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

Area of Science:

• Hepatology
• Gene Therapy
• Virology

Background:

• Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) elimination is a significant therapeutic challenge.
• HBV treatment failure is linked to mutant HBV populations and replenishment via de novo infection.
• Blocking de novo infection is crucial for finite HBV treatment regimens.

Purpose of the Study:

• To develop a gene therapy candidate, HBVZ10, for sustained inhibition of de novo HBV infection.
• To evaluate the efficacy of HBVZ10 in reducing HBV cccDNA and viral markers in a preclinical model.

Main Methods:

• Developed HBVZ10 using an optimized adeno-associated virus (AAV) vector 8 to deliver anti-HBs antibody genes.
• Administered HBVZ10 to uPA/SCID chimeric mice to assess gene expression and therapeutic function.
• Combined HBVZ10 with entecavir, an intracellular replication inhibitor, for synergistic effects.

Main Results:

• HBVZ10 achieved sustained high-level anti-HBs antibody expression (≥100,000 mIU/mL) for over 200 days post-single dose.
• Combination therapy with HBVZ10 and entecavir led to >100-fold reduction in cccDNA within months.
• Serum HBeAg and HBsAg levels were progressively reduced to undetectable levels with combination therapy.

Conclusions:

• HBVZ10 demonstrates preclinical efficacy as a novel gene therapy for hepatitis B.
• Blocking de novo HBV infection is a viable strategy for cccDNA elimination.
• This approach supports a paradigm shift towards finite HBV treatment regimens.