Gene therapy for rheumatoid arthritis using transduction with angiogenesis inhibitory factor

类风湿关节炎(RA)是以严重的滑膜慢性炎症、滑膜细胞增殖、淋巴细胞炎和血管疙瘩形成为特征，导致关节软骨侵蚀和骨破坏。许多血管生成生长因子参与了RA关节的血管生成过程。我们明确了血管内皮生长因子(VEGF)和碱性成纤维细胞生长因子(b-FGF)在RA患者滑膜组织中的表达和定位，并且其表达水平明显高于骨关节炎患者。通过抗血管生成基因治疗，我们研究了血管生成抑制物是否调节血管生成和滑膜细胞的提供。血管抑素是一种有效的内源性抗血管生成因子，来源于纤溶酶原，最初是从Lewis肺癌小鼠的血清和尿液中提纯的。纯化的重组血管抑素及其携带血管抑素表达载体直到h…在各种肿瘤模型中，More都被成功地用于抑制肿瘤生长和转移。我们建立了一个小鼠CIA模型，并检测了含有小鼠血管抑素基因的HIV载体在治疗关节炎中的效用。HIV载体介导的血管抑素基因的表达可有效抑制胶原性关节炎的进展。基于HIV的载体的一个缺点是母体病毒对人类物种的潜在致病性。尽管对重组HIV载体进行了广泛的修饰以增加安全性，但其临床应用仍受到严格限制。与其他类型的基因治疗载体相比，腺相关病毒载体是非致病性的，免疫原性较低。AAV基因组在转导细胞中表现出稳定的持久性，并实现了转基因的长期表达。AAV载体能够有效地将基因转移到软骨细胞和滑膜细胞中，膝关节滑膜增生和关节破坏的程度明显减轻。AAV-Ang载体介导的胶原诱导性关节炎的形成可能为RA的有效治疗提供一种新的途径。较少

Rheumatoid arthritis(RA) is characterized by serious chronic inflammation in the synovium, synovial cell proliferation, lymphocyte inflammation, and pannus formation, resulting in joint cartilage erosion and bone destruction. A number of angiogenic growth factor are involved in angiogenesis process in the RA joint. We have clarified that the vascular endothelial growth factor(VEGF) and basic-fibroblast growth factor(b-FGF) are expressed and localized in synovial tissues from RA patients and that there expression level is significantly higher than that from osteoarthritis. We investigated whether angiogenic inhibitors regulated the angiogenesis and synovial cell profferation using anti-angiogenic gene therapy. Angiostain is a potent endogenous anti-angiogenic factor that is derived from plasminogen and was originally purified from the serum and urine of mice with primary Lewis lung carcinoma tumors. Purified recombinant angiostatin and vectors carrying the angiostatin expression until h … More ave both been successfully used for inhibition of tumor growth and metastasis in various cancer models. We generated a murine CIA model and examined the utility of the HIV vector containing the gene for murine angiostatin in the treatment of arthritis. HIV vector-mediated expression of angiostatin efficiently inhibits the progression of collagen-induced arthritis. A disadvantage of HIV based vectors is potential pathogenicity of parent virus for human species. Although the recombinant HIV vector was extensively modified to increase the safety, its clinical application is still strictly restricted. Adeno-associated virus(AAV) vectors are nonpathogenic and less immunogenic compared with other types of gene therapy vectors. The AAV genome shows stable persistence in transduced cells and achieves long-term transgene expression. AAV vectors were capable of efficient gene transfer into chondrocytes and synovial cells, and extent of synovial hyperplasia and joint destruction were significantly reduced in the knee joints. Reduction in the number of vessels was confirmed in AAV-Ang treated joints.AAV-vector-mediated the development of collagen-induced arthritis in the treated joint Anti-angiogenic gene therapy using AAV vector may provide a new approach for the effective treatment of RA. Less