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Targeting the hepatitis B cccDNA with a sequence-specific ARCUS nuclease to eliminate hepatitis B virus in vivo
Cassandra L Gorsuch1, Paige Nemec1, Mei Yu2
1Precision BioSciences Inc, Durham, NC 27701, USA.
Insights
A novel gene-editing therapy using ARCUS nuclease (ARCUS-POL) shows promise for a chronic hepatitis B (CHB) cure. This approach effectively reduces the viral cccDNA and surface antigen, paving the way for potential elimination of the virus.
Area of Science:
- Molecular Biology
- Hepatology
- Gene Therapy
Background:
- Chronic hepatitis B (CHB) persistence is linked to the stable intrahepatic viral cccDNA pool.
- Current therapies inhibit HBV replication but do not eliminate cccDNA or viral gene expression.
- A gene-editing strategy offers a potential pathway to a functional cure for CHB.
Purpose of the Study:
- To evaluate the efficacy of a targeted engineered nuclease, ARCUS-POL, in reducing HBV cccDNA and achieving viral clearance.
- To assess the in vivo performance of ARCUS-POL using relevant animal models for CHB.
Main Methods:
- Engineered ARCUS nuclease (ARCUS-POL) designed to target the HBV genome.
- In vitro studies using HBV-infected primary human hepatocytes.
- In vivo studies utilizing adeno-associated virus (AAV) mouse and non-human primate (NHP) models harboring HBV DNA.
- Systemic delivery of ARCUS-POL mRNA via lipid nanoparticles.
Main Results:
- Transient ARCUS-POL expression significantly reduced cccDNA and HBsAg in vitro.
- In vivo studies demonstrated a decrease in viral DNA and high on-target indel frequencies in both mouse and NHP models.
- A durable 96% reduction in circulating HBsAg was observed in the mouse model.
Conclusions:
- Gene editing with ARCUS-POL offers a promising strategy for eliminating HBV cccDNA.
- This approach supports the potential for a curative treatment for chronic hepatitis B.
- Further development of gene-editing therapies could lead to a functional cure for HBV infection.
Abstract:
Persistence of chronic hepatitis B (CHB) is attributed to maintenance of the intrahepatic pool of the viral covalently closed circular DNA (cccDNA), which serves as the transcriptional template for all viral gene products required for replication. Current nucleos(t)ide therapies for CHB prevent virus production and spread but have no direct impact on cccDNA or expression of viral genes. We describe a potential curative approach using a highly specific engineered ARCUS nuclease (ARCUS-POL) targeting the hepatitis B virus (HBV) genome. Transient ARCUS-POL expression in HBV-infected primary human hepatocytes produced substantial reductions in both cccDNA and hepatitis B surface antigen (HBsAg). To evaluate ARCUS-POL in vivo, we developed episomal adeno-associated virus (AAV) mouse and non-human primate (NHP) models containing a portion of the HBV genome serving as a surrogate for cccDNA. Clinically relevant delivery was achieved through systemic administration of lipid nanoparticles containing ARCUS-POL mRNA. In both mouse and NHP, we observed a significant decrease in total AAV copy number and high on-target indel frequency. In the case of the mouse model, which supports HBsAg expression, circulating surface antigen was durably reduced by 96%. Together, these data support a gene-editing approach for elimination of cccDNA toward an HBV cure.
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