Transcriptionally active drugs improve adenovirus vector performance in vitro and in vivo

Cytomegalovirus (CMV) promoter is often present in recombinant adenovirus v ectors (AdVs) suitable for gene therapy, ensuring high levels of transgene production in a wide range of hosts. Despite this characteristic, the prese nce of the AdV genome in target cells and tissues typically lasts longer th an transgene production that may be rapidly extincted by ill-defined silenc ing mechanisms, in the present article, it is reported that transcriptional ly active drugs, retinoic acid (RA) and histone deacetylase inhibitor trich ostatin A (TSA), enhance AdV transgene expression in infected cells and tis sues. The association of RA and TSA increased more than seven-fold above co ntrol the activity of AdVs encoding for LacZ or VEGF(165). This effect was, at least in part, mediated by the direct activation of retinoic acid recep tors. Finally, administration of RA and TSA alone at days a and 5 after inf ection prolonged transgene production up to 21 days after infection versus 6-8 days in untreated controls. These results indicate that transcriptional ly active drugs improve AdV function and may represent a novel strategy to more efficiently design AdVs for gene therapy interventions.