Hepatitis B Gene Therapy Coming to Age.

Area of Science:

• Hepatology and Viral Immunology
• Gene Therapy and Molecular Medicine

Background:

• Chronic viral infections like HIV, HCV, and HBV affect millions globally, with HCV nearing eradication via direct oral antivirals.
• Biological differences in viral replication (cytosolic for HCV, nuclear for HIV/HBV) necessitate distinct therapeutic strategies.
• HBV's persistent covalently closed circular DNA (cccDNA) in hepatocytes poses a significant challenge for complete viral clearance.

Purpose of the Study:

• To review novel therapeutic strategies for chronic hepatitis B (HBV) infection, focusing on emerging gene therapies.
• To highlight the advancements and potential of gene therapy as a curative approach for HBV.
• To compare the efficacy and mechanisms of different HBV gene therapy candidates.

Main Methods:

• Review of recent therapeutic strategies presented at the European Liver meeting, focusing on HBV gene therapy candidates.
• Analysis of drug classes including interference RNA (iRNA) and nucleic acid polymers (NAPs) targeting HBV life cycle.
• Examination of clinical trial data and preclinical studies on novel HBV gene therapies.

Main Results:

• HBV gene therapies demonstrate significant reductions in serum hepatitis B surface antigen (HBsAg) and HBV-DNA.
• Interference RNA (iRNA) and nucleic acid polymers (NAPs) show promise, with several iRNA molecules in Phase II trials.
• Nucleic acid polymers (NAPs) have shown reductions in hepatic cccDNA, potentially by indirect mechanisms related to HBsAg clearance.

Conclusions:

• Gene therapy represents a highly attractive and promising therapeutic avenue for chronic hepatitis B infection.
• Advances in delivery systems and synthetic production have made gene therapies more feasible and cost-effective.
• Novel gene therapies offer the potential for significant viral load reduction and possibly a functional cure for HBV.