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
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
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DOI：
10.1073/pnas.120474397
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发表时间：
2000-06-20
影响因子：
11.1
通讯作者：
Löwenstein, PR
中科院分区：
文献类型：
--
作者：
Thomas, CE;Schiedner, G;Löwenstein, PR
虽然与外周器官相比，腺病毒载体在脑中提供了延长的基因表达，但表达被严重的炎性浸润所消除在此，我们证明了高容量腺病毒（HC-Ad）载体成功地维持了脑中的长期转基因表达，即使在用腺病毒进行主动外周免疫的情况下，也能在60天内完全消除第一代载体的表达。重要的是，即使在外周感染后60天，注射第一代载体的大脑也显示出CD 8（+）细胞慢性浸润、巨噬细胞/小胶质细胞活化和大脑MHC-I表达上调的证据。在注射HC-Ad载体的脑中未观察到炎症。因此，这些结果表明，HC-Ad载体将允许安全、稳定和长期的转基因在脑中表达，即使在存在腺病毒外周感染的情况下。这显著改善了腺病毒载体用于神经系统疾病的长期基因治疗的前景。
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.