Experimental and clinical application of plasmid DNA in the field of central nervous diseases.
Experimental and clinical application of plasmid DNA in the field of central nervous diseases.
复制标题
DOI：
10.2174/156652311798192833
复制
发表时间：
2011-11
影响因子：
3.6
通讯作者：
M. Shimamura;N. Sato;R. Morishita
中科院分区：
文献类型：
--
作者：
M. Shimamura;N. Sato;R. Morishita
利用质粒DNA （pDNA）治疗不可治疗的神经系统疾病，如缺血性中风、帕金森病（PD）、阿尔茨海默病（AD）和多发性硬化症（MS）的新策略已经被寻求。一种策略是在大脑中诱导生长因子的过度表达，如血管内皮生长因子（VEGF）、胶质细胞系衍生神经营养因子（GDNF）和肝细胞生长因子（HGF）。由于缺血性中风、帕金森病和阿尔茨海默病表现出神经元损伤，编码这些基因的pDNA的转移已经被研究并显示出保护神经元免受损伤，与更好的行为结果相关。这些生长因子也被证明可以加速血管生成、神经突生长和大脑神经发生，并且这些因子的过度表达在啮齿动物脑缺血中显示出治疗作用。pDNA的另一个应用是作为“DNA疫苗”诱导对AD中淀粉样蛋白β的免疫，这需要主要的Th2反应来避免由Th1反应引起的自身免疫性脑脊髓炎。由于pDNA与特殊装置的结合和/或pDNA的修饰可以诱导对目标抗原的主要Th2反应，因此基于pDNA的疫苗将是AD的理想疫苗。有趣的是，pDNA也可以诱导免疫耐受，基于pDNA的疫苗诱导对自身免疫抗体的免疫耐受已经在MS动物模型中进行了广泛的研究。基于这些结果，pDNA疫苗已经在MS患者中进行了试验，并在I/II期临床研究中被报道为安全且部分有效。在这篇综述中，我们讨论了pdna介导的药物在神经系统疾病中的潜力和问题。
Novel therapeutic strategies utilizing plasmid DNA (pDNA) have been sought for non-treatable neurological disorders, such as ischemic stroke, Parkinson disease (PD), Alzheimer disease (AD), and multiple sclerosis (MS). One strategy is to induce overexpression of growth factors, such as vascular endothelial growth factor (VEGF), glial cell-line derived neurotrophic factor (GDNF), and hepatocyte growth factor (HGF), in the brain. Since ischemic stroke, PD, and AD show damage of neurons, the transfer of pDNA encoding these genes has been examined and shown to protect neurons from damage, associated with a better behavioral outcome. These growth factors have also been shown to accelerate angiogenesis, neurite outgrowth, and neurogenesis in the brain, and overexpression of these factors showed therapeutic effects in cerebral ischemia in rodents. Another application of pDNA is as a "DNA vaccine" to induce immunity against amyloid Aβ in AD, which requires a predominantly Th2 response to avoid autoimmune encephalomyelitis evoked by a Th1 response. Since the combination of pDNA and special devices and/or modification of pDNA could induce a predominantly Th2 response to a targeted antigen, a pDNA-based vaccine would be ideal for AD. Interestingly, pDNA could also induce immune tolerance, and pDNA-based vaccines to induce immune tolerance to autoimmune antibodies have been extensively examined in an animal model of MS. Based on the results, a pDNA vaccine has already been tried in MS patients and reported to be safe and partly effective in phase I/II clinical studies. In this review, we discuss the potential and problems of pDNA-mediated medicine in neurological disorders.