Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs
Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs
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DOI：
10.1038/nbt1122
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发表时间：
2005-08-01
影响因子：
46.9
通讯作者：
Polisky, B
中科院分区：
文献类型：
--
作者：
Morrissey, DV;Lockridge, JA;Polisky, B
在HBV复制的体内小鼠模型中检测了脂质包裹的、化学修饰的靶向B型肝炎病毒（HBV）的短干扰RNA（siRNA）的功效。将靶向HBV RNA的稳定siRNA掺入专门的脂质体中以形成稳定的核酸脂质颗粒（SNALP），并通过静脉注射给药至携带复制HBV的小鼠中。与未配制的siRNA相比，siRNA-SNALP的改善的功效与在血浆和肝脏中更长的半衰期相关。每天3次静脉注射3 mg/kg/天可使血清HBV DNA降低>1.0 log（10）。HBV DNA的减少具有特异性，呈剂量依赖性，并持续至给药后7天。此外，每周一次给药可观察到血清HBV DNA降低长达6周。这里展示的进展，包括体内活性的持久性，使用较低剂量和降低给药频率是使siRNA成为临床可行的治疗方法的重要步骤。
The efficacy of lipid-encapsulated, chemically modified short interfering RNA ( siRNA) targeted to hepatitis B virus (HBV) was examined in an in vivo mouse model of HBV replication. Stabilized siRNA targeted to the HBV RNA was incorporated into a specialized liposome to form a stable nucleic-acid-lipid particle (SNALP) and administered by intravenous injection into mice carrying replicating HBV. The improved efficacy of siRNA-SNALP compared to unformulated siRNA correlates with a longer half-life in plasma and liver. Three daily intravenous injections of 3 mg/kg/day reduced serum HBV DNA >1.0 log(10). The reduction in HBV DNA was specific, dose-dependent and lasted for up to 7 d after dosing. Furthermore, reductions were seen in serum HBV DNA for up to 6 weeks with weekly dosing. The advances demonstrated here, including persistence of in vivo activity, use of lower doses and reduced dosing frequency are important steps in making siRNA a clinically viable therapeutic approach.