Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoimmunity
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Brain / immunology
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Brain / metabolism
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Brain / virology
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Chlorocebus aethiops
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Cytokines / genetics
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Cytokines / metabolism
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / therapy*
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Female
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Genetic Therapy
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Genetic Vectors
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Immunologic Factors / biosynthesis*
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Immunologic Factors / genetics
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Immunomodulation
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Leukemia Inhibitory Factor / biosynthesis*
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Leukemia Inhibitory Factor / genetics
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Mice
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Myelin Sheath / pathology
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Oligodendroglia / immunology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Simplexvirus / genetics*
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Spinal Cord / immunology
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Spinal Cord / metabolism
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Spinal Cord / virology
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Vero Cells
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Virus Replication
Substances
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Cytokines
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Immunologic Factors
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Leukemia Inhibitory Factor
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RNA, Messenger
Grants and funding
This study was supported by the Academy of Finland (grant number 118366 and 128915 to VH,
www.aka.fi) and the German Research Foundation (DFG Excellence Cluster EXC 62, REBIRTH – From Regenerative Biology to Reconstructive Therapy to BS,
www.dfg.de) and the EU 6th Framework Program (EU-NEST AXON SUPPORT, contract number 12702 to BS, ec.europa.eu/research/fp6/index_en.cfm). MN has been funded by Turku Doctoral Programme of Biomedical Sciences (
www.tubs.utu.fi), Turku University Foundation (
www.turunyliopistosaatio.fi), Medicinska Understödsföreningen Liv och Hälsa (
www.livochhalsa.fi), The Finnish MS foundation (
http://www.ms-saatio.fi), the Maud Kuistila Memorial Foundation (
www.maudkuistilanmuistosaatio.fi) and the German Academic Exchange Service (DAAD,
www.daad.de). HP has been funded by the Alfred Kordelin Foundation (
www.kordelin.fi) and FinPharma Doctoral program – Drug Discovery section (
http://fpdp.fi). The funders had no role in study design, data collection and analysis, design to publish, or preparation of the manuscript.