Stable transgene expression from HSV amplicon vectors in the brain: potential involvement of immunoregulatory signals

Molecular Therapy : the Journal of the American Society of Gene Therapy
Masataka SuzukiYoshinaga Saeki

Abstract

The herpes simplex virus (HSV) amplicon is a plasmid-based, infectious gene delivery system that carries up to 150 kilobase (kb) of exogenous DNA. We previously characterized early host responses and stability of transgene expression in mice systemically injected with HSV amplicon vectors. Transgene expression was readily detected primarily in the liver but rapidly declined to undetectable levels within 2 weeks. Molecular analyses revealed induction of type I interferons (IFN) as the primary response, and early transcriptional silencing of the vector followed IFN's activation of signal transducers and activators of transcription 1 (STAT1). In this study, we investigate vector administration by stereotactic injection into the striatum. In the brain, induction of type I IFN was rather modest, and transgene expression lasted more than 1 year despite dose-dependent inflammation and infiltration of immune cells around injection sites. Further analyses revealed dose-dependent upregulation of immunosuppressive cytokines and molecular markers specific to regulatory T cells in the injected brain regions, which supported the immune-privileged properties of the brain parenchyma. Overall, our findings indicate that the spectrum of host res...Continue Reading

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Jun 17, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Dmitry M ShayakhmetovKaren L Mossman
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