Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 225

eight gene segments that are enclosed in an envelope composed of
hemagglutanin (HA) neuraminidase (NA) and matrix 2 (M2) proteins.
In addition, the genome encodes three components of the viral RNA-
dependent RNA polymerase (RdRp): polymerase acidic protein (PA),
polymerase basic protein 1 (PB1) and PB2, nucleoprotein (NP), and
two non-structural proteins: NS1A and NS2. While Influenza B and
C have a limited host tropism, Influenza A can infect a variety of
mammals and is thus a major public health concern. Categorization
of Influenza A is determined by the antigenic HA and NA subtypes
that drift in prevalence from year to year escaping existing immune
defenses and limiting the eff ectiveness of prophylactic vaccines.
Approaches targeting conserved regions of Influenza A genes, such
as those aff orded by RNAi, could provide broad protection from
potentially pandemic strains.
The first in vivo studies evaluated antisense phosphorothioate
oligonucleotides (s-ODN) targeting PB-2 and PA against the H1N1
A/PR/8/34 strain. i.v. administration of ODNs encapsulated in the
cationic liposome Tfx [55, 90] prior to infection reduced target
mRNA levels and viral titers in mouse lungs resulting in reduced
neutrophil infiltration and fewer bronchiolar and alveolar edemas
thus significantly increasing the time of survival. Interestingly, i.n.
or i.p. administration of liposomally encapsulated s-ODNs failed to
promote uptake into lung tissues.
In 2004, two groups reported the results of in vivo administration
of siRNAs that targeted NP and components of the RdRp. siRNAs
directed against NP and/or PA were complexed with either PEI [41]
or lipofectamine [110] and delivered to mice i.v. prior to infection.
In both studies large reductions in viral titers up to 100-fold were
observed against several strains of influenza including H1N1,
H5N1, H7N7 and H9N2 and survival rates of mice were significantly
increased. Treatment with a combination of these siRNAs was more
potently inhibitory. Combinations of PEI complexed siRNAs targeting
NP and M2 [132] or 2 ′ O -methyl modified siRNAs complexed to
lipofectamine targeting NP and NS1 [125] have also been explored
in vivo with similar results. Treatment prior to infection increased
survival of mice (i.v. treatment) or chickens (i.n. treatment) following
challenge with lethal dose of H5N1 with significant reductions in
viral titers.