Infectious Diseases and Vaccines, Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium.
Infectious Diseases and Vaccines, Janssen Research and Development, 1400 McKean Road, Springhouse, PA 19002, USA.
Viruses. 2024 Feb 23;16(3):347. doi: 10.3390/v16030347.
Treatment with siRNAs that target HBV has demonstrated robust declines in HBV antigens. This effect is also observed in the AAV-HBV mouse model, which was used to investigate if two cycles of GalNAc-HBV-siRNA treatment could induce deeper declines in HBsAg levels or prevent rebound, and to provide insights into the liver immune microenvironment.
C57Bl/6 mice were transduced with one of two different titers of AAV-HBV for 28 days, resulting in stable levels of HBsAg of about 10 or 10 IU/mL. Mice were treated for 12 weeks (four doses q3wk) per cycle with 3 mg/kg of siRNA-targeting HBV or an irrelevant sequence either once (single treatment) or twice (retreatment) with an 8-week treatment pause in between. Blood was collected to evaluate viral parameters. Nine weeks after the last treatment, liver samples were collected to perform phenotyping, bulk RNA-sequencing, and immunohistochemistry.
Independent of HBsAg baseline levels, treatment with HBV-siRNA induced a rapid decline in HBsAg levels, which then plateaued before gradually rebounding 12 weeks after treatment stopped. A second cycle of HBV-siRNA treatment induced a further decline in HBsAg levels in serum and the liver, reaching undetectable levels and preventing rebound when baseline levels were 10 IU/mL. This was accompanied with a significant increase in inflammatory macrophages in the liver and significant upregulation of regulatory T-cells and T-cells expressing immune checkpoint receptors.
Retreatment induced an additional decline in HBsAg levels, reaching undetectable levels when baseline HBsAg levels were 3log or less. This correlated with T-cell activation and upregulation of .
靶向 HBV 的 siRNA 治疗已显示出对 HBV 抗原的显著下降。这种效应也在 AAV-HBV 小鼠模型中观察到，该模型用于研究两次 GalNAc-HBV-siRNA 治疗是否可以诱导 HBsAg 水平更深的下降或防止反弹，并深入了解肝脏免疫微环境。
C57Bl/6 小鼠用两种不同滴度的 AAV-HBV 转导 28 天，导致 HBsAg 水平稳定在约 10 或 10 IU/mL。每周期用 3mg/kg 的靶向 HBV 的 siRNA 或非相关序列对小鼠进行 12 周（每 3 周 4 次剂量）治疗，两次治疗之间有 8 周的治疗暂停。采集血液以评估病毒参数。最后一次治疗后 9 周，采集肝脏样本进行表型分析、批量 RNA 测序和免疫组织化学。
无论 HBsAg 基线水平如何，HBV-siRNA 治疗均可迅速降低 HBsAg 水平，然后在治疗停止 12 周后逐渐反弹。第二次 HBV-siRNA 治疗可进一步降低血清和肝脏中的 HBsAg 水平，达到不可检测水平，并防止反弹，当基线水平为 10IU/mL 时。这伴随着肝脏中炎症性巨噬细胞的显著增加，以及调节性 T 细胞和表达免疫检查点受体的 T 细胞的显著上调。
再治疗可诱导 HBsAg 水平进一步下降，当基线 HBsAg 水平为 3log 或更低时，可达到不可检测水平。这与 T 细胞激活和上调相关。
