Biology Reference
In-Depth Information
intervention to treat this pathological condition. On the basis of
this knowledge, new gene therapy approaches have been devel-
oped to locally express products that block pain transmission or
reverse the chronic pain state [ 39 , 59 , 60 ]. Defective HSV-1-
derived vectors expressing anti-infl ammatory cytokines, such as
IL10 or TNF
[ 61 , 62 ], have been deeply studied to examine the
involvement of cytokines in the development of infl ammatory
pain. Mata and coworkers have demonstrated, in a rat model of
infl ammatory pain, that expression of IL10 by an HSV-1 vector in
dorsal root ganglia (DRG) prevents activation of p38 mitogen-
activated protein kinase (p38 MAPK) and expression of full-length
membrane-spanning tumor necrosis factor-
α
) in dorsal
horn and spinal cord, suggesting the involvement of TNF
α
(mTNF
α
in the
development of infl ammatory and neuropathic pain [ 62 , 63 ].
Other investigators have made important observations using defec-
tive HSV-1 recombinant vectors delivering inhibitory neurotrans-
mitters at the spinal level to selectively interrupt nociceptive
neurotransmission. These include the use of genes that encode
antisense or microRNA sequences [ 59 ] and genes that antagonize
ion channel function whose activities are essential to the develop-
ment of chronic pain. The main focus is to treat the pain by manip-
ulating the neurobiology of the primary afferent nociceptor (PAN)
since the PAN is the fi rst step in the conduction of noxious stimuli
from the periphery and is accessible to manipulation that do have
access to the CNS [ 64 ]. Preclinical studies on pain animal models
have demonstrated in vivo the capacity of these vectors to effec-
tively transfer genes into the DRG neurons following subcutaneous
inoculation and to effi ciently express and release inhibitory neu-
rotransmitters or anti-infl ammatory peptides that can be used to
modulate pain-related behaviors and provide a therapeutic effect in
models of poly-neuropathy and chronic regional pain [ 39 , 65 , 66 ].
HSV-1 vectors that express glutamic acid decarboxylase (GAD)
have shown to be more effective than the opioid peptide in neuro-
pathic pain [ 65 , 66 ]. A Phase I clinical trial with HSV encephalin-
producing vector in cancer patients have been started 2 years ago
and the results that are being obtained from this fi rst clinical trial
will be an important outline to defi ne for the fi rst time the behavior
of defective HSV-1 vectors in humans [ 41 ].
α
Different replication-defective HSV-1 vectors have been also
created to deliver anticancer transgenes to tumor cells [ 67 ]. These
mutant vectors express, in association with the autologous HSV-1
thymidine kinase ( t k) gene acting as a suicide gene when accompa-
nied by its prodrug ganciclovir, further transgenes chosen for
their potential to synergize in tumor cell killing and induction of
antitumor immunity, such as genes expressing soluble human cyto-
kines (IL-2, GM-CSF, and IFN-
12.4
Brain Tumors
γ
) [ 68 , 69 ], the human B7.1
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