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Published on: February 1, 2017
Class A capsid assembly modulator RG7907 clears HBV-infected hepatocytes through core-dependent hepatocyte death and
Dieudonné Buh Kum1,2, Hannah Vanrusselt1, Abel Acosta Sanchez3
1Aligos Belgium BV, Leuven, Belgium.
Insights
New capsid assembly modulators (CAM-As) like RG7907 trigger hepatitis B virus core protein aggregation, leading to infected cell death and potential functional cure. This mechanism offers a promising strategy for chronic hepatitis B treatment.
Area of Science:
- Hepatology
- Virology
- Immunology
Background:
- Chronic hepatitis B lacks effective functional cure therapies.
- Capsid assembly modulators (CAM-As) are a promising therapeutic modality.
- CAM-As induce hepatitis B virus (HBV) core protein (HBc) aggregation, reducing HBsAg levels.
Purpose of the Study:
- To investigate the mechanism of action of the CAM-A compound RG7907.
- To elucidate how HBc aggregation leads to viral clearance and potential functional cure.
Main Methods:
- In vitro and in vivo studies using hepatoma cells, primary hepatocytes, and an adeno-associated virus (AAV)-HBV mouse model.
- Treatment with RG7907.
- Analysis of HBc aggregation, viral markers (HBsAg, HBeAg), episomal DNA, liver enzymes, apoptosis, proliferation, and gene expression via RNA sequencing.
Main Results:
- RG7907 induced extensive HBc aggregation in vitro and in cells.
- In vivo, RG7907 treatment significantly reduced serum HBsAg and HBeAg.
- Liver showed clearance of HBsAg, HBc, and AAV-HBV episomes, with transient increases in liver enzymes, apoptosis, and proliferation markers, linked to interferon signaling.
- HBc aggregation was directly linked to apoptosis and loss of infected hepatocytes.
Conclusions:
- HBc aggregation by CAM-As induces apoptosis, leading to hepatocyte turnover and loss of HBV DNA.
- An induced innate immune response may assist this process.
- This mechanism represents a novel and promising strategy for a functional cure of chronic hepatitis B.
Background And Aims:
Effective therapies leading to a functional cure for chronic hepatitis B are still lacking. Class A capsid assembly modulators (CAM-As) are an attractive modality to address this unmet medical need. CAM-As induce aggregation of the HBV core protein (HBc) and lead to sustained HBsAg reductions in a chronic hepatitis B mouse model. Here, we investigate the underlying mechanism of action for CAM-A compound RG7907.
Approach And Results:
RG7907 induced extensive HBc aggregation in vitro , in hepatoma cells, and in primary hepatocytes. In the adeno-associated virus (AAV)-HBV mouse model, the RG7907 treatment led to a pronounced reduction in serum HBsAg and HBeAg, concomitant with clearance of HBsAg, HBc, and AAV-HBV episome from the liver. Transient increases in alanine transaminase, hepatocyte apoptosis, and proliferation markers were observed. These processes were confirmed by RNA sequencing, which also uncovered a role for interferon alpha and gamma signaling, including the interferon-stimulated gene 15 (ISG15) pathway. Finally, the in vitro observation of CAM-A-induced HBc-dependent cell death through apoptosis established the link of HBc aggregation to in vivo loss of infected hepatocytes.
Conclusions:
Our study unravels a previously unknown mechanism of action for CAM-As such as RG7907 in which HBc aggregation induces cell death, resulting in hepatocyte proliferation and loss of covalently closed circular DNA or its equivalent, possibly assisted by an induced innate immune response. This represents a promising approach to attain a functional cure for chronic hepatitis B.
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