Therapeutic inhibition of hepatitis B virus surface antigen expression by RNA interference
Therapeutic inhibition of hepatitis B virus surface antigen expression by RNA interference
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DOI：
10.1016/j.bbrc.2005.08.173
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发表时间：
2005-10-28
影响因子：
3.1
通讯作者：
Chang, WT
中科院分区：
文献类型：
--
作者：
Cheng, TL;Chang, WW;Chang, WT
RNA 干扰 (RNAi) 介导的病毒特异性基因抑制已成为针对病毒引起的疾病的潜在治疗策略。人类乙型肝炎病毒（HBV）表面抗原（HBsAg）已被证明是乙型肝炎病毒引起的肝病的重要危险因素，并且已知越来越多的HBsAg突变增加了治疗干预的难度。实现有效基因沉默（特别是用于治疗目的）的关键挑战主要基于 RNAi 靶向序列的有效性和特异性。为了探索RNAi对HBV诱发的疾病，特别是由HBsAg异常或持续表达引起的疾病的治疗潜力，我们特别筛选和鉴定了直接介导抑制HBsAg表达的最有效和特异性的RNAi靶向序列。使用有效的基于DNA载体的shRNA表达系统，我们筛选了从HBsAg编码区，特别是主要S区域中选择的10个RNAi靶向序列（HBsAg-1至10），并鉴定了四个可以介导HBsAg表达的序列特异性抑制的靶向序列。在这四种 shRNA 中，发现一种极其有效且高度序列特异性的 HBsAg-3 shRNA 可抑制小鼠 HBV 模型中的 HBsAg 表达。这种抑制不仅在共转染实验中具有预防作用，而且根据治疗后方案评估也具有治疗作用。此外，这种 HBsAg-3 shRNA 在组成型表达 HBsAg 的转基因小鼠中也表现出强大的抑制效力。这些结果表明 HBsAg-3 shRNA 可被认为是治疗 HBsAg 诱发疾病的有效药物。 (c) 2005 Elsevier Inc. 保留所有权利。
RNA interference (RNAi) mediated inhibition of virus-specific genes has emerged as a potential therapeutic strategy against virus induced diseases. Human hepatitis B virus (HBV) surface antigen (HBsAg) has proven to be a significant risk factor in HBV induced liver diseases, and an increasing number of mutations in HBsAg are known to enhance the difficulty in therapeutic interventions. The key challenge for achieving effective gene silencing in particular for the purpose of the therapeutics is primarily based on the effectiveness and specificity of the RNAi targeting sequence. To explore the therapeutic potential of RNAi on HBV induced diseases in particular resulted from aberrant or persistent expression of HBsAg, we have especially screened and identified the most potent and specific RNAi targeting sequence that directly mediated inhibition of the HBsAg expression. Using an effective DNA vector-based shRNA expression system, we have screened 10 RNAi targeting sequences (HBsAg-1 to 10) that were chosen from HBsAg coding region, in particular the major S region, and have identified four targeting sequences that could mediate sequence specific inhibition of the HBsAg expression. Among these four shRNAs, an extremely potent and highly sequence specific HBsAg-3 shRNA was found to inhibit HBsAg expression in mouse HBV model. The inhibition was not only preventive in cotransfection experiments, but also had therapeutic effect as assessed by post-treatment protocols. Moreover, this HBsAg-3 shRNA also exhibited a great potency of inhibition in transgenic mice that constitutively expressed HBsAg. These results indicate that HBsAg-3 shRNA can be considered as a powerful therapeutic agent on HBsAg induced diseases. (c) 2005 Elsevier Inc. All rights reserved.