Valproic acid enhances gene expression from viral gene transfer vectors.
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.
Fan
Shongshan
S
Department of Microbiology and Immunology, University of Rochester Medical Center, 601 Elmwood Ave., Box 672 (Room 3-9609), Rochester, NY 14642, USA.
Maguire
Casey A
CA
Ramirez
Servio H
SH
Bradel-Tretheway
Birgit
B
Sapinoro
Ramil
R
Sui
Ziye
Z
Chakraborty-Sett
Shikha
S
Dewhurst
Stephen
S
D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000229:Dependovirus / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000187:drug effects*; D006564:Herpesviridae / Q000187:drug effects / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014170:Transformation, Genetic / Q000187:drug effects; D014635:Valproic Acid / Q000009:adverse effects / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D014635:Valproic Acid; D008156:Luciferases