Gene Therapy for Vaso-occlusive Disorders

血管闭塞导致微循环血流减弱和组织缺血，是心绞痛、心肌梗死、移植血管病变、高血压和中风的直接原因。我们提出的研究计划的总体目标和整合主题是开发有效的基因治疗方法来治疗血管闭塞性疾病。该计划的目标是处理在基因th3Rapy对这类疾病的潜在好处完全实现之前需要解决的未决问题。目标如下：1.开发准确、高效地将基因输送到各种相关血管结构的策略。2.研究不同载体和基因转移策略下基因表达的动力学特征，使基因表达的绝对水平和持久性能够适应特定的治疗方法。3.开发可用于在临床前和临床研究中监测治疗性转基因表达的通用策略4.开发和优化治疗血管闭塞性疾病的有前途的基因治疗方法。该方案包括四个相辅相成的项目，在核心设施的支持下，这些项目将共同实现整个方案的目标。项目1将使用一种新型的血管支架，种植转基因的血管平滑肌细胞，将血管内皮生长因子输送到冠状动脉循环中，以诱导猪慢性完全冠状动脉闭塞模型的血管生成。项目2将研究腺病毒和慢病毒载体用于同种异体心脏移植的遗传修饰，并将继续测试eNOS基因转移在控制大鼠和猪移植后血管病变方面的价值。项目3将使用腺病毒载体转移血红素蛛网膜下腔出血。项目4将开发一种普遍适用的策略，在体内监测任何载体编码的转基因的表达。这些协同研究得到了行政/生物统计学核心和已纳入项目4的载体核心支持功能的支持。项目领导人、合作者、联合董事和内部咨询委员会成员共同组成了一个高度互动的合作小组，他们拥有共同的知识、经验、动机和能力，能够在本计划项目拨款的背景下实现国家目标。

Vascular occlusion, leading to attenuated flow in the microcirculation and tissue ischemia, is the proximate cause of angina, myocardial infarction, transplant vasculopathy, hypertension and stroke. The overall goal and integrating theme of our proposed Program of research is to develop effective gene therapy approaches for the treatment of vaso-occlusive disorders. The objectives of the Program deal with the outstanding issues that will need to be addressed before the potential benefits of gene th3rapy for this group of disorders can be fully realized. The objectives are as follows: 1. To develop strategies for accurate, efficient gene delivery to various relevant vascular structures. 2. To study the kinetic profiles of gene expression using different vectors and gen transfer strategies such that absolute level and durability of gene expression can be tailored to a given therapeutic approach. 3. To develop a generic strategy that can be used to monitor the expression of therapeutic transgenes in preclinical and clinical studies 4. To develop and optimize promising gene therapy approaches to the treatment of vaso-occlusive diseases. The program comprises four mutually reinforcing projects which, with core facility support, will collective address the objectives of the overall Program. Project 1 will employ a novel vascular stent seeded with genetically modified smooth muscle cells to deliver VEGF into the coronary circulation to induce angiogenesis in a porcine model of chronic total coronary occlusion. Project 2 will study adenoviral and lentiviral vectors for genetic modification of cardiac allotransplants and will go on to test the value of eNOS gene transfer for the control of post-transplant vasculopathy in rat and porcine models. Project 3 will use adenoviral vectors to transfer heme subarachnoid hemorrhage. Project 4 will develop a generally applicable strategy to monitor in vivo the expression of any vector encoded transgene. These synergistic studies are supported by an Administrative/Biostatistics Core and by a Vector Core support function that has been incorporated into Project 4. Together, the project leaders, collaborators, co-directors and members of the Internal Advisory Board have formed a highly interactive, collegial group with the collective knowledge, experience, motivation, and ability to address the state objectives in the context of this Program Project Grant.