Biomedical Engineering Reference
In-Depth Information
Since rapid emergence of viral escape mutants often abrogates
the RNAi efficacy, continued efforts have been made to develop an
aptamer-mediated combinatorial multi-targeting RNAi approach.
In this regard, the anti-gp120 aptamer was conjugated with three
different dsiRNAs targeting HIV-1
transcripts and HIV-1 host
dependency factors (CD4 and Transportin-3 (TNPO3)) through the
“sticky” bridge [31], thus providing marked suppression of viral
loads and protection of CD4
tat/rev
+
T-cells
in vivo
(Zhou
et al
., Functional
in vivo
delivery of multiplexed anti-HIV-1 siRNAs via a chemically
synthesized aptamer with a sticky bridge,
, 2012,
submitted). The combination of aptamer and siRNAs has the added
potential benefit of multiple therapeutic modes of action thereby
minimizing the potential for viral escape by mutation.
Gene Therapy
5.3.1.3
CD4 RNA aptamer-functionalized siRNAs
CD4, the primary receptor for the human immunodeficiency virus
(HIV), plays an important role in HIV entry into host T-cells [76, 80, 81].
The anti-CD4 RNA aptamers have provided HIV inhibition in a
CD4-specific manner [28]. Most recently, a CD4 aptamer was fused
with a siRNA targeting CCR5 and shown to specifically suppress
gene expression in CD4
+
in cervicovaginal
tissue explants [82]. Moreover, the aptamer-siRNA chimeras (CD4-
AsiCs) did not activate lymphocytes or stimulate innate immunity.
When applied intravaginally to humanized mice, the CD4-AsiCs
protected against HIV vaginal transmission. CD4-AsiCs could be
used as the active ingredient of a microbicide to prevent HIV sexual
transmission.
T-cells and macrophages
5.3.2
Cell-Specific Aptamer-Functionalized Therapeutic
Nanocarriers
The advent of nanotechnology has greatly accelerated the deve-
lopment of drug delivery, providing a large variety of nanocarriers
for disease therapy [83] (Fig. 5.1D). In particular, a multifunctional
therapeutic nanocarrier system in which several desirable functions
such as therapeutics (RNAi therapeutics, chemotherapy agents, or
radioactivity agents), targeting (aptamers or other ligands), and
imaging (fluorescent dye) are combined in one nanoscale carrier is
highly desirable. As reported recently, several cell-specific aptamers
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