Biomedical Engineering Reference
In-Depth Information
this study emphasised the need to carefully consider, monitor, and
control for siRNA-mediated immune stimulation.
Immune activation in a subject receiving siRNA treatment
remains a major concern when introducing RNAi in a clinical setting.
However, it is important to note that non-specific immunostimulatory
responses may provide therapeutic benefit in the treatment of
certain diseases, particularly in the local delivery setting. Indeed,
the potential beneficial aspects of such siRNAs are only now being
realized with most studies going to great lengths to avoid any
immune stimulation. To date, the use of RNAi to augment immune
responses has only been pursued in three ways. Firstly, RNAi has
been utilised directly for immunotherapy. For example, anti-IL-10
immunostimulatory siRNAs were shown to both suppress IL-10
expression and activate the production of interferons and cytokines.
The activation of these immune mediators simultaneously inhibited
the expression of immunosuppressive factors and induced innate
immunity to enhance the response of allogeneic T cells [73].
The second application of RNAi immune activation has been for
the treatment of viruses. While targeting Influenza A, it was reported
that lipoid-delivered unmodified siRNAs had anti-viral activity.
However, as siRNAs against unrelated targets also suppressed
influenza replication
, this activity was not dependent on
sequence homology to the influenza genome [74]. Therefore, the
majority of anti-viral activity was caused by the immunostimulatory
effects of the siRNA and not by its silencing abilities. This suggests
that immune activation by RNAi may be beneficial as a therapy
for certain viruses. Furthermore, a recent study established that
immunostimulatory synthetic 20 bp RNA oligonucleotides have
the ability to block suppression by T regulatory cells via activation
through RIG-I and MDA-5 [75]. This activation enabled the generation
of an efficient immune response against viruses, indicating that
immunostimulatory RNAi may initiate multiple pathways that assist
in viral knockdown.
Thirdly, immune activating siRNAs have been used as a thera-
peutic cancer agent. A recent study reported by Poeck and colleagues
clearly indicates the potential added benefit of immune activating
siRNA in a melanoma cancer model. The activation of RIG-1 by 5
in vivo
′
triphosphate was demonstrated to synergistically promote tumour
cell apoptosis when an immunostimulatory siRNA targeting Bcl2
was administered intravenously [76]. Kortylewski and colleagues
furthered the initial idea of using immunostimulatory RNAi as an
Search WWH ::
Custom Search