Valproic acid enhances gene expression from viral gene transfer vectors

Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave., Box 672 (Room 3-9609), Rochester, NY 14642, USA.
Journal of Virological Methods (Impact Factor: 1.78). 05/2005; 125(1):23-33. DOI: 10.1016/j.jviromet.2004.11.023
Source: PubMed


Viral vectors represent an efficient delivery method for in vitro and in vivo gene transfer, and their utility may be further enhanced through the use of pharmacologic agents that increase gene expression. Here, we demonstrate that valproic acid (VPA), a drug which is widely used for the treatment of epilepsy and mood disorders, enhances and prolongs expression of exogenous genes in cells transduced with various gene transfer agents, including adenovirus, adeno-associated virus and herpesvirus vectors. This effect occurs in a wide range of cell types, including both primary cells and cell lines, and appears to be associated with VPA's ability to function as a histone deacetylase inhibitor (HDACi). VPA treatment also enhanced adenovirally-vectored expression of a luciferase reporter gene in mice, as demonstrated by in vivo imaging. VPA was also less cytotoxic than a commonly used HDAC inhibitor, TSA, suggesting its use as a safer alternative. Taken together, these results suggest that VPA treatment may represent a useful approach to various gene transfer approaches in which enhanced transgene expression is desirable.

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    • "VPA does not quantitatively affect pDNA uptake and/or stability following PEI-mediated transfection (Wulhfard et al. 2010). Additional HDAC inhibitors tested for transient transfection improvement include trichostatin A which has shown to enhance LacZ (Fan et al. 2005), IgG (Backliwal et al. 2008c), and GFP and Luciferase expression using both plasmid DNA and a BacMam virus DNA templates (Spenger et al. 2004). The effect of several transfection enhancers on the production of Gag-based virus-like particles (VLPs) in HEK 293 cultures is investigated in this work using design of experiment methodology. "
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    • "Fan and colleagues reported that treatment with VPA resulted in increased expression of exogenous genes in cells transduced with various viral-based gene transfer vectors, including adenovirus, adeno-associated virus and herpesvirus vectors 28. Recently, the effect of VPA on adenovirus vector-mediated transduction was reported. "
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    • "We examined MIE gene-expression levels after increasing MIEP activity by using transcriptional activators known to upregulate MIEP activity (Choi et al., 2005; Fan et al., 2005; Hummel and Abecassis, 2002). These transcriptional activators, Valproic "
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