Gene Delivery Using Viral Vectors - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 249

normal and cancer cells. A second approach to target viral replication to tumor cells
is to place the expression of essential viral genes under the control of tumor or tissue-
specific promoters that are preferentially active in tumor cells. The use of tissue-
specific promoters to direct viral replication to a specific tumor type has been studied
more extensively in oncolytic adenoviruses and the use of these promoters to control
HSV replication could be further explored.
5.5.3.2 Live Viral Anti-HSV Vaccine
Live attenuated viral vaccines provide a vehicle for complete presentation of all viral
antigens to the host immune system, stimulating both humoral and cell-mediated
immune responses. They can be efficiently propagated with ease and therefore are
extremely cost-effective vaccines. Live attenuated viruses have also been successful
at combating myriad human viral diseases. Barriers to the development of a live viral
vaccine for HSV are mainly safety issues revolving around the potential for reactiva-
tion from latency, recombination with wt virus, and the oncogenic potential of viral
DNA [204,205] . The goal of constructing a safe, less attenuated vaccine candidate
led to the construction of the RAV 9395 mutant. Mutations in tk , especially for HSV-
2, do not attenuate the virus sufficiently for human vaccines [206] . Other attenuated
HSV-1 and -2 viruses with single deletion in vhs or in RR , respectively, were shown
to determine a protective immunity when they were tested in animal models, but they
are too neurovirulent to be used for human trials [207,208] .
5.5.3.3 Oncolytic HSV-Attenuated Viruses
The replicating vector for cancer therapy should be derived from viruses that are natu-
rally endemic to the human population. The optimal approach might be to develop
a replicating vector from a highly prevalent but weakly pathogenic human virus.
Construction of oncolytic viruses that can not only target cancer cells, but also retain
their ability to infect, usurp host replication machinery, then release freshly made
progeny to infect other transformed cells after lysing and killing the host cell, has
become a major area of therapeutic cancer research. Several oncolytic HSV vectors
have been developed. The first generation of these vectors contained mutations in
a single gene that restricted their replication to dividing cells. Around three HSV-1
mutants were constructed: (1) dls ptk, containing a deletion in the tk gene; (2) hrR3,
containing an insertion of the Escherichia coli lac-Z gene in the early gene UL39,
encoding the large subunit of the viral RR (ICP6); (3) R3616, containing 1 kb dele-
tions in both copies of the  1 34.5 gene, encoding the neurovirulence factor ICP34.5.
These vectors have been tested for their antitumor activity against liver, breast, ovar-
ian, and metastatic prostate cancers, and show a significant increase in viral oncoly-
sis. This may lead to enhanced clinical performance in late-stage cancer patients.
5.5.3.4 Attenuated HSV Vectors for Gene Delivery to the Peripheral
Nervous System
The peripheral nervous system (PNS) is one of the potential target organs of
replication-competent HSV vector applications. Inoculating HSV vector by peripheral