Ely Abdullah, Moyo Buhle, Arbuthnot Patrick
Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Mol Ther. 2016 Apr;24(4):671-7. doi: 10.1038/mt.2016.43. Epub 2016 Feb 26.
Chronic infection with hepatitis B virus (HBV) occurs in approximately 6% of the world's population. Carriers of the virus are at risk for life-threatening complications, and developing curative treatment remains a priority. The main shortcoming of licensed therapies is that they do not affect viral covalently closed circular DNA (cccDNA), a stable intermediate of replication. Harnessing gene editing to mutate cccDNA provides the means to inactivate HBV gene expression permanently. Reports have described use of engineered zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated (Cas) nucleases. Although inhibition of viral replication has been demonstrated, reliably detecting mutations in cccDNA has been difficult. Also, the dearth of murine models that mimic cccDNA formation has hampered analysis in vivo. To reach a stage of clinical use, efficient delivery of the editors to HBV-infected hepatocytes and limiting unintended off-target effects will be important. Investigating therapeutic efficacy in combination with other treatment strategies, such as immunotherapies, may be useful to augment antiviral effects. Advancing gene editing as a mode of treating HBV infection is now at an interesting stage and significant progress is likely to be made in the immediate future.
全球约6%的人口感染慢性乙型肝炎病毒（HBV）。该病毒携带者面临危及生命的并发症风险，因此开发治愈性治疗方法仍是当务之急。现有获批疗法的主要缺点是它们不影响病毒共价闭合环状DNA（cccDNA），这是一种稳定的复制中间体。利用基因编辑使cccDNA发生突变，为永久灭活HBV基因表达提供了手段。已有报道描述了工程化锌指核酸酶（ZFN）、转录激活因子样效应物核酸酶（TALEN）以及成簇规律间隔短回文重复序列（CRISPR）与CRISPR相关（Cas）核酸酶的使用情况。尽管已证实对病毒复制有抑制作用，但可靠检测cccDNA中的突变一直很困难。此外，缺乏模拟cccDNA形成的小鼠模型也阻碍了体内分析。要达到临床应用阶段，将编辑工具高效递送至HBV感染的肝细胞并限制意外的脱靶效应将很重要。研究与其他治疗策略（如免疫疗法）联合使用时的治疗效果，可能有助于增强抗病毒作用。将基因编辑发展为治疗HBV感染的一种方式目前正处于一个有趣的阶段，近期可能会取得重大进展。
