Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 208

7.2 DNAViruses
7.2.1 Hepatitis B Virus (HBV)
HBV, a member of the Hepadnavirus family, comprises a partially
double-stranded relaxed circular DNA genome. HBV poses a threat
to public health worldwide, with an estimated 350 million people
being chronically infected with the virus and an estimated 600,000-
1,200,000 HBV-related deaths per year [74]. Chronic infection with
HBV can lead to significant health problems including cirrhosis of
the liver and hepatocellular carcinoma. Although a very eff ective
HBV vaccine exists, therapeutics for individuals infected with HBV
are lacking [74]. Currently, chronic HBV infections are treated with
interferon- α , often in combination with nucleoside or nucleotide
analogues. However, the low overall efficacy, poor compliance and
toxicity of these drug regimens [94] have spurred an interest in
potential RNAi therapies for chronic HBV infection despite the lack
of relevant and reliable small animal models for HBV [105].
One of earliest in vivo studies by McAff rey and coworkers [86]
tested a panel of seven diff erent U6 promoter driven anti-HBV
shRNAs targeting sequences conserved across HBV genotypes for
blocking HBV replication from a plasmid expressing the HBV genome.
Hydrodynamic transfection of mice via tail vein injections with both
the shRNA and HBV expression plasmids resulted in a reduction
of serum HBV surface antigen (HBsAg) and liver-associated HBV
core antigen (HBcAg). The negative strand of the HBV genome
consists of four partially overlapping open-reading frames (ORFs)
that encode the viral transcripts [104]. The most eff ective shRNA
mapped to a sequence in the overlapping reading frames enabling
the simultaneous targeting of 3 of the 4 viral RNA transcripts [86].
Another study treated mice with hepatocytes transgenic for HBV
with hepatotropic recombinant adenoviruses expressing anti-HBV
shRNAs targeting the same sequence in the overlapping ORFs. This
also led to reduced serum HBsAg and liver HBcAg levels throughout
a 26-day period of experimentation [112].
Numerous studies have since demonstrated shRNA-mediated
repression of HBV replication in murine models [18, 20, 32, 44,
45, 100-102, 105]. However, the results of one particular in vivo
study raised concern over the use of shRNAs in human therapy.