Brain Repair and Imaging in Neural Systems, 22184 Lund, Sweden.
Brain. 2010 Feb;133(Pt 2):496-511. doi: 10.1093/brain/awp314. Epub 2010 Feb 2.
Viral vector-mediated gene transfer utilizing adeno-associated viral vectors has recently entered clinical testing as a novel tool for delivery of therapeutic agents to the brain. Clinical trials in Parkinson's disease using adeno-associated viral vector-based gene therapy have shown the safety of the approach. Further efforts in this area will show if gene-based approaches can rival the therapeutic efficacy achieved with the best pharmacological therapy or other, already established, surgical interventions. One of the strategies under development for clinical application is continuous 3,4-dihydroxyphenylalanine delivery. This approach has been shown to be efficient in restoring motor function and reducing established dyskinesias in rats with a partial lesion of the nigrostriatal dopamine projection. Here we utilized high purity recombinant adeno-associated viral vectors serotype 5 coding for tyrosine hydroxylase and its co-factor synthesizing enzyme guanosine-5'-triphosphate cyclohydrolase-1, delivered at an optimal ratio of 5 : 1, to show that the enhanced 3,4-dihydroxyphenylalanine production obtained with this optimized delivery system results in robust recovery of function in spontaneous motor tests after complete dopamine denervation. We found that the therapeutic efficacy was substantial and could be maintained for at least 6 months. The tyrosine hydroxylase plus guanosine-5'-triphosphate cyclohydrolase-1 treated animals were resistant to developing dyskinesias upon peripheral l-3,4-dihydroxyphenylalanine drug challenge, which is consistent with the interpretation that continuous dopamine stimulation resulted in a normalization of the post-synaptic response. Interestingly, recovery of forelimb use in the stepping test observed here was maintained even after a second lesion depleting the serotonin input to the forebrain, suggesting that the therapeutic efficacy was not solely dependent on dopamine synthesis and release from striatal serotonergic terminals. Taken together these results show that vector-mediated continuous 3,4-dihydroxyphenylalanine delivery has the potential to provide significant symptomatic relief even in advanced stages of Parkinson's disease.
腺相关病毒载体介导的基因转移最近已进入临床试验，作为向大脑递送治疗剂的一种新工具。利用腺相关病毒载体的基因治疗在帕金森病中的临床试验显示了该方法的安全性。在该领域的进一步努力将表明，基于基因的方法是否可以与最佳药物治疗或其他已建立的手术干预相媲美，以实现治疗效果。正在开发用于临床应用的策略之一是持续输送 3,4-二羟苯丙氨酸。该方法已被证明在恢复运动功能和减少黑质纹状体多巴胺投射部分损伤大鼠的已建立运动障碍方面是有效的。在这里，我们利用高纯度重组腺相关病毒载体血清型 5 编码酪氨酸羟化酶及其共同因子合成酶鸟苷-5'-三磷酸环化水解酶-1，以最佳比例 5:1 进行递送，表明使用这种优化的递送系统获得的增强的 3,4-二羟苯丙氨酸产量可导致在多巴胺完全去神经后自发运动测试中功能的稳健恢复。我们发现治疗效果显著，并且可以维持至少 6 个月。酪氨酸羟化酶加鸟苷-5'-三磷酸环化水解酶-1 处理的动物在周围 l-3,4-二羟苯丙氨酸药物挑战时不易发生运动障碍，这与持续多巴胺刺激导致突触后反应正常化的解释一致。有趣的是，在这里观察到的抓握测试中前肢使用的恢复甚至在第二次损伤耗尽大脑前脑的 5-羟色胺输入后仍得以维持，这表明治疗效果不仅依赖于多巴胺从纹状体 5-羟色胺末梢的合成和释放。总之，这些结果表明，载体介导的持续 3,4-二羟苯丙氨酸输送具有提供显著症状缓解的潜力，即使在帕金森病的晚期也是如此。
