Remyelination induced by a DNA aptamer in a mouse model of multiple sclerosis.
Remyelination induced by a DNA aptamer in a mouse model of multiple sclerosis.
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DOI：
10.1371/journal.pone.0039595
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Maher LJ 3rd
中科院分区：
文献类型：
--
作者：
Nastasijevic B;Wright BR;Smestad J;Warrington AE;Rodriguez M;Maher LJ 3rd
多发性硬化症（MS）是中枢神经系统（CNS）的一种使人衰弱的炎症性疾病，其特征是神经元轴突周围的绝缘髓鞘局部破坏。全球有超过2亿多发性硬化症患者，缺乏预防进展或诱导修复的治疗方法构成了重大挑战。抗炎疗法仅在预防复发方面取得了有限的成功。先前对人血清样本的筛选显示，天然IgM抗体可以结合少突胶质细胞，并在thiler脑脊髓炎病毒慢性感染易感小鼠的MS模型和局灶性脱髓鞘溶卵磷脂模型中促进中枢神经系统病变的细胞信号传导和再髓鞘再生。这一有趣的结果提出了一种可能性，即对少突胶质细胞或髓鞘成分具有结合特异性的分子可能促进ms的治疗性髓鞘再生。由于IgM抗体的大小和复杂性，鉴定具有促进体内髓鞘再生能力的更小的髓鞘特异性分子是很有意义的。在这里，我们展示了一个40个核苷酸的单链DNA适体选择亲和力小鼠髓磷脂显示这种性质。该适体在体外结合多种髓磷脂成分。腹膜注射该适体导致分布到中枢神经系统组织，并促进CNS病变的再髓鞘脱髓鞘在小鼠感染Theiler的病毒。有趣的是，所选择的DNA适体含有富含鸟苷的序列，预计会诱导涉及鸟苷四重奏结构的折叠。相对于单克隆抗体，DNA适体小，稳定，非免疫原性，为MS治疗提供了新的可能性。
Multiple sclerosis (MS) is a debilitating inflammatory disease of the central nervous system (CNS) characterized by local destruction of the insulating myelin surrounding neuronal axons. With more than 200 million MS patients worldwide, the absence of treatments that prevent progression or induce repair poses a major challenge. Anti-inflammatory therapies have met with limited success only in preventing relapses. Previous screening of human serum samples revealed natural IgM antibodies that bind oligodendrocytes and promote both cell signaling and remyelination of CNS lesions in an MS model involving chronic infection of susceptible mice by Theiler’s encephalomyelitis virus and in the lysolecithin model of focal demyelination. This intriguing result raises the possibility that molecules with binding specificity for oligodendrocytes or myelin components may promote therapeutic remyelination in MS. Because of the size and complexity of IgM antibodies, it is of interest to identify smaller myelin-specific molecules with the ability to promote remyelination in vivo. Here we show that a 40-nucleotide single-stranded DNA aptamer selected for affinity to murine myelin shows this property. This aptamer binds multiple myelin components in vitro. Peritoneal injection of this aptamer results in distribution to CNS tissues and promotes remyelination of CNS lesions in mice infected by Theiler’s virus. Interestingly, the selected DNA aptamer contains guanosine-rich sequences predicted to induce folding involving guanosine quartet structures. Relative to monoclonal antibodies, DNA aptamers are small, stable, and non-immunogenic, suggesting new possibilities for MS treatment.
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