加州大学Kevin J. Bender小组宣布他们研究出CRISPR激活与SCN2A相关的神经发育障碍。这一研究成果于2025年9月17日发表在国际顶尖学术期刊《自然》上。

将SCN2A单倍体不足作为概念证明，课题组表明通过CRISPR激活（CRISPRa）上调现有功能基因拷贝可以挽救SCN2A单倍体不足小鼠的神经相关表型。该课题组首先表明，在青春期杂合子Scn2a条件敲入小鼠中恢复Scn2a的表达可以挽救与Scn2a单倍不足（Scn2a^+/-）相关的电生理缺陷。接下来，在青春期小鼠中进行基于腺相关病毒CRISPR的治疗，该课题组证明该课题组可以纠正新皮质锥体细胞的内在和突触缺陷，这是导致SCN2A单倍功能不全的神经发育障碍和癫痫病因的主要细胞类型。

此外，课题组发现系统递送CRISPRa可以保护Scn2a^+/-小鼠抗化学惊厥引起的癫痫发作。最后，该研究组还表明，腺相关病毒CRISPRa治疗可以恢复SCN2A单倍不足的人类干细胞源性神经元的兴奋性。他们的研究结果显示了这种治疗方法在挽救SCN2A单倍体缺陷方面的潜力，并表明即使在青少年阶段进行挽救也可以改善神经发育表型。

据了解，大多数被诊断为单基因的神经发育障碍都是通过单倍不全来诊断的，即两个基因拷贝中只有一个是功能性的。SCN2A单倍体功能不全是神经发育障碍最常见的症状之一，通常表现为自闭症谱系障碍、智力残疾，在一部分儿童中还表现为顽固性癫痫。

附：英文原文

Title: CRISPR activation for SCN2A-related neurodevelopmental disorders

Author: Tamura, Serena, Nelson, Andrew D., Spratt, Perry W. E., Hamada, Elizabeth C., Zhou, Xujia, Kyoung, Henry, Li, Zizheng, Arnould, Coline, Barskyi, Vladyslav, Krupkin, Beniamin, Young, Kiana, Zhao, Jingjing, Holden, Stephanie S., Sahagun, Atehsa, Keeshen, Caroline M., Lu, Congyi, Ben-Shalom, Roy, Taloma, Sunrae E., Schamiloglu, Selin, Li, Ying C., Min, Lia, Jenkins, Paul M., Pan, Jen Q., Paz, Jeanne T., Sanders, Stephan J., Matharu, Navneet, Ahituv, Nadav, Bender, Kevin J.

Issue&Volume: 2025-09-17

Abstract: Most neurodevelopmental disorders with single gene diagnoses act via haploinsufficiency, in which only one of the two gene copies is functional1. SCN2A haploinsufficiency is one of the most frequent causes of neurodevelopmental disorder, often presenting with autism spectrum disorder, intellectual disability and, in a subset of children, refractory epilepsy2. Here, using SCN2A haploinsufficiency as a proof-of-concept, we show that upregulation of the existing functional gene copy through CRISPR activation (CRISPRa) can rescue neurological-associated phenotypes in Scn2a haploinsufficient mice. We first show that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency (Scn2a+/). Next, using an adeno-associated virus CRISPRa-based treatment in adolescent mice, we show that we can correct intrinsic and synaptic deficits in neocortical pyramidal cells, a major cell type that contributes to neurodevelopmental disorders and seizure aetiology in SCN2A haploinsufficiency. Furthermore, we find that systemic delivery of CRISPRa protects Scn2a+/ mice against chemoconvulsant-induced seizures. Finally, we also show that adeno-associated virus CRISPRa treatment rescues excitability in SCN2A haploinsufficient human stem-cell-derived neurons. Our results showcase the potential of this therapeutic approach to rescue SCN2A haploinsufficiency and demonstrates that rescue even at adolescent stages can ameliorate neurodevelopmental phenotypes.

DOI: 10.1038/s41586-025-09522-w

Source: https://www.nature.com/articles/s41586-025-09522-w