{"title":"An RNA editing strategy rescues gene duplication in a mouse model of MECP2 duplication syndrome and nonhuman primates","authors":"Dong Yang, Xiaoqing Wu, Yinan Yao, Mengsi Duan, Xing Wang, Guoling Li, Aiguo Guo, Meixian Wu, Yuanhua Liu, Jin Zheng, Renxia Zhang, Tong Li, Alvin Luk, Xuan Yao, Linyu Shi, Chunlong Xu, Hui Yang","doi":"10.1038/s41593-024-01838-6","DOIUrl":null,"url":null,"abstract":"<p>Duplication of methyl-CpG-binding protein 2 (<i>MECP2</i>) gene causes <i>MECP2</i> duplication syndrome (MDS). To normalize the duplicated <i>MECP2</i> in MDS, we developed a high-fidelity Cas13Y (hfCas13Y) system capable of targeting the <i>MECP2</i> (hfCas13Y-g<i>MECP2</i>) messenger RNA for degradation and reducing protein levels in the brain of humanized <i>MECP2</i> transgenic mice. Moreover, the intracerebroventricular adeno-associated virus (AAV) delivery of hfCas13Y-g<i>MECP2</i> in newborn or adult MDS mice restored dysregulated gene expression and improved behavior deficits. Notably, treatment with AAV9-hfCas13Y-g<i>MECP2</i> extended the median survival of <i>MECP2</i> transgenic mice from 156.5 to 226 d. Furthermore, studies with monkeys showed a single injection of AAV9-hfCas13Y-g<i>MECP2</i> was sufficient to drive robust expression of hfCas13Y in widespread brain regions, with <i>MECP2</i> knockdown efficiency reaching 52.19 ± 0.03% and significantly decreased expression of biomarker gene <i>GDF11</i>. Our results demonstrate that the RNA-targeting hfCas13Y-g<i>MECP2</i> system is an effective intervention for MDS, providing a potential strategy for treating other dosage-sensitive diseases.</p>","PeriodicalId":19076,"journal":{"name":"Nature neuroscience","volume":"12 1","pages":""},"PeriodicalIF":21.2000,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41593-024-01838-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
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 226 d. 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.
期刊介绍:
Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority.
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