Gene targeting by ribozyme against TNF-α mRNA inhibits autoimmune arthritis
Gene targeting by ribozyme against TNF-α mRNA inhibits autoimmune arthritis
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DOI：
10.1038/sj.gt.3302583
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发表时间：
2005-10-01
期刊：
影响因子：
5.1
通讯作者：
Kleinau, S
中科院分区：
文献类型：
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作者：
Kumar, R;Dammai, V;Kleinau, S
核酶是结合和切割靶RNA的特定区域的催化RNA。因此，靶RNA的蛋白质合成可以被核酶特异性抑制。在这项研究中，我们已经调查，如果核酶在体内炎症过程中具有治疗活性，从关节炎模型的影响判断。设计了一种针对TNF-α的锤头状核酶，并验证了其体外催化活性。核酶在体内使用而没有任何递送系统，因为基于质粒的核酶通过静脉内注射被小鼠中的各种组织充分吸收。研究了核酶调节胶原诱导关节炎（CIA）（一种主要依赖于TNF-α的模型）发展的能力。对CFA中的II型胶原免疫的小鼠全身施用核酶显著降低了CIA的发展。用核酶的无催化活性的变体没有观察到效果。此外，核酶有效地阻止了关节中的软骨和骨破坏，并改善了已建立的CIA。这些数据首次证明，通过核酶在体内靶向TNF-α的基因在抑制自身免疫性关节炎方面是高效的，从而提供了其可用作TNF-α依赖性慢性炎性疾病的治疗工具的概念证明。
Ribozymes are catalytic RNA that bind and cleave specific regions of target RNA. Therefore, protein synthesis by the target RNA may be specifically inhibited by ribozymes. In this study, we have investigated if ribozymes possess therapeutic activity on inflammatory processes in vivo, as judged from effects on an arthritis model. A hammerhead ribozyme against TNF-alpha was designed and its catalytic activity in vitro was verified. The ribozyme was employed in vivo without any delivery system, as the plasmid-based ribozyme was taken up adequately by various tissues in mice by intravenous injection. The ability of the ribozyme to regulate the development of collagen-induced arthritis (CIA), a model largely dependent on TNF-alpha, was investigated. Systemic administration of the ribozyme to mice immunized with collagen type II in CFA significantly reduced the development of CIA. No effect was observed with a catalytically inactive variant of the ribozyme. Furthermore, the ribozyme efficiently blocked cartilage and bone destruction in the joints and ameliorated established CIA. These data demonstrate for the first time that gene targeting by a ribozyme to inactivate TNF-alpha in vivo is highly efficient in suppressing autoimmune arthritis, thus providing proof of concept that it may be used as therapeutic tool for TNF-alpha-dependent chronic inflammatory disorders.