Lipid nanoparticle-encapsulated DOCK11-siRNA efficiently reduces hepatitis B virus cccDNA level in infected mice

IF 4.6 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy-Methods & Clinical Development Pub Date : 2024-06-24 DOI:10.1016/j.omtm.2024.101289

Hikari Okada, Takeharu Sakamoto, Kouki Nio, Yingyi Li, Kazuyuki Kuroki, Saiho Sugimoto, Tetsuro Shimakami, Nobuhide Doi, Masao Honda, Motoharu Seiki, Shuichi Kaneko, Taro Yamashita

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Abstract

The hepatitis B virus (HBV) infects many people worldwide. As HBV infection frequently leads to liver fibrosis and carcinogenesis, developing anti-HBV therapeutic drugs is urgent. Therapeutic drugs for preventing covalently closed circular DNA (cccDNA) production, which can eliminate HBV infection, are unavailable. The host factor dedicator of cytokinesis 11 (DOCK11) is involved in the synthesis and maintenance of HBV cccDNA . However, the effectiveness of DOCK11 as a target for the elimination of HBV cccDNA remains unclear. In this study, we assess whether DOCK11 inhibitors suppress HBV cccDNA production in mouse models of HBV infection. The tocopherol-conjugate hetero gapmer, a DNA/RNA duplex of gapmer/complementary RNA targeting the DOCK11 sequence, partially reduces the expression of , but not that of HBV cccDNA, in the livers of HBV-infected human hepatocyte chimeric mice, along with weight loss and decreased serum human albumin levels. Lipid nanoparticle-encapsulated chemically modified siRNAs specific for suppress expression and decrease HBV cccDNA levels without adverse effects in the mice. Therefore, nucleic acid-based drugs targeting DOCK11 in hepatocytes are potentially effective anti-HBV therapeutics that can reduce HBV cccDNA levels .

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脂质纳米粒包裹的 DOCK11-siRNA 可有效降低感染小鼠体内的乙型肝炎病毒 cccDNA 水平

乙型肝炎病毒（HBV）感染着全球许多人。由于 HBV 感染经常导致肝纤维化和癌变，因此开发抗 HBV 治疗药物迫在眉睫。防止共价闭合环状 DNA（cccDNA）产生的治疗药物可以消除 HBV 感染，但目前还没有这种药物。宿主因子细胞分裂专用因子 11（DOCK11）参与了 HBV cccDNA 的合成和维持。然而，将 DOCK11 作为消除 HBV cccDNA 的靶点是否有效仍不清楚。在本研究中，我们评估了 DOCK11 抑制剂是否能抑制 HBV 感染小鼠模型中 HBV cccDNA 的产生。生育酚共轭物杂合隙合物是一种靶向 DOCK11 序列的 DNA/RNA 双链隙合物/互补 RNA，它能部分减少 HBV 感染的人肝细胞嵌合小鼠肝脏中 HBV cccDNA 的表达，但不能减少 HBV cccDNA 的表达，同时还能减轻体重和降低血清中人白蛋白的水平。脂质纳米粒子包裹的化学修饰 siRNA 可抑制 HBV cccDNA 的表达，降低 HBV cccDNA 的水平，但对小鼠无不良影响。因此，靶向肝细胞中 DOCK11 的核酸类药物可能是有效的抗 HBV 治疗药物，可以降低 HBV cccDNA 水平。

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来源期刊

Molecular Therapy-Methods & Clinical Development Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.90

自引率

4.30%

发文量

163

审稿时长

12 weeks

期刊介绍： The aim of Molecular Therapy—Methods & Clinical Development is to build upon the success of Molecular Therapy in publishing important peer-reviewed methods and procedures, as well as translational advances in the broad array of fields under the molecular therapy umbrella. Topics of particular interest within the journal''s scope include: Gene vector engineering and production, Methods for targeted genome editing and engineering, Methods and technology development for cell reprogramming and directed differentiation of pluripotent cells, Methods for gene and cell vector delivery, Development of biomaterials and nanoparticles for applications in gene and cell therapy and regenerative medicine, Analysis of gene and cell vector biodistribution and tracking, Pharmacology/toxicology studies of new and next-generation vectors, Methods for cell isolation, engineering, culture, expansion, and transplantation, Cell processing, storage, and banking for therapeutic application, Preclinical and QC/QA assay development, Translational and clinical scale-up and Good Manufacturing procedures and process development, Clinical protocol development, Computational and bioinformatic methods for analysis, modeling, or visualization of biological data, Negotiating the regulatory approval process and obtaining such approval for clinical trials.