Recombinant AAV-mediated gene delivery to the central nervous system
Recombinant AAV-mediated gene delivery to the central nervous system
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DOI：
10.1002/jgm.506
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发表时间：
2004-02-01
影响因子：
3.5
通讯作者：
Levivier, M
中科院分区：
文献类型：
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作者：
Tenenbaum, L;Chtarto, A;Levivier, M
重组腺相关病毒 (rAAV) 载体已成功转导大脑的各个区域，未检测到毒性。当使用巨细胞病毒立即早期 (CMV) 启动子时，转导细胞数量逐渐下降。相反，使用细胞启动子（例如神经元特异性烯醇化酶启动子）或混合启动子（例如鸡β-肌动蛋白/CMV启动子）会导致持续的转基因表达。 rAAV 介导的中枢神经系统 (CNS) 基因转移的细胞趋向性根据所使用的血清型而变化。血清型 2 载体优先转导神经元，而 rAAV5 和 rAAV1 转导神经元和神经胶质细胞。重组 AAV4 介导的基因转移在纹状体的神经元和神经胶质细胞（迄今为止唯一测试的结构）中效率低下，但在室管膜细胞中有效。在将 rAAV2 施用到大脑后，没有描述任何炎症反应。相比之下，引发了针对 AAV2 衣壳和转基因产物的抗体，但没有观察到转基因表达的减少，并且从第一次注射后 3 个月起，可以在不损失效率的情况下重新施用载体。基于利用标记基因进行的开创性工作的成功，设计了各种治疗性基因递送策略。其中包括溶酶体贮积病、卡纳万病和帕金森病中的酶替代；在帕金森病、亨廷顿病、阿尔茨海默病、肌萎缩侧索硬化症、缺血和脊髓损伤中输送神经保护因子；以及癫痫和帕金森病中神经传递的调节。其中一些策略已在相关动物模型中显示出有希望的结果。然而，它们在临床上的实施可能需要对治疗基因表达进行严格的调控和特定的靶向，这仍然需要载体的进一步开发。版权所有 (C) 2004 John Wiley Sons, Ltd.
Various regions of the brain have been successfully transduced by recombinant adeno-associated virus (rAAV) vectors with no detected toxicity. When using the cytomegalovirus immediate early (CMV) promoter, a gradual decline in the number of transduced cells has been described. in contrast, the use of cellular promoters such as the neuron-specific enolase promoter or hybrid promoters such as the chicken beta-actin/CMV promoter resulted in sustained transgene expression. The cellular tropism of rAAV-mediated gene transfer in the central nervous system (CNS) varies depending on the serotype used. Serotype 2 vectors preferentially transduce neurons whereas rAAV5 and rAAV1 transduce both neurons and glial cells. Recombinant AAV4-mediated gene transfer was inefficient in neurons and glial cells of the striatum (the only structure tested so far) but efficient in ependymal cells.No inflammatory response has been described following rAAV2 administration to the brain. In contrast, antibodies to AAV2 capsid and transgene product were elicited but no reduction of transgene expression was observed and readministration of vector without loss of efficiency was possible from 3 months after the first injection.Based on the success of pioneer work performed with marker genes, various strategies for therapeutic gene delivery were designed. These include enzyme replacement in lysosomal storage diseases, Canavan disease and Parkinson's disease; delivery of neuroprotective factors in Parkinson's disease, Huntington disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and spinal cord injury; as well as modulation of neurotransmission in epilepsy and Parkinson's disease.Several of these strategies have demonstrated promising results in relevant animal models. However, their implementation in the clinics will probably require a tight regulation and a specific targeting of therapeutic gene expression which still demands further developments of the vectors. Copyright (C) 2004 John Wiley Sons, Ltd.