Therapeutic inhibition of hepatitis B virus surface antigen expression by RNA interference

被引:22
|
作者
Cheng, TL
Chang, WW
Su, IJ
Lai, MD
Huang, WY
Lei, HY
Chang, WT
机构
[1] Natl Cheng Kung Univ, Inst Basic Med Sci, Coll Med, Tainan 701, Taiwan
[2] Natl Hlth Res Inst, Div Clin Res, Tainan 701, Taiwan
[3] Natl Cheng Kung Univ, Dept Biochem & Mol Biol, Coll Med, Tainan 701, Taiwan
[4] Natl Cheng Kung Univ, Coll Med, Dept Med Lab Sci & Biotechnol, Tainan 701, Taiwan
[5] Natl Cheng Kung Univ, Coll Med, Dept Microbiol & Immunol, Tainan 701, Taiwan
关键词
hepatitis B virus; HBV surface antigen; RNA interference; short hairpin RNA; hydrodynamics based transfection; HBsAg transgenic mouse;
D O I
10.1016/j.bbrc.2005.08.173
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:820 / 830
页数:11
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