Biology Reference
In-Depth Information
local or systemic toxicity towards healthy tissues [ 108 ]. Different
groups are currently working in engineering novel viruses to
explore the possibility of simultaneously addressing these strategies
[ 82 ]. However, since HSV-1 is naturally targeted to the nervous
system, most of these studies actually address other types of cancers
and will therefore not be treated here.
One of the potential target organs of replication-competent HSV-1
vector applications, the PNS, seems likely to promise the most suc-
cessful results. In fact, inoculation of HSV-1 vector by peripheral
routes can take advantage of the natural life cycle of the virus,
which usually infects axonal nerve terminal at peripheral sites
before retrograde transport to neuronal cell bodies where latency
is established. It is well known that viral replication is necessary to
cross the synapses among neurons and for effi cient establishment
of latency [ 7 ]. In the PNS, there are a number of potential applica-
tions for HSV-1 replication-competent vectors capable of periph-
eral replication and axonal transport, including the stimulation of
regrowth of damaged nerves, the study and treatment of various
pain states, the protection of neurons from further degeneration
in, e.g., motor neuron disease, the study and treatment of various
neuropathies, the study of neuronal development, and the screen-
ing of the relevance of genes implicated as being important in any
of these processes by a gene delivery approach. Therefore, viruses
mutated in either TK or RR have been extensively used, which,
while being attenuated as compared to wild-type virus, are also
replication competent at least in epithelial cells. The data obtained
to date show the potential of such vectors for gene transfer.
Attenuated vectors in fact demonstrated to be highly effi cient in
driving proenkephalin A (PA) gene expression in DRG [ 109 ], to
deliver genes into monkey eyes [ 110 ] and to rodent visual system
[ 111 ], and to express active nerve growth factor beta subunit
13.2 Gene Delivery
to the Peripheral
Nervous System
-NGF) in latently infected DRG [ 112 ].
Amplicon Vectors
Amplicon vectors [ 113 ] are advantageous tools in neuroscience
research (reviewed in [ 114 - 116 ]). Amplicons are replication-
incompetent helper-dependent vectors derived from HSV-1. These
vectors have several advantages that potentiate their use in neuro-
sciences (1) minimal toxicity: since amplicons do not encode any
virus proteins, they are not toxic for the infected cells nor patho-
genic for the inoculated animals and, in addition, amplicon infec-
tion elicits relatively low levels of adaptive immune responses;
(2) extensive transgene capacity: amplicons are capable to carry up
to and deliver almost 150 kb of foreign DNA to the nuclear envi-
ronment of mammalian cells, which means that entire genes with
Search WWH ::

Custom Search