Preexisting antiadenoviral immunity is not a barrier to efficient and stable transduction of the brain, mediated by novel high-capacity adenovirus vectors

The utility of first-generation adenovirus vectors for long-term gene transfer in humans is limited by preexisting antiadenoviral immunity. We demonstrate here that new-generation high-capacity adenovirus vectors (HC-Ads) can efficiently transduce the brain and mediate stable transgene expression for at least 2 months, even in the presence of a preexisting antiadenoviral immune response. First-generation vector-mediated transduction was almost completely abolished in preimmunized animals within 60 days of the vector injection. Levels of HC-Ad-mediated transduction by 3 days postinjection were not significantly affected by preimmunization, were reduced within 14 days to 56% of those levels seen in nonimmunized animals, and remained stable until day 60 postinjection. Acute brain inflammation elicited by the HC-Ad vector injection was more transient, and was reduced in intensity compared with brain inflammation elicited by the first-generation vector injection in immunized animals. Inflammation was significantly higher in all immunized animals than in non-immunized animals. Our results show that preexisting antiadenoviral immunity does not significantly reduce initial HC-Ad-mediated infection of the brain and is not a barrier to stable HC-Ad vector-mediated transduction of the CNS. Although input HC-Ad capsid proteins injected into the brain may contain transient targets for a brain-infiltrating cellular adenovirus-specific immune response, this fails to eliminate transgene expression. Thus HC-Ads show promise for gene therapy of chronic brain disease.