Abstract |
Gene therapy has been explored as a potential method for treating chronic inflammatory diseases such as rheumatoid arthritis. To determine the efficacy of intra-articular IL-4 gene therapy in an animal model of arthritis using a retroviral vector, a retrovirus encoding rat IL-4 (DA-IL-4) was engineered, purified and concentrated to high titer (>/=109 CFU/ml). Infectivity and expression levels were demonstrated in vitro using cultured fibroblast-like synoviocytes. Efficacy was evaluated in the rat adjuvant arthritis model. DA-IL-4 or DA-beta-gal retrovirus was injected into the intra-articular joint space of the right ankle on day 12 after immunization. Three days after joint injection, the injected paw contained increased levels of IL-4 compared with control or with the contralateral uninjected paw, demonstrating successful transgene expression. Surprisingly, 8 days after treatment IL-4 levels continued to increase in the injected and contralateral paw compared with DA-beta-gal-treated animals. Serum IL-4 levels were also elevated in DA-IL-4-treated rats. RT-PCR studies demonstrated that the transgene was expressed in the injected ankle but not in the contralateral joint. IL-4 gene therapy resulted in a significant reduction in paw swelling and decreased radiographic evidence of bone destruction. This is the first demonstration of successful intra-articular retroviral gene treatment using a therapeutic gene. In addition to its anti-inflammatory effect, this study supports the potential application of intra-articular gene therapy as a method for enhancing systemic Th2 function.
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Authors | D L Boyle, K H Nguyen, S Zhuang, Y Shi, J E McCormack, S Chada, G S Firestein |
Journal | Gene therapy
(Gene Ther)
Vol. 6
Issue 12
Pg. 1911-8
(Dec 1999)
ISSN: 0969-7128 [Print] England |
PMID | 10637442
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- RNA, Messenger
- Interleukin-4
- Interferon-gamma
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Topics |
- Animals
- Arthritis, Experimental
(immunology, therapy)
- Cells, Cultured
- Gene Transfer Techniques
- Genetic Therapy
(methods)
- Genetic Vectors
(administration & dosage)
- Humans
- Injections, Intra-Articular
- Interferon-gamma
(analysis)
- Interleukin-4
(administration & dosage, metabolism, therapeutic use)
- Male
- RNA, Messenger
(analysis)
- Rats
- Rats, Inbred Lew
- Retroviridae
(genetics)
- Reverse Transcriptase Polymerase Chain Reaction
- Synovial Membrane
(immunology)
- Tarsus, Animal
(immunology)
- Th2 Cells
(immunology)
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