Inhibition of hepatitis B virus replication by various RNAi constructs and their pharmacodynamic properties.
The strategy of RNA interference (RNAi)-based gene silencing has been suggested to have great potential in treating viral diseases. It provides new hope of being able to complement the limited therapeutic options currently available for chronic hepatitis B virus (HBV) infection. To advance such a strategy towards clinical use, the effects of various parameters on the anti-HBV efficiency of RNAi need to be well-defined. In this study, the efficacy and pharmacodynamic properties of different RNAi target sequences and constructs were examined. Several sequences were found to be effective in cell and animal models, achieving inhibition rates of approximately 80-90 %. Methyl-modified small interfering RNA (siRNA) molecules were found to be more stable inside cells than natural siRNA molecules and offered longer-lasting inhibitory effects. Both were effective at rather low doses (an equimolar ratio with HBV preS2-S protein expression vector). Plasmid DNA vectors were less dose-responsive, but their effectiveness in vivo lasted longer, for approximately 1 month. By analysing these different parameters and their possible mechanisms, some important issues in RNAi therapeutics that should assist the future development of clinical applications have been addressed.
Peng
Jinliang
J
School of Pharmacy, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.|School of Life Sciences and Technology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.
Zhao
Yonggang
Y
School of Life Sciences and Technology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.
Mai
Junhua
J
School of Life Sciences and Technology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.
Pang
Weng Ka
WK
School of Life Sciences and Technology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.
Wei
Xiaohui
X
School of Pharmacy, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.
Zhang
Peizuo
P
Shanghai GenePharma Co. Ltd, 501 Newton Road, Shanghai, PR China.
Xu
Yuhong
Y
School of Pharmacy, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.|School of Life Sciences and Technology, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030, PR China.
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D018274:Electroporation; D005260:Female; D005822:Genetic Vectors; D006509:Hepatitis B / Q000821:virology; D006510:Hepatitis B Antibodies / Q000097:blood; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000235:genetics; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000821:virology; D010957:Plasmids / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014779:Virus Replication / Q000235:genetics*
D000998:Antiviral Agents; D004279:DNA, Viral; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D034741:RNA, Small Interfering