Developmental and epileptic encephalopathies (DEEs) describe a subset of neurodevelopmental disorders categorized by refractory epilepsy that is often associated with intellectual disability and autism spectrum disorder. The majority of DEEs are now known to have a genetic basis with de novo coding variants accounting for the majority of cases. More recently, a small number of individuals have been identified with intronic SCN1A variants that result in alternative splicing events that lead to ectopic inclusion of poison exons (PEs). PEs are short highly conserved exons that contain a premature truncation codon, and when spliced into the transcript, lead to premature truncation and subsequent degradation by nonsense-mediated decay. The reason for the inclusion/exclusion of these PEs is not entirely clear, but research suggests an autoregulatory role in gene expression and protein abundance. This is seen in proteins such as RNA-binding proteins and serine/arginine-rich proteins. Recent studies have focused on targeting these PEs as a method for therapeutic intervention. Targeting PEs using antisense oligonucleotides (ASOs) has shown to be effective in modulating alternative splicing events by decreasing the amount of transcripts harboring PEs, thus increasing the abundance of full-length transcripts and thereby the amount of protein in haploinsufficient genes implicated in DEE. In the age of personalized medicine, cellular and animal models of the genetic epilepsies have become essential in developing and testing novel precision therapeutics, including PE-targeting ASOs in a subset of DEEs.
Dev Neurosci

中文翻译：

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靶向毒外显子治疗发育性和癫痫性脑病

发育性和癫痫性脑病 (DEE) 描述了神经发育障碍的一个子集，这些神经发育障碍被归类为通常与智力障碍和自闭症谱系障碍相关的难治性癫痫。现在已知大多数 DEE 具有遗传基础，其中从头编码变体占大多数情况。最近，少数人被鉴定为内含子SCN1A导致异位包含毒外显子 (PE) 的可变剪接事件的变体。PE 是高度保守的短外显子，包含过早截断密码子，当拼接到转录本中时，会导致过早截断和随后通过无义介导的衰变而降解。包含/排除这些 PE 的原因尚不完全清楚，但研究表明在基因表达和蛋白质丰度中具有自动调节作用。这在诸如 RNA 结合蛋白和富含丝氨酸/精氨酸的蛋白质等蛋白质中可见。最近的研究集中在将这些 PE 作为治疗干预的方法。使用反义寡核苷酸 (ASO) 靶向 PE 已显示通过减少含有 PE 的转录物的数量来有效调节选择性剪接事件，因此增加了全长转录物的丰度，从而增加了与 DEE 有关的单倍体不足基因中的蛋白质量。在个性化医疗时代，遗传性癫痫的细胞和动物模型已成为开发和测试新型精准疗法的必要条件，包括 DEE 子集中针对 PE 的 ASO。
开发神经科学