Histone deacetylase inhibition enhances adenoviral vector transduction in inner ear tissue

Adenovirus vectors (AdVs) are efficient tools for gene therapy in many tissues. Several studies have demonstrated successful transgene transduction with AdVs in the inner ear of rodents [Kawamoto K, Ishimoto SI, Minoda R, Brough DE, Raphael Y (2003) J Neurosci 23:4395-4400]. However, toxicity of AdVs [Morral N, O'Neal WK, Rice K, Leland MM, Piedra PA, Aguilar-Cordova E, Carey KD, Beaudet AL, Langston C (2002) Hum Gene Ther 13:143-154.] or lack of tropism to important cell types such as hair cells [Shou J, Zheng JL, Gao WQ (2003) Mol Cell Neurosci 23:169-179] appears to limit their experimental and potential clinical utility. Histone deacetylase inhibitors (HDIs) are known to enhance AdV-mediated transgene expression in various organs [Dion LD, Goldsmith KT, Tang DC, Engler JA, Yoshida M, Garver RI Jr (1997) Virology 231:201-209], but their effects in the inner ear have not been documented. We investigated the ability of one HDI, trichostatin A (TSA), to enhance AdV-mediated transgene expression in inner ear tissue. We cultured neonatal rat macular and cochlear explants, and transduced them with an AdV encoding green fluorescent protein (Ad-GFP) under the control of a constitutive promoter for 24 h. In the absence of TSA, GFP expression was limited, and very few hair cells were transduced. TSA did not enhance transduction when applied at the onset of Ad-GFP transduction. However, administration of TSA during or just after Ad-GFP application increased GFP expression in supporting cells approximately fourfold. Moreover, vestibular hair cell transduction was enhanced approximately sixfold, and that of inner hair cells by more than 17-fold. These results suggest that TSA increases AdV-mediated transgene expression in the inner ear, including the successful transduction of hair cells. HDIs, some of which are currently under clinical trials (Sandor et al., 2002), could be useful tools in overcoming current limitations of gene therapy in the inner ear using Ad-GFP.