Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 224

populations are rare, they remain a major public health concern as
potential agents of bioterrorism. There are currently no therapies
for the treatment of EBOV and fatality rates range from 42-90%
[54]. Reducing the rate of replication early in infection is expected
to aid a successful immune response against EBOV. Transcription
and replication of the filovirus genome relies on viral proteins
VP35, VP30, the nucleoprotein (NP), and the viral polymerase (L).
In addition to its role in transcription and replication, VP35 is also
thought to repress host cell type I interferon responses.
PMOs against VP35 have been developed to suppress EBOV
infection. Intracellular delivery of the PMOs was achieved by
conjugation to a cell-penetrating arginine rich peptide (P-PMO)
[36]. i.p. treatment of mice with 500 μg of P-PMO or unconjugated
PMO against VP35 prior to infection with a lethal dose of EBOV
ensured high survival rates of 100% and 85%, respectively. A single
dose of 500 μg of VP35-specific P-PMO administered 24 hours after
infection with a lethal dose of EBOV also resulted in survival rate of
100% [42]. A pool of four siRNAs against the L gene encapsulated in
SNALPs and administered to guinea pigs at 1mg/kg i.p. daily for the
first 6 days p.i. maintained plasma EBOV levels below the range of
detection from day 12 through day 30. Combinatorial targeting with
PMOs against VP35, L, and VP24, a membrane associated protein
postulated to have interferon suppressing eff ects, were tested in
multiple animal models including murine, guinea pig and non-
human primates [115]. In all three models, the results were very
promising conferring 75-100% protection against lethal challenge
with EBOV and also enabling immune T cell responses in the mouse
model that helped counter a repeat challenge with EBOV. Recently,
siRNA targeting these same genes were also tested in a non-human
primate model [43]. The siRNAs were modified with 2 ′ - O -methyl
guanosine or uridines to reduce stimulation of IFN and encapsulated
in SNALPS. When treated daily with 2mg/kg EBOV SNALPs, rhesus
macaques had a 100% survival rate and undetectable viral loads by
day 14. The availability of data from large animal studies indicates
RNAi could be a plausible treatment for EBOV.
7.5.3 Infl uenza
Influenza viruses are of the family Orthomixoviridae that have a
negative sense segmented RNA genome. Influenza A and B contain