Department of Pharmaceutical Science, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
J Pharmacol Exp Ther. 2011 Aug;338(2):443-50. doi: 10.1124/jpet.111.180042. Epub 2011 Apr 29.
Atopic dermatitis (AD) has high morbidity and poor prognosis because safe and effective treatments are scarce. Recently, short interfering RNA (siRNA) has shown promise as an effective treatment for targeting specific aberrantly expressed genes. However, naked siRNAs are too inefficient because of various enzymatic, membrane, and cellular barriers. We previously reported that a Tat analog acting as a cell-penetrating peptide, combined with AT1002, which reversibly increases paracellular transport of molecules across the epidermal barrier in epidermis-disrupted mice and enhances the skin permeation of water-soluble siRNA. In the present study, to develop a novel treatment for AD, we determined the intradermal permeation of siRNAs and the antiallergic effects of a siRNA that silences RelA, a member of the nuclear factor-κB family, using Tat and AT1002 peptides in an AD mouse model. We first showed that the Tat analog and AT1002 delivered siRNA into the skin of ICR mice and, upon topical application to the AD-induced ears of NC/Nga mice, changed zonula occludens protein 1 expression. In addition, the silencing effects on the mRNA of RelA in JAWS II cells transfected with siRNA oligonucleotides for mouse RelA, complexed with Tat, were as effective as a commercial vector. Furthermore, the ear thickness, clinical skin severity, topical cytokine levels, and serum IgE production in AD model mice treated with anti-RelA siRNA with Tat and AT1002 were improved.
特应性皮炎（AD）发病率高、预后差，因为安全有效的治疗方法稀缺。最近，短干扰 RNA（siRNA）作为一种针对特定异常表达基因的有效治疗方法显示出了前景。然而，由于各种酶、膜和细胞屏障的存在，裸露的 siRNA 效率太低。我们之前曾报道过，一种模拟 Tat 的细胞穿透肽与 AT1002 联合使用，可在表皮屏障受损的小鼠中可逆地增加分子的细胞旁转运，并增强水溶性 siRNA 的皮肤渗透。在本研究中，为了开发治疗 AD 的新方法，我们使用 Tat 和 AT1002 肽在 AD 小鼠模型中确定了 siRNA 的皮内渗透和沉默核因子-κB 家族成员 RelA 的 siRNA 的抗过敏作用。我们首先表明，Tat 类似物和 AT1002 将 siRNA 递送至 ICR 小鼠的皮肤中，并且在将其施用于 NC/Nga 小鼠诱导的 AD 耳朵上时，改变了紧密连接蛋白 1 的表达。此外，与商业载体相比，与 Tat 复合的用于小鼠 RelA 的 siRNA 寡核苷酸转染的 JAWS II 细胞中 RelA 的 mRNA 沉默效果相当有效。此外，用 Tat 和 AT1002 处理的 AD 模型小鼠的耳部厚度、临床皮肤严重程度、局部细胞因子水平和血清 IgE 产生均得到改善。
