Peripheral Infection with Adenovirus Causes Unexpected Long-Term Brain Inflammation in Animals Injected Intracranially with First-Generation, but Not with 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 inflammatory infiltration (i.e., activated macrophages/microglia and T-lymphocytes) after peripheral infection with adenovirus. Here, we demonstrate tha...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2000-06, Vol.97 (13), p.7482-7487
Main Authors: Thomas, Clare E., Schiedner, Gudrun, Kochanek, Stefan, Castro, Maria G., Lowenstein, Pedro R.
Format: Article
Language:English
Subjects:
Adenoviridae Infections - physiopathology
Adenoviridae Infections - virology
Adenovirus
Adenoviruses
Animals
Biological Sciences
Chronic Disease
Encephalitis - physiopathology
Encephalitis - virology
Gene therapy
Genetic Therapy
Genetic vectors
Genetic Vectors - administration & dosage
Genetic Vectors - adverse effects
Immune response
Infections
Inflammation
Injections, Intraventricular
Intradermal injections
Mice
neurovirology
T lymphocytes
Time Factors
Transgenes
Viruses
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Summary: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 long-term 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.120474397