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 trans fer in humans is limited by preexisting antiadenoviral immunity. We demonst rate here that new-generation high-capacity adenovirus vectors (HC-Ads) can efficiently transduce the brain and mediate stable transgene expression fo r at least 2 months, even in the presence of a preexisting antiadenoviral i mmune response. First-generation vector-mediated transduction was almost co mpletely abolished in preimmunized animals within 60 days of the vector inj ection. 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 un til day 60 postinjection. Acute brain inflammation elicited by the HC-Ad ve ctor injection was more transient, and was reduced in intensity compared wi th brain inflammation elicited by the first-generation vector injection in immunized animals. Inflammation was significantly higher in all immunized a nimals than in non-immunized animals. Our results show that preexisting ant iadenoviral immunity does not significantly reduce initial HC-Ad-mediated i nfection 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 expr ession. Thus HC-Ads show promise for gene therapy of chronic brain disease.