Flory C M, Pavco P A, Jarvis T C, Lesch M E, Wincott F E, Beigelman L, Hunt S W, Schrier D J
Department of Immunopathology, Parke-Davis Pharmaceutical Research, Division Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):754-8. doi: 10.1073/pnas.93.2.754.
Catalytic RNA molecules, or ribozymes, have generated significant interest as potential therapeutic agents for controlling gene expression. Although ribozymes have been shown to work in vitro and in cellular assays, there are no reports that demonstrate the efficacy of synthetic, stabilized ribozymes delivered in vivo. We are currently utilizing the rabbit model of interleukin 1-induced arthritis to assess the localization, stability, and efficacy of exogenous antistromelysin hammerhead ribozymes. The matrix metalloproteinase stromelysin is believed to be a key mediator in arthritic diseases. It seems likely therefore that inhibiting stromelysin would be a valid therapeutic approach for arthritis. We found that following intraarticular administration ribozymes were taken up by cells in the synovial lining, were stable in the synovium, and reduced synovial interleukin 1 alpha-induced stromelysin mRNA. This effect was demonstrated with ribozymes containing various chemical modifications that impart nuclease resistance and that recognize several distinct sites on the message. Catalytically inactive ribozymes were ineffective, thus suggesting a cleavage-mediated mechanism of action. These results suggest that ribozymes may be useful in the treatment of arthritic diseases characterized by dysregulation of metalloproteinase expression.
催化性RNA分子，即核酶，作为控制基因表达的潜在治疗剂已引起了广泛关注。尽管核酶已在体外和细胞试验中显示出作用，但尚无报告表明合成的、稳定的核酶在体内递送时的疗效。我们目前正在利用白细胞介素1诱导的关节炎兔模型来评估外源性抗基质溶解素锤头状核酶的定位、稳定性和疗效。基质金属蛋白酶基质溶解素被认为是关节炎疾病中的关键介质。因此，抑制基质溶解素似乎是治疗关节炎的一种有效方法。我们发现，关节内给药后，核酶被滑膜衬里中的细胞摄取，在滑膜中稳定，并降低了滑膜白细胞介素1α诱导的基质溶解素mRNA水平。含有各种化学修饰以赋予核酸酶抗性并识别该信使上几个不同位点的核酶证明了这种效果。催化失活的核酶无效，因此提示了一种切割介导的作用机制。这些结果表明，核酶可能对治疗以金属蛋白酶表达失调为特征的关节炎疾病有用。
