2004 Fiscal Year Final Research Report Summary
Gene therapy for rheumatoid arthritis using transduction with angiogenesis inhibitory factor
| Project/Area Number |
15591067
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
膠原病・アレルギー・感染症内科学
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| Research Institution | Nippon Medical School |
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Principal Investigator |
NAGASHIMA Masakazu Nippon Medical School, Joint Disease and Rheumatism, Associate Professor, 医学部, 助教授 (20256952)
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| Co-Investigator(Kenkyū-buntansha) |
TAKANASHI Hioshi Nippon Medical School, Joint Disease and Rheumatism, assistant, 医学部, 助手 (00277534)
SHIMADA Takashi Nippon Medical School, Biochemistry and Molecular Biology, Professor, 大学院・医学研究科, 教授 (20125074)
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| Project Period (FY) |
2003 – 2004
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| Keywords | rheumatoid arthritis / collagen-induced arthritis mice / gene therapy / angiogenic inhibitory factor / angiostatin / adeno-associated virus / human immunodeficiency virus |
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| Research Abstract |
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
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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
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