Systemic mannitol-induced hyperosmolality amplifies rAAV2-mediated striatal transduction to a greater extent than local co-infusion
Systemic mannitol-induced hyperosmolality amplifies rAAV2-mediated striatal transduction to a greater extent than local co-infusion
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DOI：
10.1016/j.ymthe.2004.08.031
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发表时间：
2005-02-01
影响因子：
12.4
通讯作者：
Mandel, RJ
中科院分区：
文献类型：
--
作者：
Burger, C;Nguyen, FN;Mandel, RJ
来源于腺相关病毒血清型2（rAAV 2）的重组病毒载体已被研究为用于基因转移至中枢神经系统（CNS）的高效载体。用rAAV2载体转导导致CNS神经元中的长期转基因表达。最佳的注射参数，导致有效的靶向和扩散的转基因大的神经解剖区域是重要的分子基因治疗研究的中枢神经系统。在本研究中，我们重新检查了局部和全身给药甘露醇诱导的高渗对促进转基因表达和载体在中枢神经系统中分布的影响。在载体给药之前全身性腹膜内给药甘露醇改善了向纹状体神经元的基因转移，使转导细胞的总数增加了400%，载体分布增加了200%。另一方面，在纹状体的甘露醇的局部共同管理增加了25%的转导纹状体神经元的数量和转导量的影响不大。总之，我们已经证明，甘露醇的全身共施用显著增强rAAV2病毒递送在脑中的转基因传播，其程度比局部共施用大得多。
Recombinant viral vectors derived from adeno-associated virus serotype 2 (rAAV2) have been investigated as highly effective vehicles for gene transfer to the central nervous system (CNS). Transduction with rAAV2 vectors results in long-term transgene expression in CNS neurons. Optimal injection parameters leading to efficient targeting and spread of the transgene to large neuroanatomical regions are important in molecular gene therapy studies of the CNS. In the present study, we reexamined the effects of both local and systemic administration of mannitol-induced hyperosmolality on facilitation of transgene expression and vector distribution in the CNS. Systemic intraperitoneal administration of mannitol prior to vector administration improved gene transfer to striatal neurons, increasing the total number of transduced cells by 400% and vector distribution by 200%. On the other hand, local coadministration of mannitol in the striatum increased the number of transduced striatal neurons by 25% and had little effect on transduction volume. In conclusion, we have demonstrated that systemic coadministration of mannitol significantly enhances transgene spread of rAAV2 viral delivery in the brain to a much greater degree than local coadministration.