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首页> 外文期刊>IBRO Reports >Functional study of a novel Charcot-Marie-Tooth disease-related gene: Promoting peripheral nerve regeneration via adeno-associated virus-mediated gene delivery
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Functional study of a novel Charcot-Marie-Tooth disease-related gene: Promoting peripheral nerve regeneration via adeno-associated virus-mediated gene delivery

机译：新型Charcot-Marie-Tooth病相关基因的功能研究：通过腺相关病毒介导的基因传递促进外周神经再生

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Recent in vivo studies using AD-like transgenic animal model revealed that LXRs ago- nists provoked inhibition of neuroinflammation, marked decrease cortical levels of amyloid beta and reversed contextual memory deficits. Unfortunately, these generation of LXRs agonists causes liver steatosis and hypertriglyceridemia, limiting its clinical appli- cation A novel LXRs agonist called DMHCA is being tested, described previously to display undetectable undesired side effects but not BBB penetration. DMHCA was encapsulated in a PEGylated den- drimer and used as nanocarrier and tested via intranasal in an AD-like transgenic mouse model. Dendrimer-DMHCA-Biotin com- plex was tested to fully describe its penetration, biodistribution and specific effects in the target areas of the transgenic mouse brain. Result: Intranasal daily dendrimer-DMHCA treatment in our mouse model facilitated significant brain amyloid beta clearance, measured by ELISA and western blotting, preventing memory decline. Age-related impairment of AB homeostatic mechanisms has been postulated to be a critical determinant of disease risk. Thus, even modest reductions in clearance of soluble AB could result in elevated levels of AB peptides and ultimately their progressive and chronic deposition within the brain. This novel therapeutic approach ameliorates cognitive deficits assessed by novel object recognition test, characteristic of our mouse model of AD; without undesirable side effects. Our studies should render suitable preclinical proof of principle for further clinical application.
机译：最近使用类似AD的转基因动物模型进行的体内研究表明，LXR的狂热者激发了神经炎症的抑制作用，显着降低了皮质淀粉样β的水平，并逆转了上下文记忆的缺陷。不幸的是，这些一代的LXRs激动剂会引起肝脏脂肪变性和高甘油三酯血症，限制了其临床应用。一种名为DMHCA的新型LXRs激动剂正在接受测试，以前显示出无法检测到的不良副作用，但没有BBB渗透。将DMHCA封装在PEG化的树状大分子中，用作纳米载体，并通过鼻内在AD样转基因小鼠模型中进行测试。测试了树状大分子-DMHCA-生物素复合物，以充分描述其在转基因小鼠大脑靶区域的渗透，生物分布和特定作用。结果：在我们的小鼠模型中，经鼻内每天进行树状大分子-DMHCA处理可通过ELISA和Western印迹法检测到明显的脑淀粉样β清除，从而防止记忆力下降。假定AB稳态机制的年龄相关损伤是疾病风险的关键决定因素。因此，即使是可溶性AB清除率的适度降低也可能导致AB肽水平升高，并最终导致其在大脑内的进行性和慢性沉积。这种新颖的治疗方法可改善通过新颖的物体识别测试评估的认知缺陷，这是我们AD小鼠模型的特征。没有不良副作用。我们的研究应为进一步的临床应用提供适当的临床前原理证明。

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