Abstract
Chronic hepatitis B virus (HBV)
infection causes hepatitis, liver cirrhosis and hepatocellular
carcinoma. Covalently closed circular DNA (cccDNA) is the transcription
template for HBV RNAs and not affected by current treatment options.
Effective therapeutics with ability to remove cccDNA need to be
developed. Previously, we established an HBV persistence mouse model via
hydrodynamic injection of a clinical isolate (BPS) and identified IL-21
as a potent inducer of viral clearance. Here, we aimed to explore the
anti-HBV effects of IL-21 messenger RNA (mRNA) delivered by lipid
nanoparticle (LNP-IL-21) system. First, LNP-IL-21 was prepared and
analyzed for its safety, expression, biodistribution and stabilityin vitro and in vivo . Next, LNP-IL-21 was injected into
two HBV persistence mouse models based on BPS and recombinant cccDNA
(rcccDNA) respectively. LNP-IL-21 administration successfully cleared
HBV serum markers, and more importantly, BPS replicons and rcccDNA in
livers, which was associated with activation of viral specific immune
responses. Notably, transfer of peripheral blood mononuclear cells from
BPS persistence mice stimulated ex vivo with LNP-IL-21 and viral
antigen could induce HBV clearance in recipient mice.
These findings suggested that
both LNP-IL-21-based gene and cellular therapies provided novel
therapeutic strategies against chronic HBV infection.