UNC Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Gene Ther. 2011 Oct;18(10):961-8. doi: 10.1038/gt.2011.49. Epub 2011 Apr 14.
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.
腺相关病毒（AAV）因其确切的疗效和缺乏明显的致病性，为神经疾病的临床治疗提供了一个很有前途的平台。然而，要将病毒载体用于治疗神经疾病，转导必须在神经病理学条件下发生。以前在啮齿动物中的研究表明，AAV5 比 AAV2 更有效地转导海马体和梨状皮层中的细胞。使用海人酸（KA）颞叶癫痫模型和携带杂交鸡β-肌动蛋白启动子驱动绿色荧光蛋白（GFP）的 AAV2 和 5，我们发现边缘性癫痫发作引起了大量的神经病理学变化，并导致随后的 AAV5 转导显著减少。尽管如此，与对照大鼠中的 AAV2 转导相比，这种减少的转导仍然更高。尽管 KA 癫痫发作会损害血脑屏障功能，可能会增加循环中和抗体对靶组织的暴露，但我们没有观察到 KA 癫痫诱导的损伤与免疫状态之间对 AAV 转导的相互作用。最后，虽然我们在对照大鼠中证实了两种血清型的近全部神经元特异性转基因表达，但 AAV5-GFP 表达在损伤区域中越来越定位于星形胶质细胞。因此，受损大脑的病理环境会降低转导效率并改变病毒的嗜性——这在考虑神经疾病的病毒载体基因治疗时都是相关的问题。
