Gene Therapy for Vaso-occlusive Disorders

血管闭塞导致微循环中的流动减弱和组织缺血，是心绞痛、心肌梗塞、移植血管病变、高血压和中风的近因。我们提出的研究计划的总体目标和综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。该计划的目标是解决在基因疗法对这类疾病的潜在益处能够充分实现之前需要解决的悬而未决的问题。研究目标如下：1.发展准确、有效的基因传递到各种相关血管结构的策略。2.研究使用不同载体和基因转移策略的基因表达的动力学特征，使得基因表达的绝对水平和持久性可以针对给定的治疗方法进行定制。3.开发一种通用策略，可用于监测临床前和临床研究中治疗性转基因的表达4.开发和优化有前景的基因治疗方法，以治疗血管闭塞性疾病。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将采用一种新型的血管支架，植入基因修饰的平滑肌细胞，将VEGF输送到冠状动脉循环中，以诱导慢性完全冠状动脉闭塞的猪模型中的血管生成。项目2将研究用于心脏同种异体移植物基因修饰的腺病毒和慢病毒载体，并将继续测试eNOS基因转移在大鼠和猪模型中控制移植后血管病变的价值。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来监测体内任何载体编码的转基因的表达。这些协同研究得到了行政/生物统计核心和已纳入项目4的矢量核心支持功能的支持。项目领导者、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议小组，拥有集体知识、经验、动力和能力，可以在本计划项目资助的背景下实现州目标。

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.