Inhibition of hepatitis B virus replication in vivo using lipoplexes containing altritol-modified antiviral siRNAs.

Justin Hean, Carol Crowther, Abdullah Ely, Rafique Ul Islam, Samantha Barichievy, Kristie Bloom, Marc S Weinberg, Willem Al van Otterlo, Charles B de Koning, Felix Salazar, Patricia Marion, Eric B Roesch, Marc Lemaitre, Piet Herdewijn, Patrick Arbuthnot
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引用次数: 37

Abstract

Chronic infection with the hepatitis B virus (HBV) occurs in approximately 6% of the world's population and carriers of the virus are at risk for complicating hepatocellular carcinoma. Current treatment options have limited efficacy and chronic HBV infection is likely to remain a significant global medical problem for many years to come. Silencing HBV gene expression by harnessing RNA interference (RNAi) presents an attractive option for development of novel and effective anti HBV agents. However, despite significant and rapid progress, further refinement of existing technologies is necessary before clinical application of RNAi-based HBV therapies is realized. Limiting off target effects, improvement of delivery efficiency, dose regulation and preventing reactivation of viral replication are some of the hurdles that need to be overcome. To address this, we assessed the usefulness of the recently described class of altritol-containing synthetic siRNAs (ANA siRNAs), which were administered as lipoplexes and tested in vivo in a stringent HBV transgenic mouse model. Our observations show that ANA siRNAs are capable of silencing of HBV replication in vivo. Importantly, non specific immunostimulation was observed with unmodified siRNAs and this undesirable effect was significantly attenuated by ANA modification. Inhibition of HBV replication of approximately 50% was achieved without evidence for induction of toxicity. These results augur well for future application of ANA siRNA therapeutic lipoplexes.

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含altritol修饰的抗病毒sirna的脂质体在体内抑制乙型肝炎病毒复制
慢性乙型肝炎病毒(HBV)感染约占世界人口的6%,该病毒携带者有并发肝细胞癌的风险。目前的治疗方案疗效有限,慢性乙型肝炎病毒感染可能在未来许多年内仍是一个重大的全球医学问题。利用RNA干扰(RNAi)沉默HBV基因表达为开发新型有效的抗HBV药物提供了一个有吸引力的选择。然而,尽管取得了重大而迅速的进展,但在实现基于rnai的HBV治疗的临床应用之前,还需要进一步完善现有技术。限制脱靶效应、提高给药效率、调节剂量和防止病毒复制的再激活是需要克服的一些障碍。为了解决这个问题,我们评估了最近描述的一类含altritol的合成sirna (ANA sirna)的有效性,这些sirna作为脂质体给予,并在严格的HBV转基因小鼠模型中进行了体内测试。我们的观察表明,ANA sirna能够在体内沉默HBV复制。重要的是,未经修饰的sirna可以观察到非特异性免疫刺激,而这种不良影响通过ANA修饰显着减弱。在没有诱导毒性的证据的情况下,实现了约50%的HBV复制抑制。这些结果预示着ANA siRNA治疗脂肪瘤的未来应用。
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