Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 72

[ 151 ]. A further study from the same group analyzed the effects of
ex vivo transduction of mesencephalic reaggregates with the anti-
apoptotic protein bcl-2 on grafted dopamine neuron survival.
Using an amplicon expressing bcl-2 under the control of the TH
promoter (HSV-TH9bcl-2) to transduce mesencephalic reaggre-
gates, it was shown that, in spite of the effi ciency of the infection,
since many cells were effectively transduced, amplicon-mediated
overexpression of bcl-2 did not lead to an increase in grafted
TH-immune-reactive neuron number [ 152 ].
Mitochondrial alterations are detected in most neurodegen-
erative disorders and may contribute to the dysfunction and
demise of neurons. Rotenone or 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridina (MPTP) inhibits the mitochondrial complex I,
causing the death of SN dopaminergic neurons, and provides acute
models of PD. It has been recently demonstrated that mitochon-
drial hexokinase II promotes neuronal survival in rotenone treated
cells and that this enzyme acts downstream of glycogen synthase
kinase-3 (GSK-3), which is considered to be a critical factor in
regulating neuronal cell survival and death [ 153 ]. More recently,
the same group generated amplicons expressing hexokinase II and
showed that overexpression of this protein in SN of mice, subse-
quently administered with rotenone or MPTP, prevented neuronal
cell death induced by both drugs and reduced the associated motor
defects. These results provide the fi rst proof that hexokinase II
could protect against dopaminergic neurodegeneration in vivo and
suggest that increase of hexokinase II expression could represent a
promising approach to treat PD [ 154 ].
Narcolepsy is a neurodegenerative sleep disorder that is linked
to the loss of neurons containing the neuropeptide orexin (also
known as hypocretin). Liu and collaborators inoculated an ampli-
con vector expressing prepro-orexin into the lateral hypothalamus
of orexin KO mice and showed that exogenous expression of
orexin signifi cantly improved sleeping in these animals [ 155 ].

14.3 Neuro-
protection and
Synapse Restoration

In several neuropathologies, traumas, or interventions in the brain,
neuronal death is a common outcome. Therefore, delivery of
transgenes that could prevent cell loss and progression of symp-
toms, using amplicons expressing neurotrophic and antiapoptotic
factors, or other approaches reducing neurotoxicity, has been
widely explored.
Neurotrophins are a family of growth factors that play impor-
tant roles in the development and maintenance of the nervous
system. Amplicons expressing the human brain-derived neuro-
trophic factor (BDNF) cDNA were used in different studies.
BDNF participates in the maturation and function of mammalian
auditory neurons, and amplicons expressing this molecule were
used to evaluate the feasibility of gene therapy of deafness. These
vectors effi ciently express BDNF in many cell types, including