The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5.
The influence of epileptic neuropathology and prior peripheral immunity on CNS transduction by rAAV2 and rAAV5.
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作者：
腺相关病毒（Adeno-associated virus，AAV）具有良好的疗效和无明显的致病性，为神经系统疾病的临床治疗提供了一个很有前途的平台。然而，为了使用病毒载体治疗神经疾病，转导必须在神经病理学条件下发生。先前在啮齿动物中的研究已经表明，AAV 5比AAV 2更有效地转导海马和梨状皮质中的细胞。使用颞叶癫痫的红藻氨酸（KA）模型和携带驱动绿色荧光蛋白（GFP）的杂合鸡β-肌动蛋白启动子的AAV 2和5，我们发现边缘癫痫活动引起实质性神经病理学，并导致随后的AAV 5转导的显著减少。尽管如此，这种减少的转导仍然大于对照大鼠中的AAV 2转导。尽管KA癫痫发作损害血脑屏障功能，可能增加靶组织对循环中和抗体的暴露，但我们观察到KA癫痫发作诱导的损伤与AAV转导的免疫状态之间没有相互作用。最后，虽然我们证实了对照大鼠中两种血清型的神经元特异性转基因表达接近全部，但AAV 5-GFP表达越来越多地定位于脑损伤区域的星形胶质细胞。因此，受损脑的病理环境可以降低转导功效并改变病毒嗜性-当考虑用于神经病症的病毒载体基因疗法时，这两个问题都是相关的。
Adeno-associated virus (AAV) provides a promising platform for clinical treatment of neurological disorders owing to its established efficacy and lack of apparent pathogenicity. To use viral vectors in treating neurological disease, however, transduction must occur under neuropathological conditions. Previous studies in rodents have shown that AAV5 more efficiently transduces cells in the hippocampus and piriform cortex than AAV2. Using the kainic acid (KA) model of temporal lobe epilepsy and AAV2 and 5 carrying a hybrid chicken β-actin promoter driving green fluorescent protein (GFP), we found that limbic seizure activity caused substantial neuropathology and resulted in a significant reduction in subsequent AAV5 transduction. Nonetheless, this reduced transduction still was greater than AAV2 transduction in control rats. Although KA seizures compromise blood–brain barrier function, potentially increasing exposure of target tissue to circulating neutralizing antibodies, we observed no interaction between KA seizure-induced damage and immunization status on AAV transduction. Finally, while we confirmed the near total neuronal-specific transgene expression for both serotypes in control rats, AAV5–GFP expression was increasingly localized to astrocytes in seizure-damaged areas. Thus, the pathological milieu of the injured brain can reduce transduction efficacy and alter viral tropism- both relevant concerns when considering viral vector gene therapy for neurological disorders.
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影响因子：
12.7
作者：
Fasen, K;Elger, CE;Lie, AA
通讯作者：
Lie, AA
DOI：
10.1016/j.nurt.2009.01.004
发表时间：
2009-04
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
McCown TJ
通讯作者：
McCown TJ
影响因子：
12.7
作者：
MIHALY, A;BOZOKY, B
通讯作者：
BOZOKY, B
影响因子：
15.1
作者：
Lawlor, Patricia A.;Bland, Ross J.;Golde, Todd E.
通讯作者：
Golde, Todd E.
影响因子：
15.9
作者：
Kreutzberg, GW
通讯作者：
Kreutzberg, GW