Abstract
RNA interference, mediated by small interfering RNA (siRNA), is effective in silencing genes with a high degree of specificity. To explore the therapeutic potential of systemically administered siRNA for rheumatoid arthritis (RA), we tested the complex of siRNA and the recently developed wrapsome (siRNA/WS) containing siRNA-encapsulated liposome in mice with collagen-induced arthritis (CIA). Mice with CIA received an intravenous injection of Cy5-labeled siRNA/WS. Fluorescence stereoscopic microscopy and flow cytometry were used to assess the siRNA/WS tissue distribution. The efficacy of siRNA-targeting tumor necrosis factor (TNF)-α/WS in CIA was evaluated by arthritis score. TNF-α mRNA levels in the joints were measured by real-time reverse transcriptase-polymerase chain reaction. The intensity of Cy5 fluorescence was higher in arthritic joints than in nonarthritic sites in Cy5-siRNA/WS-treated mice and remained higher up to 48 h after injection, compared with that in naked Cy5-siRNA-treated mice. Cy5 fluorescence intensity was higher in synovial cells than in splenocytes, bone marrow cells, and peripheral blood leukocytes. The majority of Cy5-positive synovial cells were CD11b+ with only a few CD3+ cells. Treatment with TNF-α siRNA/WS resulted in significant decreases in severity of arthritis and TNF-α mRNA level in the joints compared with control siRNA/WS. In conclusion, the use of our WS allowed efficient and targeted delivery of siRNAs to arthritic joints. The siRNA/WS was mainly incorporated into CD11b+ cells, including macrophages and neutrophils, in the inflamed synovium, suggesting its potential therapeutic effects in RA by silencing the expression of inflammatory molecules produced by these cells.
Footnotes
This work was supported in part by the Ministry of Health, Labor and Welfare; the Ministry of Education, Culture, Sports, Science and Technology, Japan; and the Japanese Ministry of Education, Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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ABBREVIATIONS:
- siRNA
- small interfering RNA
- RA
- rheumatoid arthritis
- WS
- wrapsome
- TNF-α
- tumor necrosis factor-α
- CIA
- collagen-induced arthritis
- mAb
- monoclonal antibody
- RT
- reverse transcriptase
- PCR
- polymerase chain reaction
- MFI
- mean fluorescence intensity
- IL
- interleukin.
- Received July 13, 2011.
- Accepted October 11, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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