Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 13, Pages 7482-7487Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.120474397
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Although adenoviral vectors provide prolonged gene expression in the brain by comparison to peripheral organs, expression is eliminated by a severe inflammatory infiltration (i.e,, activated macrophages/microglia and T-lymphocytes) after peripheral infection with adenovirus, Here, we demonstrate that high-capacity adenoviral (HC-Ad) vectors succeed in maintaining long-term transgene expression in the brain, even in the presence of an active peripheral immunization with adenovirus that completely eliminates expression from first-generation vectors within 60 days. Importantly, even 60 days after the peripheral infection, brains injected with first-generation vectors exhibited evidence of a chronic infiltration of CD8(+) cells, macrophage/microglial activation, and up-regulation of brain MHC-I expression. No inflammation was observed in the brains injected with the HC-Ad vector. Thus, these results demonstrate that HC-Ad vectors will allow safe, stable, and longterm transgene expression in the brain, even in the presence of peripheral infection with adenovirus, This markedly improves the prospects for the use of adenoviral vectors for long-term gene therapy of neurological disorders.
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