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Recent advances in gene therapy for neurodevelopmental disorders with epilepsy
Journal of Neurochemistry ( IF 4.7 ) Pub Date : 2020-09-02 , DOI: 10.1111/jnc.15168
Thomas J Turner 1 , Clara Zourray 1, 2 , Stephanie Schorge 2 , Gabriele Lignani 1
Affiliation  

Neurodevelopmental disorders can be caused by mutations in neuronal genes fundamental to brain development. These disorders have severe symptoms ranging from intellectually disability, social and cognitive impairments, and a subset are strongly linked with epilepsy. In this review, we focus on those neurodevelopmental disorders that are frequently characterized by the presence of epilepsy (NDD + E). We loosely group the genes linked to NDD + E with different neuronal functions: transcriptional regulation, intrinsic excitability and synaptic transmission. All these genes have in common a pivotal role in defining the brain architecture and function during early development, and when their function is altered, symptoms can present in the first stages of human life. The relationship with epilepsy is complex. In some NDD + E, epilepsy is a comorbidity and in others seizures appear to be the main cause of the pathology, suggesting that either structural changes (NDD) or neuronal communication (E) can lead to these disorders. Furthermore, grouping the genes that cause NDD + E, we review the uses and limitations of current models of the different disorders, and how different gene therapy strategies are being developed to treat them. We highlight where gene replacement may not be a treatment option, and where innovative therapeutic tools, such as CRISPR‐based gene editing, and new avenues of delivery are required. In general this group of genetically defined disorders, supported increasing knowledge of the mechanisms leading to neurological dysfunction serve as an excellent collection for illustrating the translational potential of gene therapy, including newly emerging tools.

中文翻译:

癫痫神经发育障碍基因治疗的最新进展

神经发育障碍可能是由对大脑发育至关重要的神经元基因突变引起的。这些疾病具有严重的症状,包括智力障碍、社交和认知障碍,其中一部分与癫痫密切相关。在这篇综述中,我们关注那些经常以癫痫 (NDD + E) 为特征的神经发育障碍。我们将与 NDD + E 相关的基因以不同的神经元功能松散地分组:转录调节、内在兴奋性和突触传递。所有这些基因在定义早期发育过程中的大脑结构和功能方面具有共同的关键作用,当它们的功能发生改变时,症状就会出现在人类生命的最初阶段。与癫痫的关系是复杂的。在某些 NDD + E 中,癫痫是一种合并症,在其他情况下,癫痫发作似乎是病理的主要原因,这表明结构变化 (NDD) 或神经元通讯 (E) 可导致这些疾病。此外,将导致 NDD + E 的基因分组,我们回顾了当前不同疾病模型的用途和局限性,以及如何开发不同的基因治疗策略来治疗它们。我们强调基因替换可能不是治疗选择的地方,以及需要创新治疗工具(例如基于 CRISPR 的基因编辑)和新的递送途径的地方。总的来说,这组基因定义的疾病,支持增加对导致神经功能障碍的机制的了解,作为说明基因治疗转化潜力的绝佳集合,
更新日期:2020-09-02
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