Tenenbaum L, Chtarto A, Lehtonen E, Velu T, Brotchi J, Levivier M
Laboratory of Experimental Neurosurgery, Université Libre de Bruxelles, Hôpital Erasme, 808, Route de Lennik, B-1070 Brussels, Belgium.
J Gene Med. 2004 Feb;6 Suppl 1:S212-22. doi: 10.1002/jgm.506.
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.
重组腺相关病毒（rAAV）载体已成功转导大脑的各个区域，且未检测到毒性。使用巨细胞病毒立即早期（CMV）启动子时，已观察到转导细胞数量逐渐减少。相比之下，使用细胞启动子（如神经元特异性烯醇化酶启动子）或混合启动子（如鸡β-肌动蛋白/CMV启动子）可导致转基因持续表达。rAAV介导的基因转移在中枢神经系统（CNS）中的细胞嗜性因所用血清型而异。2型载体优先转导神经元，而rAAV5和rAAV1则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，但在室管膜细胞中效率较高。向大脑注射rAAV2后未观察到炎症反应。相比之下，可引发针对AAV2衣壳和转基因产物的抗体，但未观察到转基因表达降低，且首次注射后3个月起可重新注射载体而不损失效率。基于使用标记基因的开创性工作的成功，设计了多种治疗性基因递送策略。这些策略包括溶酶体贮积病、卡纳万病和帕金森病中的酶替代；帕金森病、亨廷顿病、阿尔茨海默病、肌萎缩侧索硬化症、缺血和脊髓损伤中的神经保护因子递送；以及癫痫和帕金森病中的神经传递调节。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，它们在临床上的应用可能需要严格调控和治疗性基因表达的特异性靶向，这仍需要载体的进一步发展。
