Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 212

HSV-2, a member of the Herpesviridae family of viruses is a
double-stranded DNA virus with a complex genome that encodes
more than 80 proteins. In a study conducted to evaluate the use of
siRNAs as topical vaginal microbiocides, the HSV-2 genes UL27 (the
HSV-2 envelope glycoprotein), and UL29 (the gene encoding ICP8, a
DNA binding protein) were targeted [98]. Mice treated intravaginally
with the two siRNAs complexed with a transfection lipid prior
to lethal challenge with HSV-2 exhibited increased survival rates
(60% and 75% with the anti-UL27 and -UL29 siRNAs, respectively,
compared with a 25% survival in control groups) and decreased
viral shedding. When siRNAs were administered 3 and 6 hours after
lethal challenge with HSV-2, only a combination of both UL27 and
UL29 siRNAs resulted in protection. This study highlighted that
siRNA can be eff ectively taken up at mucosal surfaces; however, the
lipid vehicle used to deliver the siRNA unfortunately also helped
transmit the virus nucleic acid.
A subsequent study by the same group investigated the eff ects
of treating mice with cholesterol-conjugated siRNAs that enable
direct entry across the cell membrane [124]. A solution made
of siRNAs targeting UL29 and the host gene nectin-1 (the HSV-2
cellular receptor) led to rapid but short-lived viral suppression
while targeting UL27, and a delayed but long-lasting suppression
for up to a week when the host molecule was targeted. This study
demonstrated the benefits of using fast-acting-but-short-lived RNAi
with the slower-acting-but-long-lived RNAi and underscored the
feasibility of treating HSV-2, and possibly other sexually transmitted
diseases, by topical application of cholesterol-conjugated siRNAs.

7.3 Positive-Strand RNA Viruses

7.3.1 Flaviviruses

The genus Flavivirus comprises approximately 70 species of small,
enveloped viruses with ~ 11 kilobase long positive-sense genomic
RNA [49] encoding a single ORF of three structural and seven
nonstructural (NS) proteins [81] bounded by a 5 ′ and 3 ′ untranslated
region (UTR). At least 38 flaviviruses (55% of all flaviviruses) are
medically important causing severe human disease with diff erent
clinical manifestations [52]. The extraordinary ability of flaviviruses