辉大基因公司杨辉等研究人员合作发现，一种RNA编辑策略可拯救MECP2重复综合征小鼠模型和非人灵长类动物中的基因重复。相关论文于2024年12月12日在线发表于国际学术期刊《自然—神经科学》。

据研究人员介绍，甲基-CpG结合蛋白2（MECP2）基因的重复导致了MECP2重复综合征（MDS）。

为了正常化MDS中重复的MECP2基因，研究人员开发了一种高保真Cas13Y（hfCas13Y）系统。该系统能够靶向MECP2（hfCas13Y-gMECP2）信使RNA进行降解，从而减少人源化MECP2转基因小鼠大脑中的蛋白水平。此外，将hfCas13Y-gMECP2通过脑室内腺相关病毒（AAV）递送给新生或成年的MDS小鼠，恢复了失调的基因表达并改善了行为缺陷。值得注意的是，AAV9-hfCas13Y-gMECP2治疗将MECP2转基因小鼠的中位生存期从156.5天延长至226天。

此外，猴子研究表明，单次注射AAV9-hfCas13Y-gMECP2足以驱动hfCas13Y在广泛脑区的强烈表达，MECP2敲低效率达到52.19 ± 0.03%，并显著降低了生物标志基因GDF11的表达。这些研究结果表明，靶向RNA的hfCas13Y-gMECP2系统是治疗MDS的有效干预策略，为治疗其他剂量敏感性疾病提供了潜在的治疗方法。

附：英文原文

Title: An RNA editing strategy rescues gene duplication in a mouse model of MECP2 duplication syndrome and nonhuman primates

Author: Yang, Dong, Wu, Xiaoqing, Yao, Yinan, Duan, Mengsi, Wang, Xing, Li, Guoling, Guo, Aiguo, Wu, Meixian, Liu, Yuanhua, Zheng, Jin, Zhang, Renxia, Li, Tong, Luk, Alvin, Yao, Xuan, Shi, Linyu, Xu, Chunlong, Yang, Hui

Issue&Volume: 2024-12-12

Abstract: Duplication of methyl-CpG-binding protein 2 (MECP2) gene causes MECP2 duplication syndrome (MDS). To normalize the duplicated MECP2 in MDS, we developed a high-fidelity Cas13Y (hfCas13Y) system capable of targeting the MECP2 (hfCas13Y-gMECP2) messenger RNA for degradation and reducing protein levels in the brain of humanized MECP2 transgenic mice. Moreover, the intracerebroventricular adeno-associated virus (AAV) delivery of hfCas13Y-gMECP2 in newborn or adult MDS mice restored dysregulated gene expression and improved behavior deficits. Notably, treatment with AAV9-hfCas13Y-gMECP2 extended the median survival of MECP2 transgenic mice from 156.5 to 226d. Furthermore, studies with monkeys showed a single injection of AAV9-hfCas13Y-gMECP2 was sufficient to drive robust expression of hfCas13Y in widespread brain regions, with MECP2 knockdown efficiency reaching 52.19±0.03% and significantly decreased expression of biomarker gene GDF11. Our results demonstrate that the RNA-targeting hfCas13Y-gMECP2 system is an effective intervention for MDS, providing a potential strategy for treating other dosage-sensitive diseases.

DOI: 10.1038/s41593-024-01838-6

Source: https://www.nature.com/articles/s41593-024-01838-6