Background Gene therapy is a promising strategy for rheumatoid arthritis. Adeno-associated virus (AAV) are recently developed vectors with unique set of characteristics like their ability to infect host cells at any time of their division cycle, and their possible weak immunogenicity in mammals. IL-4 is a Th-2 anti-inflammatory cytokine that is efficient if delivered by continuous administration in collagen-induced arthritis (CIA) in mice.
Objectives The present study was undertaken to investigate the possibility to use AAV vectors in CIA.
Methods AAV vectors, expressing lacZ (AAV-lacZ) or IL-4 (AAV-IL-4) cDNA under CMV promotor control, were produced and purified by Généthon (Evry, France). DBA/1 mice were used for all studies. After i.m. injection of 2.5 109 AAV-lacZ particles, lacZ expression was examined on tissue cryosection by X-gal staining. IL-4 transgene expression was evaluated in vivo different times after i.m. injection of AAV-IL-4 by an IL-4 ELISA on muscles lysates. LacZ quantitative expression was evaluated after i.m. injections of AAV-lacZ by X-gal colorimetric assay on muscle lysates. AAV antibodies levels were measured by a neutalizing assay. CIA was induced by immunisation with bovine type II collagen. For treatment, 1.3 1010 AAV-IL-4 were administered i.m. to mice 11 days prior to induction of CIA.
Results Peri-articular injection of AAV-lacZ showed an expression of the transgene localised in the deep muscles cells near the bone. IL-4 in vivo expression was detected at least 120 days after AAV-IL-4 injection i.m. Anti-AAV neutralising antibodies were detected in the serum after AAV-lacZ administration in vivo, but they didn’t altered the transgene expression after readministration of AAV-lacZ. CIA mice treated with AAV-IL-4 were significantly improved in comparisation to control, in terms of prevalence of the disease, arthritis scores, and histological evaluation. Locally, a slight inflammation at the point of vector injection was noted.
Conclusion AAV is a powerful vector for gene therapy in CIA. AAV IL-4 prevent the development of CIA. In addition, our data are consistent with a long term persistance of the transgene and the possibility of a readministration.
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