Gene Delivery Using Viral Vectors - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 222

E1a or E1b attenuates viral replication in normal cells with functional Rb and p53 ,
respectively. Viruses are capable of productively replicating and ultimately lysing the
cell in cancer cells where p53 and Rb are often mutated during the course of onco-
genesis. Oncolytic, first-generation Ads can treat the cancer by selectively replicating
in tumor cells, but not in normal cells. One such type of virus, Onyx-015, has pro-
gressed to clinical trial [75,76] . Onyx-015 is unable to replicate in cells that express
wild-type p53 because Onyx-015 lacks the E1b proteins. In normal cells, Onyx-015
is expected to be replication deficient and replication competent in tumor cells with
p53 mutations. In preclinical studies, investigators have increased the potency of
Onyx-015 by inserting coding sequences for the HSV-TK gene, creating a bivalent
therapeutic [77,78] .
5.2.6.4 Adenovirus as Recombinant Vaccines
In vitro engineering of adenoviral vectors has been done to express a number of het-
erologous proteins. These recombinant adenoviral vectors are efficient in inducing
protective immunity against various pathogens. The intrinsic immunogenicity of
these vectors is a most desirable feature for vaccine development of many infectious
agents including HIV type1 and for biodefense against potential bioterror pathogens
[77,79] . The tropism of adenoviral vectors for mucosal epithelium makes them ideal
vectors for the development of recombinant Ad-HIV vaccines.
Replication-defective Ad-simian immunodeficiency virus (SIV) gag vaccines elic-
ited cellular responses that could control i.v. infection with an HIV/SIV chimeric
immunodeficiency virus and replication-competent Ad-SIV env/rev/gag/nef vaccines
have induced cellular and humoral responses and protected rhesus monkeys from a
mucosal challenge with pathogenic SIV [78] .
Ad-HIV vaccine candidates are being progressed under several clinical and pre-
clinical trials. Intranasal administration of Ad vectors expressing HSV glycoprotein
B could give greater protection than i.p. inoculation [80] . Ad vector-mediated cel-
lular immune response also plays a pivotal role in the clearance of hepatitis C virus
(HCV) infection.
Another new class of nonreplicative adenoviral vector influenza vaccines has
been developed without the prerequisite of growing influenza virus. Administration
of vaccines by nasal spray or skin patches are found to be well tolerated by human
volunteers [81] . The nasal vaccine is a potential candidate for further human testing
of needleless vaccines and a promising alternative to current vaccines, which offers a
less invasive means of delivery.
5.2.6.5 Gene Transfer to Stem Cells
Stem cells are inert, self-renewing cells that can differentiate into different lineages
by the expression of specific transcription factors. Conventional DNA/RNA transfec-
tion method is inefficient for the delivery of transcription factors to the stem cells.
Recently, many studies have shown that adenoviral vectors could be used as an effec-
tive tool for gene transfer to stem cells. Some adenoviral vector-mediated transcrip-
tion factors are shown in Table 5.3 [73,82-84] .