NF-?B promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector.

ABSTRACT: The replication-incompetent adenovirus (Ad) vector is one of the most promising vectors for gene therapy; however, systemic administration of Ad vectors results in severe hepatotoxicities, partly due to the leaky expression of Ad genes in the liver. Here we show that nuclear factor-kappa B (NF-?B) mediates the leaky expression of Ad genes from the Ad vector genome, and that the inhibition of NF-?B leads to the suppression of Ad gene expression and hepatotoxicities following transduction with Ad vectors. Activation of NF-?B by recombinant tumor necrosis factor (TNF)-? significantly enhanced the leaky expression of Ad genes. More than 50% suppression of the Ad gene expression was found by inhibitors of NF-?B signaling and siRNA-mediated knockdown of NF-?B. Similar results were found when cells were infected with wild-type Ad. Compared with a conventional Ad vector, an Ad vector expressing a dominant-negative I?B? (Adv-CADNI?B?), which is a negative regulator of NF-?B, mediated approximately 70% suppression of the leaky expression of Ad genes in the liver. Adv-CADNI?B? did not induce apparent hepatotoxicities. These results indicate that inhibition of NF-?B leads to suppression of Ad vector-mediated tissue damages via not only suppression of inflammatory responses but also reduction in the leaky expression of Ad genes.

SUBMITTER: Machitani M 

PROVIDER: S-EPMC4728692 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature