Gene Delivery Using Viral Vectors - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 223

Table 5.3 Adenoviral Vector-Mediated Transcription Factor

Name of Adenoviral Vector-Mediated
Transcription Factor

Functions

Oct-3/4 transcription factor A critical regulator of embryonic stems ES cell

differentiation in neurospheres consisting of
neural stem cells and neural progenitor cells
has influenced cell fate

Mesenchymal stem cells transduced with
an Ad vector carrying the human interferon-
 (IFN-) gene

Target delivery of IFN- to tumors, which
inhibited tumor cell growth

Angiogenic mitogens Bv8 and endocrine
gland-derived vascular endothelial growth
factor

Delivered by Ad vectors, promotes the
survival of hematopoietic cells and enhances
progenitor mobilization, where Bv8 induces
differentiation of the granulocytic and
monocytic lineages

New chimeric Ad5/F35 vectors Engineered to substitute the shorter-shafted fiber

protein from Ad35 and efficiently infect the
committed hematopoietic cells with low toxicity

Some recent studies show that Ad vector was not considered an efficient gene trans-
fer vector for the cells of hematopoietic origin. This inefficiency is the result of the cells
lacking receptors for Ad vectors. Ad infection has inherent limitations, such as short-
term expression and a nonintegrating nature, whereas hematopoietic stem cells (HSCs)
require long-term expression [85] . The transduced HSCs of mouse bone marrow can
be transduced with Ad5 at a low multiplicity of infection (MOI) and have shown nor-
mal in vitro myeloid differentiation potential, retained long-term in vivo repopulating
activity, and contributed to all blood cell lineages. Ad5 transduction of mouse HSCs
was dependent on Coxsackie and adenovirus receptor (CAR) because the use of anti-
CAR blocking antibody greatly reduced transduction [74] . Ad vector properties include
synthetic polymer coatings, genetically modified capsid proteins, antibody-redirected
fibers, and novel cis -acting integration sequences. Above all, these properties could
redirect and retarget Ad vectors to transfer genes into HSCs [79] .

5.2.6.6 Small Interfering RNA (shRNA) and Ad Vectors
Successful application of siRNA depends on the efficient delivery of siRNA into the
target cells that are refractory to transfection by DNA or RNA, and can be useful in
functional genomics and proteomics, cancer gene therapy, and virus protection. The
advantages of adenoviral vector-based siRNA delivery as a useful tool are high virus
titer, a broad spectrum of cell-type infectivity, and independence of active cell divi-
sion [70] . Targeting of Ad vectors expressing siRNA molecules against p53 or VprBP/
KIAA0800, a cellular protein that interacts with the human immunodeficiency virus
(HIV) auxiliary protein Vpr, has shown specific reduction in the target protein and the
corresponding mRNA level [68] . The adenoviral system containing two vectors, used
for efficient and controlled expression of hairpin siRNA (shRNA) by a tet operator, has