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| FRIDAY
JUNE 16, 2000 |
| 12:00-12:30 |
CYTOKINE GENE
THERAPY OF AUTOIMMUNE DEMYELINATION USING NON REPLICATIVE HERPES-SIMPLEX
TYPE-1-DERIVED VECTORS
Gianvito Martino
Dept. of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
The systemic delivery of drugs in patients affected by central nervous
system (CNS)-confined diseases is therapeutically limited by the
presence of the blood-brain barrier which forms an inaccessible wall to
the majority of CNS targeting molecules. When molecules with an
anti-inflammatory profile have been systemically administered to
patients affected by a chronic inflammatory demyelinating disease of the
CNS, such as multiple sclerosis (MS), results have been disappointing. A
successful therapeutic approach in MS should therefore consider the
delivery of anti-inflammatory molecules directly into the CNS in order
to inhibit blood-borne CNS-confined mononuclear cells that act as
ultimate effector cells by directly destroying oligodendrocytes and/or
releasing myelinotoxic substances. Biological and physical vectors
engineered with heterologous genes coding for immunomodulatory cytokines
with an anti-inflammatory profile might represent the appropriate tool
to deliver therapeutic genes into the CNS of patients with MS. So far,
cytokine-gene therapy has never been attempted in MS, but encouraging
results have been obtained in the animal model of MS, experimental
autoimmune encephalomyelitis (EAE), using viral vectors or plasmids
engineered with cytokine genes. We have developed a non-toxic system to
deliver cytokines within the CNS based on the intracisternal (i.c.)
administration of non-replicative herpes simplex (HSV) type-1-derived
viral vectors engineered with heterologous cytokine genes. Mice
preventively treated with vectors containing the IL-1 receptor
antagonist (IL-1ra) or the IL-4 gene showed a significant amelioration
of clinical and pathological signs of EAE. Delivery of the IL-4 but not
of the IL-1ra gene-containing vector showed to be protective also when
administered after EAE onset. Peripheral T cells from vector-treated
mice were not affected by the treatment both in their antigen-specific
proliferation and cytokine secretion. Our results indicate that CNS
cytokine gee delivery with HSV-1-derived vectors is a feasible
therapeutic strategy and might represent an alternative approach for the
treatment of immune-mediated demyelinating diseases. Advantages of this
approach over systemic cytokine administration are the high cytokine
level reached within the CNS and the absence of side effects on the
peripheral immune system. The short-lasting cytokine production in the
CNS after a single vector administration (4 weeks) is the limiting
factor of this novel technology which, although promising, has to be
improved. |
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