Base editing the synapse: Modeling a complex neurological disorder in non-human primates.
Base editing the synapse: Modeling a complex neurological disorder in non-human primates.
复制标题
突触碱基编辑：模拟非人类灵长类动物的复杂神经系统疾病。
DOI：
10.1016/j.ymthe.2022.05.009
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Helbig,Ingo
中科院分区：
文献类型：
--
作者：
Prosser,BenjaminL;Helbig,Ingo
自2016年发现以来，1碱基编辑--单核苷酸的有效化学修饰--与更广泛的基因编辑领域一起取得了迅猛的进展。在这一期的《分子治疗》中，Lu和他的同事2在使这些技术应用于人类疾病方面向前迈出了重要的一步，他们报告了成功地使用碱基编辑来模拟非人类灵长类动物的复杂神经疾病。STXBP1相关神经发育障碍(STXBP1-NDD)是最常见的遗传性神经发育障碍之一，以癫痫、认知、行为和运动障碍3、4为特征。然而，由于缺乏足够的模型系统，阻碍了对潜在病理生理学的理解。虽然小鼠模型概括了疾病的某些方面，但5、6这些模型也有重要的局限性。这里生成的灵长类动物模型展示了难以在啮齿动物身上捕获的电异常，因此提供了双管齐下的进步--一个用于碱基编辑领域，另一个用于发育性癫痫的翻译工具包。碱基编辑程序从CRISPR-Cas9系统进化而来，并利用类似的组件来靶向DNA的特定区域。然而，碱基编辑应用了一个独特的脱氨酶结构域来进行DNA修饰，并应用了一个修改后的Cas9“尼克酶”，它只切割了一条DNA链。这允许精确的单核苷酸编辑，同时将双链断裂的意外后果降至最低。非预期的靶点编辑(双链断裂部位的插入/缺失)的减少以及即使在未分裂的细胞中碱基编辑的高效率也导致了对其治疗的相当大的热情
Since its discovery in 2016, 1 base editing—the efficient chemical modification of single nucleotides—has enjoyed a blistering pace of advance alongside the broader field of gene editing. In this issue of Molecular Therapy, Lu and colleagues 2 take an important step forward in making these technologies applicable to human disease, reporting on the successful use of a base editor to model a complex neurological disorder in nonhuman primates. STXBP1-related neurodevelopmental disorder (STXBP1-NDD) represents one of the most common genetic neurodevelopmental disorders and is characterized by epilepsy and cognitive, behavioral, and motor impairments 3, 4 Yet, a lack of adequate model systems has hindered understanding of the underlying pathophysiology. While mouse models recapitulate certain aspects of the disease, 5, 6 these models also have important limitations. The primate model generated here exhibits electrical abnormalities difficult to capture in rodents, thus offering a two-pronged advance—one for the field of base editing, and one for the translational toolkit of developmental epilepsies.Base editors evolved from the CRISPR-Cas9 system and utilize similar components for targeting specific regions of DNA. Yet, base editors apply a unique deaminase domain for DNA modification and a modified Cas9 “nickase” that cuts only one DNA strand. This allows precise, single-nucleotide edits while minimizing the unintended consequences of double-stranded breaks. The reduction in unintended, on-target editing (insertions/deletions at the site of doublestrand breaks) and high efficiency of base editing even in non-dividing cells has led to considerable enthusiasm for its therapeutic