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.
Highlights
Delivering transgenes by viral vectors into the central nervous system (CNS) enables gene therapy of chronic diseases that are characterized by pathological changes in the brain and the spinal cord
We investigated the therapeutic effect of an Herpes simplex virus (HSV)-leukemia inhibitory factor (LIF) vector, expressing the neuroprotective cytokine LIF, on acute PLP-induced EAE in SJL/J mice and characterized the therapy-associated changes in the immunological balance in the CNS
The vectors were detected in the CNS and trigeminal ganglia (TG) early at days 6–10 post induction and viral DNA persisted in the nervous system until later time points
Summary
Delivering transgenes by viral vectors into the central nervous system (CNS) enables gene therapy of chronic diseases that are characterized by pathological changes in the brain and the spinal cord. Herpes simplex virus (HSV) vectors are good candidates for gene delivery to the nervous system for several reasons: HSV vectors are neurotropic, have a large transgene capacity, infect a variety of cell types and persist lifelong in a latent form in neurons. We and others have previously used Th2 cytokine-expressing, nonreplicating or c134.5-deletion HSV vectors for gene therapy of the autoimmune CNS disease model experimental autoimmune encephalomyelitis (EAE) [12,13,14], the premier animal model for multiple sclerosis (MS)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
