Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 215

dengue hemorrhagic fever (DHF) and dengue shock syndrome
(DSS). Annually, DENV infects an estimated 100 million people
[49] with 500,000 of these cases resulting in DHF/DSS and 25,000
deaths per year [84]. The high amount of morbidity and mortality
associated with this virus makes DENV the most epidemiologically
significant arthropod-borne virus [57]. As with most flaviviruses, no
vaccines or therapies exist for DENV infections. Small animal models
that manifest clinical signs consistent with viscerotropism, acute
hepatitis, and hemorrhagic fever upon infection with these viruses
have been lacking, limiting evaluation of antiviral RNAi strategies to
cell lines and mosquito vectors.
Using an intracerebral acute challenge murine model for YFV, the
ability of shRNAs targeting highly conserved sites in the YFV genome
to protect from lethal challenge was investigated [97]. I.c. injection
with a plasmid expressing the anti-NS1 shRNA but not anti-envelope
shRNA provided a small, but significant amount of protection from
lethal challenge . The study suggested that RNAi may be a feasible
YFV therapy but would likely depend on the sequences targeted.
An adeno-associated virus carrying an siRNA targeting the 3 ′ UTR
of DENV resulted in a dose-dependent inhibition of DENV in human
dendritic cells (DCs), the primary cell target of the virus [49]. In an
eff ort to target these cells in vivo , a DC3 peptide previously identified
to bind DCs was modified to incorporate the 9R carrier (as described
above in [72]).Treatment with this DC3-9dR nanocarrier complexed
to siRNA targeting the DENV envelope gene inhibited DENV
replication in both DCs and macrophages [108]. The cytokine TNF- α
is believed to be the mediator of plasma leakage seen in DHF/DSS
patients [103]. A siRNA targeting TNF- α used in conjunction with
the DC3-9R nanocarrier significantly reduced DENV-induced TNF- α
expression in DCs in vitro and poly-IC-induced TNF- α expression
in vivo . DENV infected DCs that were simultaneously treated with
DENV and TNF- α siRNAs showed decreased TNF- α expression and
decreased viral loads. Taken together these results suggest an RNAi-
therapy targeting both the virus and a host gene could be developed
to control the immunopathology associated with DENV infection.
7.3.3 Hepatitis C Virus (HCV)
HCV is a member of the genus hepacivirus in the family Flaviviridae
and causes serious liver diseases such as cirrhosis and hepatocellular