Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 78

Finally, Liu and coworkers [ 202 ] recently reported that an
amplicon expressing small interfering RNA (siRNA) for the
gamma-Aminobutyric acid A (GABA A ) receptor 2 subunit infused

into the central nucleus of the amygdala (CeA) of alcohol-preferring
rats, (1) caused profound and selective reduction of binge drinking
associated with inhibition of a2 subunit expression, (2) decreased
GABA A receptor density, and (3) inhibited Toll-like receptor 4
(TLR4) expression [ 202 ]. Moreover, infusion of an amplicon
expressing TLR4 siRNA into CeA also inhibited binge drinking, but
neither vector caused such changes when infused into the ventral
pallidum nucleus. On the other hand, binge drinking was effectively
inhibited by a GABA A receptor a1 subunit siRNA expressing ampli-
con, when infused into the ventral pallidum nucleus, unrelated to
TLR4. Those data indicate that GABA A a2-regulated TLR4 expres-
sion in the CeA contributes to binge drinking and may be a key for
early neuroadaptation in excessive drinking [ 202 ].

α

15 Concluding Remarks

The only HSV-1 vectors that have already achieved Phase I clinical
studies for the treatment of brain diseases are the attenuated onco-
lytic vectors G207 and 1716 [ 90 , 203 - 207 ]. In particular, G207
vector is now undergoing Phase II [ 204 , 205 ]. Other oncolytic
HSV-1 vectors, such as N1020 and OncoVEX GM-CSF, are also
being used for malignancies but not related to the nervous system.
The main reasons underlying the relative success of clinical trials
using oncolytic HSV-1 are the fact that these vectors can amplify
within the tumor mass, thus overcoming the requirement to inoc-
ulate large amounts of purifi ed vectors, and the fact that selective
toxicity is the major issue that these vectors should resolve, a goal
that is relatively easy to attain. Phase I studies of these vectors have
demonstrated that they are well tolerated and safe and no serious
adverse events have been reported, but we still need more informa-
tion with Phase II/III studies regarding effi cacy.
Replication-incompetent recombinant vectors have reached a
developmental stage that has completely eliminated toxicity, and
these vectors are therefore safe for the target cells, even when
infected at high multiplicities. Furthermore, these vectors have
proven suitable and powerful tools for different types of experi-
mental gene therapy settings in small animals, as well as for studies
of neural functions. However, some major diffi culties, that still
remain to be resolved in many cases, account for the fact that
these vectors are only now reaching the clinics for neurological
disorders other then cancer. These diffi culties are related to the
complexity of targeting entry or expression of the vectors, in order
to strictly transduce the cells requiring gene therapy, and to the