[Antisense oligodeoxynucleotides: the certain but limited efficacy and the uncovering mechanisms for the cure of chronic hepatitis B].

Recently, several phase I and phase II clinical trials of antisense oligodeoxynucleotides (ASOs) targeting to the commonly shared conserved sequences of HBV transcripts brought us some promising results. Particularly in the report of phase IIb clinical trial of Bepirovirsen (GSK3228836), approximately 9-10% patients with low baseline serum HBsAg (> 100 IU/ml & < 3 000 IU/ml) achieved functional cure after 24 weeks' of Bepirovirsen treatment. After reviewing the results of other clinical trials, one would be impressed to know that ALG-020572 (Aligos), RO7062931 (Roche) and GSK3389404 (GSK) all failed to sufficiently suppress serum HBsAg expression though the hepatocyte-targeted delivery of these ASOs were enhanced via N-acetyl galactosamine conjugation. Bepirovirsen enabled some patients to achieve sustained disappearance of serum HBsAg. The analysis of its distribution in different tissues of patients after drug administration showed that only a few fractions of ASOs entered liver tissues and far fewer eventually entered hepatocytes. Taking into consideration that only a few hepatocytes could be expected positive for HBsAg staining among these participants with low serum HBsAg level. We suspect that the mechanistic contribution of ASOs declining the serum HBsAg is not only via directly acting on the HBV transcripts in hepatocytes, but also via entering non-parenchymal cells such as Kupffer cells and resulting in stimulation and activation of innate immunity. Eventually the serum HBsAg declines in most participants and even disappears in a small fraction of patients with low baseline HBsAg level, via attack the infected hepatocytes evidenced by the aberrant elevation of ALT. Nevertheless, the functional cure of CHB remains a challenging issue and more efforts are needed.近期报道的靶向乙型肝炎病毒（HBV）转录本保守区的反义寡核苷酸（ASO）药物I期和II期临床试验结果令人振奋。特别是在Bepirovirsen（GSK3228836）的IIb期临床试验报告中，大约9%~10%的低基线血清HBsAg（> 100 IU/ml和< 3 000 IU/ml）患者在Bepirovirsen治疗的24周内实现了HBV功能性治愈。而其他通过偶联N-乙酰半乳糖胺（GalNAc）配体增强了肝细胞靶向性的ASO药物，如ALG-020572（Aligos）、RO7062931（Roche）和GSK3389404（GSK）等，都未能充分降低患者血清HBsAg的水平。在临床试验中使部分患者实现停药后血清HBsAg持续消失的Bepirovirsen（GSK3228836），用药后其在患者不同组织的分布分析结果显示只有少部分ASOs进入肝脏组织，最终进入肝细胞的则更少。此外，考虑到参与临床试验的患者基线血清HBsAg水平较低，那该ASO降低血清HBsAg的主要作用机制可能不是直接作用于感染肝细胞内的HBV转录本，而更可能是通过非特异地进入肝脏非实质细胞如库普弗细胞等，最终通过刺激和激活宿主免疫，攻击被感染的肝细胞，使得大多数患者的血清HBsAg下降，甚至小部分基线HBsAg水平较低的患者达到HBsAg阴转。而报导的临床试验中观察到的较高比例患者出现ALT水平异常升高的现象则在一定程度上支持上述推测。本文在系统阐述ASOs的发现与作用机制的基础上，讨论分析了ASOs在慢性乙型肝炎功能性治愈中的潜在价值及所面临的挑战。.