|Budget Amount *help
¥12,900,000 (Direct Cost: ¥12,900,000)
Fiscal Year 2002: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2001: ¥6,900,000 (Direct Cost: ¥6,900,000)
Novel histone deacetylase inhibitors (HDACIs) CHAP31 and FR901228 could enhance adenovirus-mediated β-galactosidase expression more than ten times in cultured cells. Similar augmentative effects were observed not only in AdLacZ, a reporter gene, but also in adenovirus-mediated heat shock protein 72 (HSP72), a functional gene. Amplification of the transgene expression was strongly related to the acetylation state of core histones, not to the over-expression of coxsackie and adenovirus receptor (CAR). It was suggested that histone acetylation, which had been thought to be connected with endogenous gene expression, was also related to transgene expression.
HDACIs did not amplify endogenous HSP72 expression induced by hyperthermia, suggesting that the augmentative effect on gene expression by HDACIs was specific in transduced genes.
CHAP31 and FR901228 enhanced adenovirus-mediated β-galactosidase expression in mice liver. It has not been reported that trichostatin A (TSA), a well-documented classical HDACI, enhanced transgene expression in in vivo model. CHAP31 and FR901228 are much more stable than TSA, and their stability was thought to contribute to the effect in in vivo model. Furthermore, similar augmentative effects were observed not only in the liver, but also in the kidney, lung, and heart although transduction efficacy to the three organs were much lower than the liver.
Now we are conducting the experiment about the effect of HSP72 transduction on ischemia-reperfusion injury of the liver. There is a dilemma that hepatic toxicity of adenovirus vector becomes remarkable when the vector dose is raised to achieve sufficient transgene expression. There. is an expectation that co-administration of the novel HDACIs with adenovirus vector can reduce the vector dose and may lead to a breakthrough in the gene therapy using adenovirus vector.