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Gene therapy for rheumatoid arthritis using transduction with angiogenesis inhibitory factor

使用血管生成抑制因子转导治疗类风湿性关节炎的基因疗法

基本信息

批准号：
15591067
负责人：
NAGASHIMA Masakazu
金额：
$ 1.54万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

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

风湿性关节炎（rheologicarthritis，RA）是一种以滑膜慢性炎症、滑膜细胞增殖、淋巴细胞炎症和血管翳形成为特征，导致关节软骨侵蚀和骨质破坏的疾病。RA关节内的血管生成过程中有多种血管生长因子参与。我们已经阐明，血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（b-FGF）的表达和定位在滑膜组织从RA患者，其表达水平显着高于骨关节炎。我们用抗血管生成基因治疗来研究血管生成抑制剂是否能调节血管生成和滑膜细胞的增殖。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，最初从原发性刘易斯肺癌小鼠的血清和尿液中纯化。纯化的重组血管抑素和携带血管抑素表达的载体，直到h ...更多信息已经成功地用于在各种癌症模型中抑制肿瘤生长和转移。我们建立了一个小鼠CIA模型，并研究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表达有效抑制胶原诱导的关节炎的进展。基于HIV的载体的缺点是亲本病毒对人类物种的潜在致病性。尽管重组HIV载体经过了大量的改造以提高其安全性，但其临床应用仍受到严格限制。腺相关病毒（AAV）载体是非致病性的，与其他类型的基因治疗载体相比，免疫原性较低。AAV基因组在转导的细胞中显示稳定的持久性，并实现长期的转基因表达。AAV载体能够有效地将基因转移到软骨细胞和滑膜细胞中，并且膝关节中滑膜增生和关节破坏的程度显著降低。AAV载体介导的胶原诱导关节炎的发生利用AAV载体进行抗血管生成基因治疗可能为RA的有效治疗提供新的途径。少