Herpes Simplex Virus 1 (HSV-1)-Based Vectors - Viral Vector Approaches in Neurobiology and Brain Diseases - page 60

(the episode of prolonged seizures) causes a damage pattern in the
hippocampus that closely mimics the one observed in many patients
affected by the most common adult epileptic syndrome [ 52 ]. In
time, animals begin to display spontaneously recurrent seizures,
i.e., they become truly epileptic, again reproducing the situation
observed in patients [ 52 - 54 ]. Paradiso and coworkers demon-
strated that recombinant HSV-1-based vectors expressing a combi-
nation of two NTFs, fi broblast growth factor-2 (FGF-2) and
brain-derived neurotrophic factor (BDNF), increased survival and
proliferation of freshly isolated neural progenitors and favored
their differentiation into neurons in vitro [ 36 ]. These vectors were
tested in vivo, in the pilocarpine model of status epilepticus-
induced neurodegeneration and epileptogenesis. When injected in
the hippocampus 3 days after status epilepticus, FGF-2/BDNF
expressing vectors partially repaired neuronal damage and pre-
vented the occurrence of spontaneous seizures [ 36 ]. Thus, viral
vector-mediated supplementation of both FGF-2 and BDNF pro-
motes neurogenesis and repair of an existing neuronal damage and
these effects are disease modifying in epilepsies associated with hip-
pocampal sclerosis, demonstrating the feasibility of use of HSV-1
vectors expressing NTFs to provide recovery from damage and to
prevent the development of epilepsy [ 36 ].

One of the most important human demyelinating diseases of
unknown etiology is multiple sclerosis (MS), an autoimmune-
mediated infl ammatory disease of the central nervous system
(CNS) with infl ammatory infi ltrates containing autoreactive T cells
and a multitude of pathogenic nonspecifi c lymphocytes that might
benefi t from anti-infl ammatory therapies [ 55 , 56 ]. Furlan and
coworkers have used HSV-1 vectors expressing immune-
modulators to treat EAE, which is a mouse model for MS, showing
the therapeutic effi cacy of defective HSV-1 vectors expressing anti-
infl ammatory genes, such as interleukin-4 (IL4) [ 57 ] or interleu-
kin-1 receptor antagonist (IL-1ra) [ 37 , 57 , 58 ]. They have
demonstrated that, after disease onset, CNS administration of
HSV-1 defective recombinant vectors expressing IL-4 or IL-1ra
genes into Biozzi AB/H mice stopped the progression of relaps-
ing-remitting form of EAE. The treated mice showed a shorter
duration of the fi rst EAE attack, a longer interrelapse period, and a
reduction in the severity and duration of the fi rst relapse. The
results obtained by this group have revealed an in situ modulation
of the cytokine/chemokine circuits, demonstrating that the local
administration of anti-infl ammatory cytokines by viral vectors can
be effective in the preventive treatment of chronic EAE [ 37 ].

12.2 Experimental
Autoimmune
Encephalomyelitis

Over the past several years, studies of the mechanisms that are
involved in the development of chronic pain have generated novel
information that can lead to identify multiple points of

12.3 Nociception