Herpes simplex virus type 1 (HSV-1) has properties that can be exploited for the development of gene therapy vectors. The neurotropism of HSV enables delivery of therapeutic genes to the nervous system. Using a bacterial artificial chromosome (BAC), we constructed an HSV-1(17(+))-based replicative vector deleted of the neurovirulence gene γ134.5, and expressing
leukemia inhibitory factor (LIF) as a transgene for treatment of
experimental autoimmune encephalomyelitis (EAE). EAE is an inducible T-cell mediated
autoimmune disease of the central nervous system (CNS) and is used as an animal model for
multiple sclerosis.
Demyelination and
inflammation are hallmarks of both diseases. LIF is a
cytokine that has the potential to limit
demyelination and oligodendrocyte loss in CNS
autoimmune diseases and to affect the T-cell mediated autoimmune response. In this study SJL/J mice, induced for EAE, were treated with a HSV-LIF vector intracranially and the subsequent changes in disease parameters and immune responses during the
acute disease were investigated. Replicating HSV-LIF and its
DNA were detected in the CNS during the acute
infection, and the vector spread to the spinal cord but was non-virulent. The HSV-LIF significantly ameliorated the EAE and contributed to a higher number of oligodendrocytes in the brains when compared to untreated mice. The HSV-LIF
therapy also induced favorable changes in the expression of immunoregulatory
cytokines and T-cell population markers in the CNS during the
acute disease. These data suggest that BAC-derived HSV vectors are suitable for gene therapy of
CNS disease and can be used to test the therapeutic potential of immunomodulatory factors for treatment of EAE.