AAV-mediated bone gene therapy targeting nitric oxide synthase

点击翻译按钮获取中文摘要

Nitric oxide, a highly reactive free radical, is involved in the inflammation of bone tissues. We have shown that proinflammatry cytokines, tumor necrosis factor (TNF)-α combined with interleukin-1 (IL-1)-β, induce excessive production of nitric oxide (NO) and its cytotoxic metabolite, peroxynitrite (ONOO-) via inducible nitric oxide synthase (iNOS) in mouse osteoblasts. Among the nitric oxide synthases, inducible nitric oxide synthase (iNOS) has been considered as a potential target for gene therapy of chronic diseases including rheumatoid arthritis (RA). The recombinant adeno-associated virus (rAAV) vector offers new strategy for gene therapy, since it maintains transgene expression for alon time in vivo. AAV mediated the most effective gene expression in cells from arthritic rats. To identify the inhibitory effect of iNOS, rAAV, encoding iNOS antisense, was injected into ankle joints of arthritic rats. Compared to control animals, rAAV iNOS antisense injected rats were found to reduce paw volume, radiological and pathological scores. Thus, rAAV iNOS antisense gene therapy may be promising as a novel option in the treatment of RA.