影响．中华心血管病杂志．1999；p27：349-352．
28. Jun Dai, Runlin Gao, Jian Tang, et al. Local Plasmid-Mediated Human Inducible Nitric Oxide Synthase Gene Transfer with Protein-Coated Metallic Stents Inhibits Intimal Hyperplasia following Coronary Angioplasty in Mini-Swine Model. Chinese Medical Joumal.2000;113 (Suppl) :29-30.
29. Jinqing Yuan, Runlin Gao, Ruiwen Shi, et al. Decreased platelet deposition and thromboses after intracoronary local prourokinase gene transfer with protein-coated metallic stents in mini-swine model. Chinese Medical Journal. 2000; 113(Suppl):74-75.
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31．戴军，高润霖，史瑞文，等．蛋白涂层支架携带质粒介导的一氧化氮合酶基因预防冠状动脉球囊扩张后再狭窄的实验研究．中华心血管病杂志．2001；29：1-4．
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8．Genebank L09210检索结果见附录．
9．Genebank L24553检索结果见附录．
10．发明人：史瑞文，高润霖．发明名称：用于携载基因的蛋白质涂层医用载体及其制作方法．中国专利号：ZL 95 1 18371．0．
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