Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 214

in their capacity to complex siRNAs. The ability of JetSI/DOPE to
package a higher dosage of siRNA improved survival statistics with
60% of the mice treated as late as 18 hrs post challenge recovering
from encephalitis. The study demonstrated that short-lived synthetic
siRNAs were sufficient to protect against acute neuronal infections
like flaviviral encephalitis by persisting for extended periods of time
in non-dividing cells like neurons. Perhaps the most notable feature
of the study was the ability of a synthetic siRNA designed against the
conserved fusion-loop region of the flaviviral envelope to provide
cross-protection against both JEV and WNV. 100% of the mice were
protected when treated with lipid-siRNA complexes before viral
challenge while 80% of mice having an established infection with
WNV or JEV were protected. These results emphasized the power
of RNAi therapeutics as broad-spectrum antivirals against related
viruses with practically indistinguishable clinical manifestations.
Furthering their studies, the same group developed a novel
method for the transvascular delivery of siRNAs into the brain tissue
across the BBB [72]. A chimeric peptide consisting of a 32 amino
acid sequence derived from the RVG for binding of the α7 subunit of
the nicotinic actylcholine receptor expressed on neuronal cells and a
positively charged D-arginine nonamer for siRNA binding was used
as the siRNA nanocarrier. This peptide electrostatically complexed
siRNA at a 10:1 M ratio to form particles ~110 nm in diameter and
delivered the payload specifically into mouse brain tissue in vivo
after simple intravenous (i.v.) injection. Treatment with complexes
containing siRNA targeting the flaviviral envelope gene protected
80% of mice from a lethal challenge with JEV, without activating an
innate interferon response. Taken together, the results from these
studies suggested that siRNA-nanocarriers are a viable therapy for
treating acute flaviviral encephalitis.
7.3.1.2 Hemorrhagicfl aviviruses: Yellow fever virus (YFV) and
dengue virus (DENV)
YFV, also a mosquito-borne flavivirus causes severe hepatitis and
hemorrhagic fever. Despite the existence of an eff ective vaccine
for more than 70 years now, YFV still results in nearly 200,000
human infections per year, mostly in Africa and South America due
to incomplete vaccination of endemic inhabitants [7]. The closely
related DENV is a group of four antigenically distinct serotypes
(DENV1-4) that cause dengue fever (DF), and in more severe cases