ANTI-ANGIOGENIC GENE THERAPY FOR RHEUMATOID ARTHRITIS

这些研究的目的是评估血管生成抑制剂血栓反应蛋白-1、血管抑制素和内皮抑制素在类风湿性关节炎基因治疗中的治疗潜力。使用慢病毒和辅助依赖腺病毒载体作为这些血管生成抑制剂的基因传递系统，我们建议开发一种关节内治疗类风湿性关节炎的方法。大量的实验和临床数据证明，类风湿关节炎的发病过程涉及诱导新生血管反应。新血管形成或血管生成的过程涉及刺激或抑制内皮细胞增殖和迁移的物质的相互作用。在类风湿关节炎等病理过程中，血管生成刺激因子的表达增加或抑制因子的产生减少会改变内皮细胞增殖的正、负输入平衡，有利于活跃的新生血管形成。我们假设，在慢性炎症期间，通过增加滑膜组织中这些血管生成抑制剂的浓度，我们可以阻止新血管的诱导并延缓疾病的进展。拟议中的实验将使我们能够：1)在慢病毒和辅助性腺病毒载体关节内给药后，优化编码血管生成抑制剂thrombospontin -1、内皮抑制素和血管抑制素的转基因的传递和表达；2)确定系统吸收的程度，并研究关节内传递的抗血管生成慢病毒和腺病毒载体的系统效应。3)确定血管生成抑制剂局部表达增加对关节炎疾病建立的体内化学预防作用；4)确定慢病毒和腺病毒介导的递送和局部抗血管生成基因的过表达抑制已建立关节炎疾病进展和血管生成的能力。开发一种有效的抗血管生成治疗类风湿性关节炎的方法，利用一种相对非侵入性的关节内基因传递策略，可能对患者的生活质量产生重大影响，并可能改善长期预后。此外，通过利用关节内途径易于进入的优势，我们预计将有可能建立高局部浓度的强效血管生成抑制剂，同时最大限度地减少与全身给药相关的潜在不良反应。

The purpose of these studies is to evaluate the therapeutic potential of the angiogenesis inhibitors thrombospondin-1, angiostatin, and endostatin, for gene therapy of rheumatoid arthritis. Using lentiviral and helper-dependent adenoviral vectors as gene delivery systems for these angiogenesis inhibitors, we propose to develop an intra-articular treatment for rheumatoid arthritis. A considerable body of experimental and clinical data has documented that the pathogenetic process in rheumatoid arthritis involves the induction of a neovascular response. The process of new blood vessel formation, or angiogenesis, involves the interaction of substances that either stimulate or inhibit endothelial cell proliferation and migration. During pathologic processes such as rheumatoid arthritis, increased expression of angiogenic stimulators or decreased production of inhibitors alters the balance of positive and negative inputs of endothelial cell proliferation in favor of active neovascularization. We hypothesize that by increasing the concentration of these angiogenesis inhibitors in the synovial tissues during chronic inflammation, we may prevent the induction of new blood vessels and retard disease progression. The proposed experiments will allow us to: 1) optimize delivery and expression of transgenes encoding the angiogenesis inhibitors thrombospondin-1, endostatin and angiostatin, following intra- articular administration of lentiviral and helper-dependent adenoviral vectors, 2) to determine the extent of systemic absorption and investigate the systemic effects of intra- articularly delivered anti-angiogenic lentiviral and adenoviral vectors, 3) to determine the in vivo chemopreventive effects of increased local expression of angiogenesis inhibitors on the establishment of arthritic disease, and 4) to determine the ability of lentiviral-and adenoviral-mediated delivery and local overexpression of anti-angiogenic genes to inhibit disease progression and angiogenesis in established arthritis. The development of an effective anti-angiogenic therapy for rheumatoid arthritis utilizing a relatively non-invasive intra- articular gene delivery strategy could have significant impact on patient quality of life, and potentially improve long-term outcome. In addition, by taking advantage of the ease of access by the intra-articular route, we anticipate that it will be possible to establish high local concentrations of potent angiogenic inhibitors while minimizing potentially adverse effects associated with systemic administration.