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immune responses due to Toll-like receptor (TLR) engagement. Proinflammatory
responses are highly detrimental, particularly in inflammatory disorders. The endo-
cytic pathway undertaken by particles can increase delivery into a TLR-rich
environment that can inadvertently potentiate the response. Fortunately, these TLR-
dependent (through TLR-3, -7 and -8 signalling) or independent (through RIG-1
and PKR activation) adverse side effects can be avoided by siRNA structure and
sequence modification such as 2ยข - O -methyl substitutions. Induction of non-specific
immune responses is particularly pertinent in the mucosal immune system rich in
immunocompetent sites evolved to recognise and protect against foreign luminal
material. Evaluation of immune responses to both siRNA and carrier needs to be
adequately addressed going forward.
In the foreseeable future, clinical trials are set to seemingly follow the lead
towards treatment of pulmonary diseases such as RSV infection. Established pul-
monary delivery technologies used for traditional inhalable drugs should allow
rapid clinical translation. Identification of novel targets will push the field forward.
An interesting approach is targeting host factors required for viral replication such
as influenza rather than viral-specific targets [ 56 ] .
There is a general shift in the RNAi field from conventional siRNA to miRNA-
based agents that is set to follow for mucosal RNAi therapeutics. Deep sequencing
technologies are set to be used for rapid identification of mucosal miRNA targets.
Mucosal delivery holds many advantages over the systemic approach and is now
showing promise for delivery of siRNA that could lead to rapid clinical translation
of mucosal-based RNAi therapeutics.
References
1. Davidson BL, McCray PB (2011) Current prospects for RNA interference-based therapies.
Nat Rev Genet 12(5):329-340
2. de Fougerolles A, Vornlocher H-P, Maraganore J, Lieberman J (2007) Interfering with dis-
ease: a progress report on siRNA-based therapeutics. Nat Rev Drug Discov 6(6):443-453
3. Wu L, Belasco JG (2008) Let me count the ways: mechanisms of gene regulation by miRNAs
and siRNAs. Mol Cell 29(1):1-7
4. Gao S, Dagnaes-Hansen F, Nielsen EJB, Wengel J, Besenbacher F, Howard KA, Kjems J
(2009) The effect of chemical modification and nanoparticle formulation on stability and
biodistribution of siRNA in mice. Mol Ther 17(7):1225-1233
5. Bramsen JB, Kjems J (2011) Chemical modification of small interfering RNA. Methods Mol
Biol 721:77-103
6. Soutschek J, Akinc A, Bramlage B et al (2004) Therapeutic silencing of an endogenous gene
by systemic administration of modified siRNAs. Nature 432(7014):173-178
7. Howard KA, Rahbek UL, Liu X et al (2006) RNA interference in vitro and in vivo using a
chitosan/siRNA nanoparticle system. Mol Ther 14(4):476-484
8. Akinc A, Zumbuehl A, Goldberg M et al (2008) A combinatorial library of lipid-like materi-
als for delivery of RNAi therapeutics. Nat Biotechnol 26(5):561-569
9. Rettig GR, Behlke MA (2011) Progress toward in vivo use of siRNAs-II. Mol Ther 20(3):483-
512. doi: 10.1038/mt.2011.263
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