Biomedical Engineering Reference
In-Depth Information
treatment unlike lentivirally delivered shRNA. However, the greatest
impediment to the use of siRNA for HIV therapy is the intransigence
of immune cells, particularly primary T cells to siRNA uptake. Using
a single-chain antibody to the human T cell-specific surface molecule
CD7 coupled to the siRNA carrier oligo-9-D-arginine (scFVCD7-9R),
Kumar and coworkers showed that systemic T cell specific siRNA
delivery for the treatment of HIV is a feasible strategy [70]. Binding of
the scFv to CD7 induced internalization enabling cytoplasmic delivery
of the siRNAs. Weekly treatment with scFVCD7-9R complexed to a
combination of siRNAs targeting the viral genes vif and tat and/or
CCR5 enabled control of HIV infection in two diff erent humanized
mouse models NOD-SCID-IL2r γ mice reconstituted with human
PBMC or HSC. The treatment was also able to suppress endogenous
virus in mice reconstituted with PBMC from a HIV-positive donor.
Significantly this approach enabled siRNA delivery into naïve and
resting T cells, important reservoirs for latent HIV that develop in
NOD-SCID-IL2r γ mice reconstituted with human HSC, and resulted in
reduced viral loads and maintenance of normal CD4 T cell numbers
with no toxicity or disruption of endogenous RNAi pathway.
One drawback of using scFvCD7 was the inability to target
other cells infectable with HIV such as macrophages and dendritic
cells. Recently, this group tested a new strategy where neutral lipid
based siRNA carriers were surface modified to include an antibody
directed against LFA-1, an integrin present on all leukocytes [66].
These nanoliposomes allowed the delivery of a siRNA payload 3
logs greater than the arginine carrier. i.v. treatment of humanized
mice with 50 μ g encapsulated siRNA targeting CCR5 three times
during viral challenge enabled control of viral replication for nearly
2 months and did not require the weekly treatment regimen used in
the previous study.
An alternate approach targeted HIV infected cells using RNA
aptamers against HIV gp120 that get internalized after binding their
target. The gp-120 aptamer was either (i) covalently linked to siRNAs
that target the HIV-1 tat/rev common exon, or (ii) non-covalently
linked to siRNAs via complementary GC-rich sticky bridge sequences
attached to the 3 end of the aptamer and to one of the two siRNA
strands, which allowed Watson-Crick base pairing [135]. While the
first method allowed delivery of a single siRNA the second facilitated
the eff ective interchange of diff erent siRNAs with a single aptamer.
Hence this approach was tested with a combination of siRNAs
 
Search WWH ::




Custom Search