Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA
Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA
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DOI：
10.1038/sj.gt.3302846
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发表时间：
2007-01-01
期刊：
影响因子：
5.1
通讯作者：
Tao, M-H
中科院分区：
文献类型：
--
作者：
Chen, C-C;Ko, T-M;Tao, M-H
据报道，RNA 干扰 (RNAi) 可在体外和体内阻断乙型肝炎病毒 (HBV) 基因表达和复制。然而，基于RNAi的疗法如何在慢性HBV感染中实现长期且完全的抑制效果仍然是一个技术挑战，这可能需要对整个感染的肝细胞进行更广泛和均匀的转导。为了提高肝脏体内转染效率，我们使用双链腺相关病毒8假型载体（dsAAV2/8）来传递shRNA。使用 HBV 转基因小鼠作为动物模型来评估基于 RNAi 的基因治疗的抑制效果。单次施用携带 HBV 特异性 shRNA 的 dsAAV2/8 载体，可有效抑制 HBV 转基因小鼠肝脏中 HBV 蛋白、mRNA 和复制 DNA 的稳定水平，导致循环中 HBV 负荷降低高达 2-3 log(10)。载体施用后，显着的 HBV 抑制持续至少 120 天。 shRNA的治疗效果是靶序列依赖性的，并且不涉及干扰素的激活。这些结果强调了通过 dsAAV2/8 载体开发基于 RNAi 的疗法来治疗 HBV 慢性感染以及可能的其他持续性肝脏感染的潜力。
RNA interference (RNAi) was reported to block hepatitis B virus (HBV) gene expression and replication in vitro and in vivo. However, it remains a technical challenge for RNAi-based therapy to achieve long-term and complete inhibition effects in chronic HBV infection, which presumably requires more extensive and uniform transduction of the whole infected hepatocytes. To increase the in vivo transfection efficiency in liver, we used a double-stranded adeno-associated virus 8-pseudotyped vector (dsAAV2/8) to deliver shRNA. HBV transgenic mice were used as an animal model to evaluate the inhibition effects of the RNAi-based gene therapy. A single administration of dsAAV2/8 vector, carrying HBV-specific shRNA, effectively suppressed the steady level of HBV protein, mRNA and replicative DNA in liver of HBV transgenic mice, leading to up to 2-3 log(10) decrease in HBV load in the circulation. Significant HBV suppression sustained for at least 120 days after vector administration. The therapeutic effect of shRNA was target sequence dependent and did not involve activation of interferon. These results underscore the potential for developing RNAi-based therapy by dsAAV2/8 vector to treat HBV chronic infection, and possibly other persistent liver infections as well.