Long-term inhibition of Hepatitis B virus gene expression by a primary microrna expressing ancestral adeno-associated viral vector

• Published in: Virology journal Vol. 22; no. 1; p. 41
• Main Authors: Mnyandu, Njabulo Ziphezinhle, Limani, Shonisani Wendy, Ely, Abdullah, Wadee, Reubina, Arbuthnot, Patrick, Maepa, Mohube Betty
• Format: Journal Article
• Language: English
• Published: London BioMed Central 17.02.2025; BioMed Central Ltd; BMC
• Subjects: AAV; Ancestral AAV; Animals; Anopheles; Antigens; biomarkers; Biomedical and Life Sciences; Biomedicine; chemical bonding; Circular DNA; Dependovirus - genetics; Gene expression; Gene Expression Regulation, Viral; Genes; Genetic aspects; Genetic engineering; Genetic Therapy - methods; Genetic transcription; Genetic Vectors; genetically modified organisms; Health aspects; Hepatitis B; Hepatitis B Core Antigens - blood; Hepatitis B Surface Antigens - blood; Hepatitis B virus; Hepatitis B virus - genetics; Hepatitis B virus - physiology; Hepatitis B, Chronic - therapy; Hepatitis B, Chronic - virology; hepatotoxicity; Humans; Infection; Liver; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Research Article; Review; serotypes; surface antigens; Trans-Activators - genetics; transcription (genetics); Viral Regulatory and Accessory Proteins; Virology; South Africa; Microrna; Ancestral AAV; Hepatitis B virus; AAV
• ISSN: 1743-422X; 1743-422X
• DOI: 10.1186/s12985-025-02662-5

Current treatments for chronic infection with the hepatitis B virus (HBV) rarely cure carriers from the disease. Previously reported use of serotype 8 adeno-associated viral (AAV8) vectors to deliver expression cassettes encoding anti-HBV artificial primary microRNAs (apri-miRs) has shown promise in preclinical studies. A recently designed synthetic ancestral AAV (Anc80L65) with high liver transduction efficiency is a promising new addition to the anti-HBV vector toolbox. This study engineered Anc80L65 to express HBx -targeting apri-miRs. Single dose administration of the vectors to cultured cells and HBV transgenic mice effected reductions of secreted HBV surface antigen (HBsAg). Circulating HBV particles and HBV core antigen (HBcAg) were also significantly diminished in mice receiving the anti-HBV apri-miR-expressing ancestral AAVs. Downregulation of HBV biomarkers occurred over a period of 12 months. Absence of inflammatory responses or liver toxicity indicated that the vectors had a good safety profile. These data suggest that a single dose of apri-miR-expressing Anc80L65 is safe and capable of mediating durable suppression of HBV gene expression. Targeting HBx , which is required for transcriptional activity of covalently closed circular DNA of HBV, makes this Anc80L65-derived vector a promising candidate for functional cure from chronic HBV infection.