Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
RNAi-Mediated Gene Therapy of PBEF Reduces the Severity of Collagen-Induced Arthritis in Mice
Courties1, Gabriel, Kyburz2, Diego, Escriou3, Virginie, Scherman4, Daniel, Jorgensen5, Christian, Gay6, Steffen, Apparailly7, Florence
Inserm U844, Montpellier, France
Center of Experimental Rheumatology, University Hospital Zurich and Zurich Center of Integrative Human Physiology (ZIHP). Zurich, Switzerland
Inserm U640,CNRS, UMR8151, University Paris Descartes, ENSCP, Paris, France
Inserm U640, CNRS, UMR8151, University Paris Descartes, ENSCP, Paris, France
Inserm u844, Unite ImmunoRhumatologie Therapeutique, Montpellier, France
Ctr Exp Rheum, Univ Hosp Zurich/Zurich Ctr Integr Hum Physiol (ZIHP), Zurich, Switzerland
Inserm u844, Montpellier, France
PBEF (Pre-B cell colony-enhancing factor/visfatin) is a hormone released by adipose tissue described as a new marker of inflammation in rheumatoid arthritis (RA) with pro-inflammatory and matrix-degrading activities. We previously showed that in vitro PBEF lead to the expression of pro-inflammatory mediators (IL-6, TNF) and matrix degrading enzymes (MMPs) in synovial fibroblasts and/or monocytes. The purpose of this study was to examine the therapeutic effects of systemic delivery of anti-PBEF siRNA lipoplexes in mouse arthritis pre-clinical model.
Collagen-induced arthritis (CIA) was induced in male DBA/1 mice, and 0,5 mg/Kg small interfering (si)RNA against mouse PBEF (siPBEF) or non targeting siRNA (siCT) sequences formulated with the cationic liposome RPR209120/DOPE were injected intravenously weekly during arthritis progression. Clinical and biological features of the disease were investigated.
Systemic siPBEF delivery significantly decreased clinical disease activity scores of CIA as evidenced by paw swelling measures. Importantly, RNAi-mediated PBEF silencing significantly decreased IL-6 secretion in both sera and spleen, without altering serum anti-collagen (bCII) antibodies levels and bCII-specific T cell proliferation. Importantly, frequencies of the IFN-g- and IL-17A-producing CD4+ cells were decreased within spleen and liver, while frequency of the IL-10-producing CD4+/CD25+/Foxp3 cells was increased. Histological scores of inflammation and cartilage damage, bone erosion, and mRNA levels of pro-inflammatory cytokines and MMPs in the joints will be investigated, as well as immunohistochemical staining of PBEF in the joints.
These results provide novel evidence that systemic PBEF inhibition efficiently reduces experimental arthritis and might be proposed as novel therapeutic target for RA.
To cite this abstract, please use the following information:
Courties, Gabriel, Kyburz, Diego, Escriou, Virginie, Scherman, Daniel, Jorgensen, Christian, Gay, Steffen, et al; RNAi-Mediated Gene Therapy of PBEF Reduces the Severity of Collagen-Induced Arthritis in Mice [abstract]. Arthritis Rheum 2009;60 Suppl 10 :20