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: 1.88). 05/2005; 125(1):23-33. DOI: 10.1016/j.jviromet.2004.11.023
Source: PubMed

ABSTRACT 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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    • "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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    ABSTRACT: Virus vector-mediated gene transfer has been developed as a treatment for cystic fibrosis (CF) airway disease, a lethal inherited disorder caused by somatic mutations in the cystic fibrosis transmembrane conductance regulator gene. The pathological proinflammatory environment of CF as well as the naïve and adaptive immunity induced by the virus vector itself limits the effectiveness of gene therapy for CF airway. Here, we report the use of an HDAC inhibitor, valproic acid (VPA), to enhance the activity of the regulatory T cells (Treg) and to improve the expression of virus vector-mediated gene transfer to the respiratory epithelium. Our study demonstrates the potential utility of VPA, a drug used for over 50 years in humans as an anticonvulsant and mood-stabilizer, in controlling inflammation and improving the efficacy of gene transfer in CF airway.Gene Therapy advance online publication, 2 January 2014; doi:10.1038/gt.2013.78.
    Gene therapy 01/2014; 21(2). DOI:10.1038/gt.2013.78 · 4.20 Impact Factor
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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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    ABSTRACT: Many signaling circuits face a fundamental tradeoff between accelerating their response speed while maintaining final levels below a cytotoxic threshold. Here, we describe a transcriptional circuitry that dynamically converts signaling inputs into faster rates without amplifying final equilibrium levels. Using time-lapse microscopy, we find that transcriptional activators accelerate human cytomegalovirus (CMV) gene expression in single cells without amplifying steady-state expression levels, and this acceleration generates a significant replication advantage. We map the accelerator to a highly self-cooperative transcriptional negative-feedback loop (Hill coefficient ∼7) generated by homomultimerization of the virus's essential transactivator protein IE2 at nuclear PML bodies. Eliminating the IE2-accelerator circuit reduces transcriptional strength through mislocalization of incoming viral genomes away from PML bodies and carries a heavy fitness cost. In general, accelerators may provide a mechanism for signal-transduction circuits to respond quickly to external signals without increasing steady-state levels of potentially cytotoxic molecules.
    Cell 12/2012; 151(7):1569-80. DOI:10.1016/j.cell.2012.11.051 · 33.12 Impact Factor
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    • "It inhibits class I HDACs and also shows anti-tumour activity in a variety of human cancer cell lines including estrogen-sensitive and estrogen- insensitive breast cancer cell lines [40,41]. It is less toxic compared to TSA [42] and is in phase II and III clinical trials for many human cancers [43]. MS-275 and VPA are selected for this study for their functional similarity and low toxicity. "
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    ABSTRACT: Background The behaviour of tumour cells depends on factors such as genetics and the tumour microenvironment. The latter plays a crucial role in normal mammary gland development and also in breast cancer initiation and progression. Breast cancer tissues tend to be highly desmoplastic and dense matrix as a pre-existing condition poses one of the highest risk factors for cancer development. However, matrix influence on tumour cell gene expression and behaviour such as cell migration is not fully elucidated. Results We generated high-density (HD) matrices that mimicked tumour collagen content of 20 mg/cm3 that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm3. Live-cell imaging showed breast cancer cells utilizing cytoplasmic streaming and cell body contractility for migration within HD matrix. Cell migration was blocked in the presence of both the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugs individually. This suggests roles for ROCK1 and MMP in cell migration are complicated by compensatory mechanisms. ROCK1 expression and protein activity, were significantly upregulated in HD matrix but these were blocked by treatment with a histone deacetylase (HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirect and relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA or DAPT abrogated the inhibition of ROCK1 by MS-275. Conclusion Increased matrix density elevates ROCK1 activity, which aids in cell migration via cell contractility. The upregulation of ROCK1 is epigenetically regulated in an indirect manner involving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1 expression.
    BMC Cell Biology 05/2012; 13(1):12. DOI:10.1186/1471-2121-13-12 · 2.84 Impact Factor
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