Biomedical Engineering Reference
In-Depth Information
been reported for transcriptional coactivator p300 regulation. In this system the tetra-
cycline repressor protein (TetR) encoded in a second Ad represses shRNA expression,
but the addition of tetracycline abolished TetR binding allowed shRNA transcription,
leading to targeted reduction of mRNA and protein level
[70]
. Regulated adenoviral
shRNA vectors are able to infect a wide array of replicating and nonreplicating cells
and can also allow controlled gene silencing.
The siRNA expression efficiently drives in islet
-cells and
-cell-derived cell
lines using recombinant adenoviral vectors; therefore, the recombinant Ad siRNA
vectors are useful for suppression of specific genes in pancreatic islets and
-cell
lines. The Ad-based siRNA gene transfer approach could be a potentially effective
adjuvant strategy for cancer treatment. Expression levels of hypoxia-inducible factor
1
(HIF-1
) could be significantly attenuated by the use of siRNA in combination
with Ad-mediated gene transfer, and downregulation of the HIF-1
protein could
enhance hypoxia-mediated tumor cell apoptosis
in vitro
[71]
.
5.3 Adeno-Associated Virus (AAV)
Human AAV was discovered in 1965
[86]
as a contaminant of adenovirus (Ad) prepa-
rations. AAV is one of the smallest viruses, with a nonenveloped capsid of approxi-
mately 22 nm, and it is replication defective, infecting humans and some other primate
species. AAV can infect both dividing and nondividing cells and may incorporate its
genome into that of the host cell. These AAV are not currently known to cause disease,
but the virus causes a very mild immune response. All these features make AAV a very
attractive candidate for creating viral vectors for gene therapy
[86]
. AAV serotypes
are ascribed to a separate genus in the
Parvoviridae
family designated
Dependovirus
.
Advantages and drawbacks of AAV vectors are shown in
Table 5.4
.
5.3.1 Classification of Adeno-Associated Virus
Group: Group II (ssDNA)
Family: Parvoviridae
Subfamily: Parvovirinae
Genus: Dependovirus
Species: Adeno-associated virus
Accordingly, the majority of clinical trials currently in progress involve deliv-
ery of AAV2 into the brain, a relatively immunologically privileged organ. AAV2
is strongly neuron specific in the brain
[86-89]
. Clinical trials for the treatment of
prostate cancer have reached phase III; however, these
ex vivo
studies do not involve
direct administration of AAV to patients
[90,91]
.
5.3.2 Pathology
AAV does not have a specific known role in any disease, but it has been suggested
that it plays a role in male infertility
[92]
. AAV DNA is more commonly found in
semen samples from men with abnormal semen, but no causal link has been found
between AAV infection and male infertility.
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