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Hot News: Hepatitis B Gene Therapy Coming to Age.
AIDS Reviews ( IF 2.2 ) Pub Date : 2018-06-26
Vicente Soriano 1
Affiliation  

The major pandemics caused by chronic viral infections is produced by HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV), with estimates of 38, 70, and 250 million people worldwide, respectively (Fig. 1). During the last couple of years, the advent of direct oral antivirals has allowed pursuing global HCV eradication. In an unprecedented manner, these drugs cure more than 95% of hepatitis C patients when given for only 2-3 months. The enthusiasm on HCV has renewed the interest for curative strategies for both HIV and HBV. However, important biological differences between all three viruses may preclude envisioning a similar rapid success for either HIV or HBV than for HCV infection. As shown in figure 1, once infection of targeted cells has occurred, the viral genetic material only replicates in the cytosol for HCV whereas it enters the nucleus and integrates into the chromosomes as provirus for HIV or is converted in a circular covalently closed form (cccDNA) for HBV (Fig. 1). Blocking viral nucleic acid replication for a minimum lag of time allows definitive clearance of HCV infection, with degradation of residual cytoplasmic HCV-RNA strands. In contrast, blocking viral replication has only a transient effect on HIV or HBV, as mRNA expression resumes following treatment discontinuation, given the stability of the HIV provirus or the HBV cccDNA, respectively. The European Liver meeting took held in Paris on April 2018. A relatively large number of presentations addressed distinct new hepatitis B therapeutic strategies. Table 1 summarizes some of the molecules that have been investigated so far with more promising results, grouping them into distinct drug classes (Soriano et al. Exp Op Inv Drugs 2017;26:843-51), based on their distinct mechanism of action and targeted steps in the HBV life cycle (Fig. 2). Considering the pros and cons of novel HBV therapeutic candidates, it has become apparent new HBV gene therapies among the most attractive. Several advances have contributed to position gene therapy in front within the experimental HBV armamentarium. First, progresses in delivery systems, including the use of polymers and nanoformulations have allowed developing easier forms of administration that now are becoming subcutaneous and monthly. Second, the synthetic production of oligonucleotide formulations has reduced costs. Third, the specificity against HBV is higher than for other experimental agents, as immune modulators that enhance innate immunity, such as TLR agonists (i.e., GS-9620) or checkpoint inhibitors (i.e., nivolumab). Fourth, significant declines in serum hepatitis B surface antigen (HBsAg) are demonstrated during gene therapy, which have never been seen using the most potent polymerase inhibitors (i.e., tenofovir or entecavir). Finally, unanticipated significant reductions in cccDNA are seen with HBV gene therapy, most likely as prove of an indirect benefit of waning the immunosuppressive effect of large over amounts of HBsAg released by infected hepatocytes that contributes to T-cell exhaustion. In a pioneering study, Roche was the first to publish the potent effect of an oral small molecule that blocked HBV gene expression (Mueller et al. J Hepatol 2018;68:412-20). The drug belonged to the dihydroquinolizinone class, and directly or indirectly modified viral RNAs, promoting their degradation. This posttranscriptional silencing was accompanied by rapid drops in HBV-DNA and more importantly in serum HBsAg in the humanized mice. However, Roche decided to discontinue any further clinical development of the drug. Nowadays, two major groups of agents are being developed as HBV gene therapies. At this time, interference RNA (iRNA) molecules and nucleic acid polymers (NAPs) are the most promising. Overall, iRNA is double-stranded RNA molecules, 20 nucleotides long. One strand matches a segment of specific HBV mRNA and induces its degradation. Several iRNA molecules have entered into Phase II clinical trials (Flisiak et al. Exp Op Biol Ther, in press), including ARB-1467 and AB-729 (Arbutus), ARO-HBV (Arrowhead), ALN-HBV (Alnylam), and IONIS-HBVRx (Ionis). In most cases, they are tested as part of combination therapy with nucleos(t)ide analogs and/or peginterferon. NAPs are phosphorothioate 40 length oligonucleotides that no map any HBV sequence. However, they interact with a liver host target protein (apolipoprotein-like) and result in specific inhibition of HBV mRNAs. This is followed by rapid suppression of HBsAg release (Roehl et al. Mol Ther Nuc Acids 2017;8:1-12). In a pilot study with intravenous REP-2139, investigators from Replicor demonstrated strong reductions in HBV-DNA along with significant drops in HBsAg and seroconversion in some patients. More interestingly was the recognition of significant reductions in hepatic cccDNA, most likely a result of an indirect effect following the removal of large amounts of HBsAg from the bloodstream that contributes to impaired T-cell responses in chronic hepatitis B patients (Bazinet et al. EASL, Paris 2018; abstract FRI-343). An improved NAP, named REP-2165 and subcutaneous administration are currently being tested.

