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 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.
Thomas
C E
CE
Molecular Medicine and Gene Therapy Unit, Room 1.302, Stopford Building, School of Medicine, University of Manchester, Manchester M13 9PT, United Kingdom.
Schiedner
G
G
Kochanek
S
S
Castro
M G
MG
Löwenstein
P R
PR
D000257:Adenoviridae Infections / Q000503:physiopathology / Q000821:virology*; D000818:Animals; D002908:Chronic Disease; D004660:Encephalitis / Q000503:physiopathology / Q000821:virology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D007276:Injections, Intraventricular; D051379:Mice; D013997:Time Factors