Kanazawa Takanori, Tamano Kuniko, Sogabe Kana, Endo Takahiro, Ibaraki Hisako, Takashima Yuuki, Seta Yasuo
School of Pharmacy, Nihon University.
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences.
Biol Pharm Bull. 2017;40(11):1929-1933. doi: 10.1248/bpb.b17-00481.
Small interfering RNAs (siRNAs) are expected to offer a means of treating rheumatoid arthritis (RA) because they allow the specific silencing of genes related to RA pathogenesis. In our previous study, we reported that the siRNA targeted against RelA (anti-RelA siRNA), an important nuclear factor-kappaB (NF-κB) subdomain, was an effective therapeutic in atopic dermatitis and RA model animals. In this study, to develop an intra-articular injectable gel formulation against RA, we prepared a hydrogel that contains anti-RelA siRNA, and determined the in vitro release profile (%) and in vivo intra-articular retention of fluorescence-labeled model siRNA, and the anti-arthritic effects of the anti-RelA siRelA containing hydrogel in RA model mice. We selected the silk protein, sericin (SC), as an aqueous gel base, as it is a biocompatible and useful for forming hydrogels without a cross-linker. We showed that fluorescence-labeled model siRNA was continuously released from SC hydrogel in vitro, and retained in the knee joint of rats after injection of siRNA hydrogel. In addition, the knee joint thickness, clinical severity and incidence (%) in collagen-induced arthritis (CIA) mice as RA model treated with anti-RelA siRNA containing hydrogel were more improved than untreated, anti-RelA siRNA solution and negative control siRNA containing hydrogel group. Therefore, the intra-articular injectable sericin hydrogel formulation containing of anti-RelA siRNA could be a great potential therapeutic in rheumatoid arthritis.
小分子干扰RNA（siRNA）有望成为治疗类风湿性关节炎（RA）的一种手段，因为它们能够特异性沉默与RA发病机制相关的基因。在我们之前的研究中，我们报道了靶向RelA（抗RelA siRNA）的siRNA，RelA是一种重要的核因子-κB（NF-κB）亚结构域，在特应性皮炎和RA模型动物中是一种有效的治疗方法。在本研究中，为了开发一种针对RA的关节内注射凝胶制剂，我们制备了一种含有抗RelA siRNA的水凝胶，并测定了荧光标记的模型siRNA的体外释放曲线（%）和体内关节内保留情况，以及含抗RelA siRNA的水凝胶在RA模型小鼠中的抗关节炎作用。我们选择丝蛋白丝胶蛋白（SC）作为水性凝胶基质，因为它具有生物相容性，并且无需交联剂即可用于形成水凝胶。我们发现荧光标记的模型siRNA在体外从SC水凝胶中持续释放，并在注射siRNA水凝胶后保留在大鼠膝关节中。此外，作为RA模型的胶原诱导性关节炎（CIA）小鼠，用含抗RelA siRNA的水凝胶治疗后的膝关节厚度、临床严重程度和发病率（%）比未治疗组、抗RelA siRNA溶液组和含阴性对照siRNA的水凝胶组有更大改善。因此，含有抗RelA siRNA的关节内注射丝胶蛋白水凝胶制剂在类风湿性关节炎中可能具有巨大的潜在治疗价值。
