Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 62

gene, encoding a costimulatory surface antigen (CD80) [ 70 ],
rat connexin 43 gene, which improves the HSV-1 TK/GCV killing
of glioma cells by increasing the bystander effect [ 71 ], or rat con-
nexin and human TNF [ 72 ]. However, and in spite of encourag-

ing results obtained, the antitumor approach that is most widely
employed nowadays with HSV-1 is the use of oncolytic vectors
(see below).
Therefore, a number of different HSV-1-based defective vec-
tors for specifi c gene therapy applications in CNS and peripheral
nervous system (PNS) have been developed so far and have been
applied using different routes of inoculation to effi ciently deliver
genes into the CNS and PNS in both small (mice) and large (non-
human primates) animals, specially for neurodegenerative diseases
that involve large areas of the CNS [ 72 , 73 ]. Recent advances and
current applications of existing vectors are still focused in improv-
ing the properties of these vectors, in particular in modulating the
intensity and time course of transgene expression [ 13 , 74 ]. Long-
term gene expression is still diffi cult to achieve, although some
success has been obtained in the PNS with the HSV-1 latency-
active promoter 2 (LAP2) [ 45 , 74 ]. Other recent studies have
focused in improving target expression to specifi c neuronal popu-
lations [ 75 ] and, since there is considerably neuronal heterogene-
ity in both the PNS and CNS, it would be naive to presume that
the behavior of viral vectors will be the same for all neuronal popu-
lations in different regions of the nervous system. Because of this
intrinsic complexity, it is more feasible that neural targeting may
be achieved through the use of specifi c promoters to drive expres-
sion of the therapeutic gene, such as promoters of genes encoding
neuropeptides or of enzymes involved in the synthesis of neu-
rotransmitters, which are attractive candidates for cell targeting
because many types of neurons are defi ned by their neurotrans-
mitters [ 76 , 77 ].

α

13 Attenuated Recombinant Vectors

Several genes involved in HSV-1 replication, virulence, and
immune evasion that are nonessential for viral life cycle in vitro
have been identifi ed. These genes are usually involved in multiple
interactions with cellular proteins that optimize the ability of the
virus to grow within cells. Understanding such interactions has
permitted the deletion of these genes, alone or in combination, to
create HSV-1 mutants with a reduced ability to replicate in normal
quiescent cells, but that can replicate in tumor or in dividing cells.
These attenuated viruses are not only mainly used as oncolytic
vectors for the treatment of different types of cancers, but they can
also be used for gene delivery to the PNS (Fig. 6 ).