Biomedical Engineering Reference
In-Depth Information
trials in 2007 [29]. In both trials no serious adverse events were
reported with single doses up to 150 mg or daily doses up to 150
mg daily for 5 days. This provided the foundation for a phase II trial
whose promising results were recently reported [30]. Eighty five
healthy males ages 18-45 were dosed i.n. two days before and three
days after challenge with ~4.7 log PFU RSV A (Memphis 37). The
dosages were 75 mg and 150 mg of ALN-RSV01 for the pre- and post
infection studies. When compared with placebo-treated group, the
ASN-RSV01 treated groups had a statistically lower proportion of
subjects infected (44% vs. 71%) and a lower acquisition of infection
over time. While not powered to show significance, the ALN-RSV01-
treated groups trended toward lower viral loads when compared
with placebo. Based on results from this trial, volunteers are now
being recruited for a Phase IIb trial to assess efficacy of ALN-RSV01
in lung transplant patients infected with RSV [23].
RSV NS1 is thought to antagonize the host cell IFN response
through an unknown mechanism and deletion of NS1 or NS2
attenuates RSV infection both
in vivo
and
in vitro
rendering NS1 a
potential therapeutic target for siRNA mediated knockdown [109,
117]. Nanoparticles consisting of siRNA directed against NS1
complexed to a nanochitosan polymer eff ectively knocked down
NS1 expression in mice treated i.n. [130]. This corresponded to
significant decreases in viral titer, and a significant increase in IFN-β
production for up to 4 days when treated prior to infection and up
to 2 days p.i. The RSV phosphoprotein (P) complexes with the large
protein (L) to form the viral RNA-dependent RNA polymerase. P
protein is an essential transcription factor of L and inhibition of P
has been shown to decrease viral transcription and replication [9].
Naked or TransitIT-TKO complexed siRNA against a P gene sequence
was administered i.n. to mice prior to infection [11]. The complexed
siRNA reduced pulmonary titers of RSV by 99.98% while naked
siRNA was ~80% as eff ective. The advantage of siRNA therapy for
lung infections is the reduced side eff ects in non-targeted tissues as
siRNA and the transfection reagents congregate solely in the lung
following i.n. administration.
7.5.2 Ebola(EBOV)
EBOV is a filovirus that causes severe hemorrhagic fever in
humans and non-human primates. Although outbreaks in human
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