HBVZ10, an AAV8 vector-based new HBV therapy candidate for cccDNA elimination

Eliminating hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) remains a major challenge, requiring innovative treatment strategies and drug candidates. Clinical studies reveal that wild-type HBV in the blood is often replaced by gradually rising mutant populations. This replacement reflects loss of the early cccDNA pool, then replenished predominantly through <i>de novo</i> infection. We proposed that blocking <i>de novo</i> infection is essential for cccDNA elimination and establishing a finite HBV treatment regimen. To achieve sustained inhibition of <i>de novo</i> cccDNA replenishment, we developed HBVZ10, a gene therapy candidate that utilizes an optimized adeno-associated virus (AAV) vector 8 to deliver human anti-HBs antibody genes into muscle cells for expanding endogenous anti-HBs antibody production capacity. HBVZ10 expression and therapeutic function were evaluated in uPA/SCID chimeric mice. HBVZ10 therapy achieved sustained antibody expression of ≥100,000 mIU/mL for at least 200 days following a single dose administration. Combining HBVZ10 with intracellular replication inhibitor entecavir resulted in >100-fold reductions in cccDNA within a few months, accompanied by progressive reductions in serum HBeAg and HBsAg to undetectable levels. These findings establish preclinical evidence of HBVZ10 as a novel gene therapy candidate and support a paradigm-shifting cccDNA elimination strategy.