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IL-12p70); however, some non-specific silencing intrinsic to the formulation was
observed. Colitis protection (moderate intestinal inflammation and healthy colon
morphology) was only evident in the anti-TNF-a siRNA-treated mice.
An alternative strategy based on a systemic RNAi-based IBD treatment was
revealed by the elegant study by Peer et al. [ 91 ]. In this study, i.v. administration of
particles targeting a specific leucocyte subset (b7 integrin expressing gut mononu-
clear leucocytes) was utilised for the treatment of DSS-induced colitis. The design
of the system, termed b7-I-tsNPs, has a protamine/siRNA core complex coated
within a unilamellar vesicle decorated with an anti-integrin b -7 antibody.
Administration of CyD1-specific siRNA (~50 m g/dose) b7-I-tsNPs at days 0, 2, 4
and 6 resulted in reduced intestinal mRNA levels of this cell cycle regulatory mole-
cule and simultaneous mRNA reduction of the proinflammatory cytokines TNF-a
and IL-12. This resulted in significantly less severe lesions at the intestinal tissue
and the reversal of clinical and pathological characteristics associated with the onset
of the DSS-induced colitis. The observed local effect may be attributed to the CyD1
silencing of peripheral blood and spleen leucocytes prior their recruitment to the
in fl amed gut.
We are currently evaluating the potential of siRNA nanoparticles formulated
with the non-toxic, biodegradable and mucoadhesive polymer chitosan for the
reduction of proinflammatory cytokines after oral administration. Encouraging
results have been recently obtained in animal experiments, suggesting strong nucle-
ase-protection and high gastrointestinal siRNA deposition provided by this system
(unpublished results).
5.5
Rectal Delivery
Rectal administration is an attractive route for siRNA delivery as it circumvents the
low stomach pH, is an established route for traditional drugs and the colon presents
a low enzymatic milieu. In addition, direct access to the site of several diseases such
as colorectal carcinoma or ulcerative colitis further promotes this route.
Zhang et al. [ 92 ] demonstrated that rectal administration of lipoplexes containing
anti-TNF-a siRNA (two doses of ~53 m g siRNA) signi fi cantly reduced the upregu-
lation of TNF-a mRNA in a DSS-induced ulcerative colitis mouse model. Reduced
perirectal TNF- a mRNA levels were associated with mild or moderated inflammation
at the mucosa of the descending colon compared to the severe inflammation observed
in the controls. Interestingly, despite toxicity previously reported with similar lipo-
somal formulations, no increase in proinflammatory cytokines (IL-1, IL-10, TNF-a )
or interferon responses was found. In a later study [ 93 ] , fl uorescent and chemically
modified siRNA contained within DOTAP liposomes was detected in the spleen,
bone marrow, colon and liver after rectal administration in mice. This supports the
capability for nanoparticles to migrate into the systemic circulation that could be
exploited for both local and systemic gene silencing.
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