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以CRISPR为媒介的转录激活作为SYNGAP1相关的智力障碍的突变独立治疗策略

Laura Sichlinger^1,2,3, Molly B Reilly^1,2,3, Sakshi Arora^3,4

¹Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.

bioRxiv : the preprint server for biology

|November 24, 2025

概括

在SYNGAP1相关智力障碍 (SRID) 的小鼠模型中,CRISPR转录激活疗法成功地调高了功能Syngap1等位基因. 这种方法使蛋白质水平正常化并挽救认知缺陷,显示出治疗这种遗传性疾病的希望.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
分子生物学分子生物学

背景情况:

突触Ras GTPase激活蛋白 (SynGAP) 对突触功能和神经元发育至关重要.
在SYNGAP1中的功能丧失变体导致SYNGAP1相关的智力障碍 (SRID),严重的神经发育障碍.
目前对SRID的治疗方法没有解决潜在的遗传原因,通常是由于单 haploinsufficiency.

研究的目的:

开发和评估一种CRISPR介导的转录激活 (CRISPRa) 策略,以提高SRID中的功能Syngap1等位基因的调节.
评估CRISPRa在SRID的小鼠模型和人类细胞中的治疗潜力.

主要方法:

开发了一个CRISPRa系统来准和激活内源Syngap1基因.
使用了SRID小鼠模型和人类诱导的多能干细胞 (hiPSC) 衍生的刺激性皮质神经元.
在接受治疗的模型中评估了SynGAP蛋白水平,下游信号通路和认知功能 (工作记忆).

主要成果:

克里斯普拉成功激活了Syngap1的表达,导致SynGAP蛋白水平正常化,并恢复了下游的信号传输.
在SRID小鼠模型中,工作记忆缺陷得到了拯救.
克里斯普拉在人类iPSC衍生的神经元中表现出有效性,具有明显的SYNGAP1功能丧失变异.

结论:

使用CRISPRa的突变独立转录激活是SRID的可行治疗策略.
这种方法对治疗由哈普洛缺乏症引起的遗传疾病具有前景.
克里斯普拉为SRID提供了潜在的基因向疗法,解决了根源的遗传原因.

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