Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 205

the intended tissue is sometimes plausible as with intranasal (i.n.)
and intraocular inoculations. Further, the impenetrance of several
cell types to naked siRNA and impracticality of physical methods like
electroporation and hydrodynamic injections for clinical application
makes it essential to find a means to target delivery upon systemic
administration of inhibitory RNAs. A few approaches have been
achieved in vivo by encasing siRNAs within lipids that enable delivery
to the liver [92] or conjugation to molecules like tetramers, peptides
or antibodies that recognize surface receptors on target cells [70, 72,
135]. This also enables uptake of the siRNAs not capable of passive
diff usion into cells.
Designing RNAi-therapeutics to treat viral infections faces
additional and unique challenges. The high sequence specificity of
siRNAs allows mutating viruses to escape under siRNA pressure.
Escape can occur by changing just one nucleotide within the target
sequence [12]. Further, numerous viruses have evolved efficient
suppressors of RNAi that could compromise antiviral RNAi strategies
[8, 80]. Targeting an early stage in the viral life cycle before a
suppressor accumulates, or directly targeting the suppressor mRNA,
may be necessary to circumvent these mechanisms of viral resistance.
The use of inhibitory RNAs that target multiple highly conserved
regions of the viral RNA where mutations would be associated with
a loss in viral fitness or host factors that are immutable and do not
cause adverse eff ects upon being depleted (i.e., the HIV coreceptor
CCR5) may prevent escape mutants.
Since RNAi was first described we have been witness to
identification of potent problems associated with RNAi therapeutics
and several innovations for overcoming them to enable the potential
translation of RNAi into a viable clinical therapeutic modality. The
first siRNA-based antiviral to successfully enter phase I clinical trials
in 2007 used siRNAs to target Respiratory syncytial virus (RSV)
infection [29]. Since then several other RNAi-based drugs are being
tested in clinical trials, with many more in the pipeline. In this chapter,
we lay a special emphasis on the numerous RNAi-based approaches
that have shown promise as antivirals in preclinical animal models
and clinical trials (summarized in Table 7.1).