AAV9 supports wide-scale transduction of the CNS and TDP-43 disease modeling in adult rats
AAV9 supports wide-scale transduction of the CNS and TDP-43 disease modeling in adult rats
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DOI：
10.1038/mtm.2015.36
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发表时间：
2015-01-01
影响因子：
4.7
通讯作者：
Klein, Ronald L.
中科院分区：
文献类型：
--
作者：
Jackson, Kasey L.;Dayton, Robert D.;Klein, Ronald L.
AAV 9已经成为用于基因转移到中枢神经系统的有效腺相关病毒（AAV）血清型。我们已经使用这种技术来研究肌萎缩性侧索硬化症（ALS）的各个方面，通过给新生大鼠施用编码ALS相关基因反式反应DNA结合蛋白43 kDa（TDP-43）的AAV。然而，在成人受试者中诱导表达对于模拟ALS中的成人症状发作将是优选的。我们在成年大鼠中表达绿色荧光蛋白（GFP）或TDP-43，给药途径，以尝试脊髓的大规模转导用于疾病建模。为了优化基因转移，我们根据年龄、性别和几种AAV血清型（AAV 1、AAV 8、AAV 9和AAV 10）进行了效率比较。数据表明在新生儿中更有效的神经元转导，在任一年龄几乎没有神经胶质转导的证据，转导中没有性别相关的差异，并且相对于测试的其他血清型，AAV 9在成人中是有效的。基于这些数据，AAV 9 TDP-43在成年雌性大鼠中以三种载体剂量表达，产生高度一致的剂量依赖性运动缺陷。AAV 9可以i. v.成年大鼠，以实现一致的病理生理学变化和相关的成年发病系统的疾病建模。
AAV9 has emerged as an efficient adeno-associated virus (AAV) serotype for gene transfer to the central nervous system. We have used this technique to study aspects of amyotrophic lateral sclerosis (ALS) by administering AAV encoding the ALS-related gene transactive response DNA binding protein of 43 kDa (TDP-43) to neonatal rats. However, inducing the expression in adult subjects would be preferable to mimic the adult onset of symptoms in ALS. We expressed either green fluorescent protein (GFP) or TDP-43 in adult rats after an intravenous (i.v.) route of administration to attempt wide-scale transduction of the spinal cord for disease modeling. In order to optimize the gene transfer, we made comparisons of efficiency by age, gender, and across several AAV serotypes (AAV1, AAV8, AAV9, and AAV10). The data indicate more efficient neuronal transduction in neonates, with little evidence of glial transduction at either age, no gender-related differences in transduction, and that AAV9 was efficient in adults relative to the other serotypes tested. Based on these data, AAV9 TDP-43 was expressed at three vector doses in adult female rats yielding highly consistent, dose-dependent motor deficits. AAV9 can be delivered i. v. to adult rats to achieve consistent pathophysiological changes and a relevant adult-onset system for disease modeling.