Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 213

to utilize new vectors for transmission and spread to new geographic
regions highlights the need for a safe and efficient antiviral therapy
for these emergent and recurrent infectious agents [84]. Flaviviruses,
like other positive-sense RNA viruses, use their RNA genomes for both
replication and translation in the host cell cytoplasm, making them an
attractive target for the cytoplasmically located host RNAi machinery.
7.3.1.1 Encephaliticfl aviviruses: Japanese encephalitis virus
(JEV) and West Nile virus (WNV)
Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is the
major cause of pediatric encephalitis in Asia resulting in up to 50,000
cases reported annually [118]. West Nile virus (WNV) another closely
related mosquito-borne encephalitic flavivirus was endemic in Africa,
Asia and Europe before 1999 [48]. In 1999 after the first incidence in
New York, USA, the virus quickly spread becoming endemic to all the
50 states within 4 years causing thousands of human infections and
hundreds of deaths each year [48]. Two prophylactic JEV vaccines
are available for human use; however, no antiviral therapies exist for
any flavivirus.
The major hurdle for harnessing the therapeutic efficacy of RNAi
for flaviviral encephalitis is the presence of a blood brain barrier
(BBB) that restricts siRNA delivery into the brain tissue. The very
first in vivo demonstration of the feasibility of RNAi therapy for
encephalitic flaviviruses tested the eff ects of two diff erent siRNAs
targeting the WNV envelope gene in the murine model of WNV
infection [5]. Only one of the siRNAs reduced the viral load and
aff orded partial protection when administered in the naked form by
hydrodynamic tail vein injection 24h before lethal challenge with an
intraperitoneal (i.p.) inoculum of WNV. The poor in vivo efficacy was
perhaps due to the inefficient delivery of siRNA to brain tissue.
In 2006, a study by Kumar and coworkers [71] examined the
protective eff ects of RNAi therapies using intracranial (i.c.) injections
for the delivery of si/shRNA targeting sequences in the envelope
gene of JEV and WNV. Using a lentiviral vector pseudotyped with the
rabies virus glycoprotein (RVG) for improved neuronal spread, they
achieved complete protection of mice against challenge with both
WNV and JEV using shRNAs targeting the corresponding envelope
gene sequences. Excellent protection was also observed upon i.c.
injection of synthetic siRNA complexed to lipid delivery reagents.
The study tested two cationic lipids i-Fect and JetSI/DOPE that varied