Haploinsufficiency in retinoic acid induced 1 (RAI1) causes Smith-Magenis syndrome (SMS), a severe neurodevelopmental disorder characterized by neurocognitive deficits and obesity. Currently, curative treatments for SMS do not exist. Here, we take a recombinant adeno-associated virus (rAAV)-clustered regularly interspaced short palindromic repeats activation (CRISPRa) approach to increase expression of the remaining intact Rai1 allele. Building upon our previous work that found the paraventricular nucleus of hypothalamus plays a central role in SMS pathogenesis, we performed paraventricular nucleus of hypothalamus–specific rAAV-CRISPRa therapy by increasing endogenous Rai1 expression in SMS (Rai1^±) mice. We found that rAAV-CRISPRa therapy rescues excessive repetitive behavior, delays the onset of obesity, and partially reduces hyperphagia in SMS mice. Our work provides evidence that rAAV-CRISPRa therapy during early adolescence can boost the expression of healthy Rai1 allele and modify disease progression in a mouse model of Smith-Magenis syndrome.

视黄酸诱导 1 ( RAI1 ) 的单倍体不足导致 Smith-Magenis 综合征 (SMS)，这是一种以神经认知缺陷和肥胖为特征的严重神经发育障碍。目前，SMS 的治疗方法尚不存在。在这里，我们采用重组腺相关病毒 (rAAV) 成簇的规则间隔短回文重复序列激活 (CRISPRa) 方法来增加剩余的完整Rai1等位基因的表达。基于我们之前发现下丘脑室旁核在 SMS 发病机制中起核心作用的工作，我们通过增加 SMS 中的内源性Rai1表达来进行下丘脑室旁核特异性 rAAV-CRISPRa 治疗（Rai1 ^±） 老鼠。我们发现 rAAV-CRISPRa 疗法可以挽救 SMS 小鼠的过度重复行为，延缓肥胖的发生，并部分减少食欲过盛。我们的工作提供的证据表明，在 Smith-Magenis 综合征小鼠模型中，青春期早期的 rAAV-CRISPRa 疗法可以促进健康Rai1等位基因的表达并改变疾病进展。