中文翻译:

热门新闻:乙肝基因治疗正在走向成熟。

HIV,丙型肝炎病毒(HCV)和乙型肝炎病毒(HBV)引起了由慢性病毒感染引起的主要流行病,估计全世界分别有38、70和2.5亿人(图1)。在过去的几年中,直接口服抗病毒药的出现使人们得以在全球范围内根除HCV。仅用2到3个月就可以治愈95%以上的丙型肝炎患者。对HCV的热情重新激发了人们对HIV和HBV治愈策略的兴趣。但是,所有三种病毒之间的重要生物学差异可能无法预见到HIV或HBV的快速成功与HCV感染的相似。如图1所示,一旦靶细胞被感染,病毒的遗传物质仅在HCV的胞质溶胶中复制,而进入细胞核并作为HIV的原病毒整合到染色体中,或者以HBV的环状共价闭合形式(cccDNA)转化(图1)。在最短的时间间隔内阻断病毒核酸复制,可以最终清除HCV感染,同时降解残留的细胞质HCV-RNA链。相反,鉴于分别给予HIV前病毒或HBV cccDNA的稳定性,在停止治疗后恢复mRNA表达,阻断病毒复制仅对HIV或HBV产生短暂影响。欧洲肝病会议于2018年4月在巴黎举行。相对大量的演讲探讨了独特的新型乙肝治疗策略。表1总结了迄今为止已研究的一些分子,并获得了更可喜的结果,并根据其独特的作用机理和作用机制将它们分为不同的药物类别(Soriano等人,Exp Op Inv Drugs 2017; 26:843-51)。 HBV生命周期中的目标步骤(图2)。考虑到新型HBV治疗候选药物的利弊,新的HBV基因治疗已成为最有吸引力的新疗法。多项进展有助于在实验性HBV武器库内将基因治疗摆在前面。首先,输送系统的进步,包括使用聚合物和纳米制剂,已经使开发更容易的给药形式成为可能,如今这种给药方式正在皮下和每月使用。第二,寡核苷酸制剂的合成生产降低了成本。第三,作为增强先天免疫力的免疫调节剂,例如TLR激动剂(即GS-9620)或检查点抑制剂(即nivolumab),其对HBV的特异性高于其他实验剂。第四,在基因治疗期间,血清乙型肝炎表面抗原(HBsAg)明显下降,这是使用最有效的聚合酶抑制剂(如替诺福韦或恩替卡韦)从未见过的。最后,用HBV基因治疗发现cccDNA出现了意料不到的显着减少,最有可能证明是逐渐减少了被感染的肝细胞释放的大量HBsAg的免疫抑制作用的间接益处,而这种作用有助于T细胞衰竭。在一项开创性研究中,罗氏(Roche)率先发布了阻断HBV基因表达的口服小分子的强效药物(Mueller等人,J Hepatol 2018; 68:412-20)。该药物属于二氢喹啉嗪酮类,可直接或间接修饰病毒RNA,从而促进其降解。转录后沉默伴随着人源化小鼠中HBV-DNA的快速下降,更重要的是血清HBsAg的快速下降。但是,罗氏决定终止该药物的任何进一步临床开发。如今,正在开发两大类药物作为HBV基因疗法。目前,干扰RNA(iRNA)分子和核酸聚合物(NAP)是最有前途的。总的来说,iRNA是双链RNA分子,长20个核苷酸。一条链与特定的HBV mRNA片段匹配并诱导其降解。几种iRNA分子已进入II期临床试验(Flisiak等人,Exp Op Biol Ther,印刷中),包括ARB-1467和AB-729(杨梅),ARO-HBV(箭头),ALN-HBV(Alnylam)和IONIS-HBVRx(爱奥尼斯)。在大多数情况下,将它们作为与核苷酸类似物和/或聚乙二醇干扰素联合治疗的一部分进行测试。NAP是硫代磷酸酯40长度的寡核苷酸,没有映射任何HBV序列。但是,它们与肝脏宿主靶蛋白(载脂蛋白样)相互作用,并导致HBV mRNA的特异性抑制。随后快速抑制HBsAg释放(Roehl等人,Mol Ther Nuc Acids 2017; 8:1-12)。在一项使用静脉REP-2139进行的试点研究中,来自Replicor的研究人员证明了某些患者中HBV-DNA的强烈降低,以及HBsAg和血清转化的明显下降。更有趣的是,人们认识到肝cccDNA的显着减少,最有可能是从血液中去除大量HBsAg后间接作用导致慢性乙型肝炎患者T细胞反应受损的原因(Bazinet et al.EASL,Paris 2018; abstract FRI-343)。目前正在测试一种名为REP-2165的改良型NAP和皮下给药的方法。
更新日期:2019-11-01
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