Comparison of anti-rheumatic effects of local RNAi-based therapy in collagen induced arthritis rats using various cytokine genes as molecular targets
Comparison of anti-rheumatic effects of local RNAi-based therapy in collagen induced arthritis rats using various cytokine genes as molecular targets
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DOI：
10.3109/s10165-008-0131-3
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发表时间：
2009-04
影响因子：
2.2
通讯作者：
A. Inoue;Kenji A. Takahashi;O. Mazda;Y. Arai;M. Saito;T. Kishida;M. Shin-Ya;T. Morihara;H. Tonomura;K. Sakao;J. Imanishi;T. Kubo
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文献类型：
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作者：
A. Inoue;Kenji A. Takahashi;O. Mazda;Y. Arai;M. Saito;T. Kishida;M. Shin-Ya;T. Morihara;H. Tonomura;K. Sakao;J. Imanishi;T. Kubo
RNA干扰（RNAi）提供了一种强有力的序列特异性基因沉默手段。多项研究表明，RNA干扰可能通过抑制体内疾病相关基因来提供治疗人类疾病的有希望的策略。在运动性疾病中，胶原诱导的关节炎（CIA）的进展被递送到关节中的肿瘤坏死因子-α（TNF-α）特异性小干扰RNA（siRNA）抑制。本研究的目的是比较关节内给予靶向TNF-α、白细胞介素-1 β（IL-1β）、白细胞介素-6（IL-6）和NF-κB受体激活因子配体（RANKL）的siRNA对大鼠CIA的影响。我们证实了siRNA双链体在体外对大鼠TNF-α、IL-1β、IL-6和RANKL的特异性沉默作用。在用胶原免疫后7、10、13和16天，通过体内电穿孔方法将每种siRNA递送到CIA大鼠的膝关节中。局部递送TNF-α或IL-1β特异性siRNA在大体形态学、放射学和组织学评估中有效地改善了大鼠中的CIA。提示TNF-α和IL-1β是治疗类风湿关节炎的关节靶向细胞因子。体内siRNA转染方法可用于选择待沉默的靶分子以治疗关节疾病。
RNA interference (RNAi) provides a powerful means of sequence-specific gene silencing. Several studies show that RNAi may provide promising strategies to treat human diseases by suppressing disease responsible genes in vivo. In locomotor diseases, the progression of collagen-induced arthritis (CIA) is suppressed by tumor necrosis factor-α (TNF-α)-specific small interfering RNA (siRNA) delivered into the joint. The aim of this study, is to compare the effects of intraarticularly administered siRNAs targeting TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6) and receptor activator of NF-κB ligand (RANKL) on CIA in rats. We confirmed that the silencing effects of siRNA duplexes specific for rat TNF-α, IL-1β, IL-6 and RANKL in vitro. Each siRNA was also delivered into the knee joint of CIA rats by the in vivo electroporation method 7, 10, 13 and 16 days after immunization with collagen. Local delivery of TNF-α or IL-1β-specific siRNA ameliorated CIA in rats effectively at the gross morphological, radiographical and histological evaluations. Our results suggested that TNF-α and IL-1β were the cytokines to be targeted in the joint for the treatment of rheumatoid arthritis. The in vivo siRNA transfection method may be useful for selection of target molecules to be silenced for treatment of joint diseases.