Muramatsu Shin-ichi
Division of Neurology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan.
Brain Nerve. 2007 Apr;59(4):425-30.
Recombinant adeno-associated viral (rAAV) vectors are safer and more effective than other in vivo gene delivery methods. Stereotaxic injection of the vectors provides continuous and selective expression of therapeutic proteins throughout the target area in primate brains without toxicity. Three phase I clinical trials for gene therapy for Parkinson's disease (PD) using rAAV vectors are currently underway. One trial involves gene transfer of aromatic L-amino acid decarboxylase (AADC), an enzyme that converts L-dopa to dopamine, to restore therapeutic windows of orally administered L-dopa in advanced idiopathic PD. After AADC transduction, the daily required dose of L-dopa can be reduced and the duration of the ON period is prolonged. Another trial involves transduction of the subthalamic nucleus (STN) with rAAV vectors expressing glutamic acid decarboxylases, a rate-limiting enzyme for synthesizing inhibitory the neurotransmitter gamma-aminobutyric acid (GABA). This strategy, which is similar to deep brain stimulation, aims at modulating hyperactive STN neurons, thereby alter the resulting activity of down-stream targets, which influence movement. However, the mechanism of stimulation remains unknown, and there are some theoretical concerns of chemical alteration. The other trial involves delivery of rAAV vectors expressing neurturin, a natural analog of a glial cell line-derived neurotrophic factor, into the putamen to slow down the ongoing degeneration of nigral dopaminergic neurons. Positron emission tomography with various tracers has been used to monitor the effects of therapeutic gene expression in vivo. Although no serious adverse effects of gene transfer have been reported so far in these trials, vector systems that regulate transgene expression are necessary to increase safety, and the development of such systems is in progress. Gene therapy using rAAV vectors may be a promising option for treatment of PD in the near future.
重组腺相关病毒（rAAV）载体比其他体内基因递送方法更安全、更有效。立体定向注射这些载体可在灵长类动物大脑的整个靶区域持续且选择性地表达治疗性蛋白质，且无毒性。目前正在进行三项使用rAAV载体治疗帕金森病（PD）的I期临床试验。一项试验涉及将芳香族L-氨基酸脱羧酶（AADC，一种将左旋多巴转化为多巴胺的酶）进行基因转移，以恢复晚期特发性PD患者口服左旋多巴的治疗窗口。AADC转导后，每日所需的左旋多巴剂量可减少，“开”期持续时间延长。另一项试验涉及用表达谷氨酸脱羧酶的rAAV载体转导丘脑底核（STN），谷氨酸脱羧酶是合成抑制性神经递质γ-氨基丁酸（GABA）的限速酶。这种类似于深部脑刺激的策略旨在调节STN过度活跃的神经元，从而改变下游靶点的活性，进而影响运动。然而，刺激机制尚不清楚，并且存在一些关于化学改变的理论担忧。另一项试验涉及将表达神经营养因子（一种胶质细胞源性神经营养因子的天然类似物）的rAAV载体递送至壳核，以减缓黑质多巴胺能神经元的进行性退化。已使用带有各种示踪剂的正电子发射断层扫描来监测体内治疗性基因表达的效果。尽管目前在这些试验中尚未报告基因转移的严重不良反应，但调节转基因表达的载体系统对于提高安全性是必要的，并且此类系统的研发正在进行中。使用rAAV载体的基因治疗在不久的将来可能是治疗PD的一个有前景的选择。
