Peripheral infection with adenovirus causes unexpected long-term brain inflammation in animals injected intracranially with first-generation, but notwith high-capacity, adenovirus vectors: Toward realistic long-term neurological gene therapy for chronic diseases

Although adenoviral vectors provide prolonged gene expression in the brain by comparison to peripheral organs, expression is eliminated by a severe in flammatory infiltration (i.e,, activated macrophages/microglia and T-lympho cytes) after peripheral infection with adenovirus, Here, we demonstrate tha t high-capacity adenoviral (HC-Ad) vectors succeed in maintaining long-term transgene expression in the brain, even in the presence of an active perip heral immunization with adenovirus that completely eliminates expression fr om first-generation vectors within 60 days. Importantly, even 60 days after the peripheral infection, brains injected with first-generation vectors ex hibited evidence of a chronic infiltration of CD8(+) cells, macrophage/micr oglial activation, and up-regulation of brain MHC-I expression. No inflamma tion was observed in the brains injected with the HC-Ad vector. Thus, these results demonstrate that HC-Ad vectors will allow safe, stable, and longte rm transgene expression in the brain, even in the presence of peripheral in fection with adenovirus, This markedly improves the prospects for the use o f adenoviral vectors for long-term gene therapy of neurological disorders.