AbstractDuplication 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.

摘要甲基CpG结合蛋白2（MECP2）基因的重复导致MECP2重复综合征（MDS）。为了使MDS中重复的MECP2正常化，我们开发了一种高保真Cas13Y（hfCas13Y）系统，能够靶向MECP2（hfCas13Y-gMECP2）信使RNA降解并降低人源化MECP2转基因小鼠大脑中的蛋白质水平。

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.

此外，在新生或成年MDS小鼠中脑室内腺相关病毒（AAV）递送hfCas13Y-gMECP2恢复了失调的基因表达并改善了行为缺陷。。

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..

此外，对猴子的研究表明，单次注射AAV9-hfCas13Y-gMECP2足以驱动广泛大脑区域中hfCas13Y的强烈表达，MECP2敲低效率达到52.19±0.03%，生物标志物基因GDF11的表达显着降低。我们的研究结果表明，靶向RNA的hfCas13Y-gMECP2系统是MDS的有效干预措施，为治疗其他剂量敏感疾病提供了潜在的策略。。

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Fig. 1: Screening of hfCas13Y variants and efficient gRNAs for MECP2 RNA knockdown.Fig. 2: MECP2 in vivo knockdown efficiency mediated by the AAV-hfCas13Y RNA editing system.Fig. 3: Knockdown of MeCP2 by the AAV-PHP.eB-hfCas13Y v3-mediated RNA editing system rescues impaired behaviors of MECP2 TG mice.Fig.

图1：筛选hfCas13Y变体和用于MECP2 RNA敲低的有效gRNA。。图3:AAV-PHP.eB-hfCas13Y v3介导的RNA编辑系统对MeCP2的敲低挽救了MeCP2-TG小鼠的受损行为。图。

4: AAV9-mediated delivery of hfCas13Y normalizes MECP2 levels and rescues behavioral deficits in the P1 MECP2 TG mice.Fig. 5: AAV9-mediated delivery of hfCas13Y v3 via ICV injection normalizes MECP2 levels in a single neuron in the cortex of the MECP2 TG mouse model.Fig. 6: AAV9-mediated delivery of hfCas13Y-gMECP2 via ICV injection normalized MECP2 levels and mitigated behavioral deficits in 2-month-old MECP2 TG mice.Fig.

4： AAV9介导的hfCas13Y递送使MECP2水平正常化并挽救P1 MECP2-TG小鼠的行为缺陷。图5：通过ICV注射AAV9介导的hfCas13Y v3递送使MECP2-TG小鼠模型皮层中单个神经元中的MECP2水平正常化。图6:AAV9介导的通过ICV注射递送hfCas13Y-gMECP2使2个月大的MECP2-TG小鼠的MECP2水平正常化并减轻了行为缺陷。图。

7: AAV9-mediated delivery of hfCas13Y v3 via ICV injection decreased MECP2 levels in the brain of WT male cynomolgus monkeys..

7： AAV9介导的通过ICV注射递送hfCas13Y v3降低了WT雄性食蟹猴大脑中的MECP2水平。。

Data availability

数据可用性

Deep-seq data are deposited to the Sequence Read Archive (SRA) database (accession numbers: PRJNA1101724 (https://www.ncbi.nlm.nih.gov/sra/PRJNA1101724), PRJNA1102504 (https://www.ncbi.nlm.nih.gov/sra/PRJNA1102504) and PRJNA1101197 (https://www.ncbi.nlm.nih.gov/sra/PRJNA1101197)), and plasmids are available from the corresponding authors upon request.

Deep-seq数据保存到序列读取存档（SRA）数据库（登录号：PRJNA1101724）(https://www.ncbi.nlm.nih.gov/sra/PRJNA1101724)，PRJNA1102504(https://www.ncbi.nlm.nih.gov/sra/PRJNA1102504)和PRJNA1101197(https://www.ncbi.nlm.nih.gov/sra/PRJNA1101197))，质粒可应要求从通讯作者处获得。

Source data are provided with this paper..

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Code availability

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No code was written in the study.

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Download referencesAcknowledgementsWe thank the laboratory animal center at HuidaGene Therapeutics Inc. for technical support. H.Y. was sponsored by the National Natural Science Foundation of China (grant nos. 31925016 and 82021001); the National Science and Technology Innovation 2030 Major Program (grant no.

下载参考文献致谢我们感谢HuidaGene Therapeutics Inc.的实验动物中心提供的技术支持。H、 Y.由国家自然科学基金资助（批准号31925016和82021001）；国家科技创新2030重大项目（批准号：。

2021ZD0200900); the Basic Frontier Scientific Research Program of Chinese Academy of Sciences From 0 to 1 original innovation project (grant no. ZDBS-LY-SM001); and the Project of Shanghai Municipal Science and Technology Commission (grant no. 23HC1401100). C.X. was sponsored by the Lingang Laboratory intramural fund and the Shanghai City Committee of Science and Technology Project (grant no.

2021ZD0200900）；中国科学院基础前沿科学研究计划从0到1原始创新项目（批准号：ZDBS-LY-SM001）；上海市科学技术委员会项目（批准号23HC1401100）。C、 X.由临港实验室校内基金和上海市科学技术委员会项目（批准号：。

22QA1412300). X. Wang was sponsored by the China Postdoctoral Science Foundation (grant no. 2023M741325).Author informationAuthor notesThese authors contributed equally: Dong Yang, Xiaoqing Wu, Yinan Yao, Mengsi Duan.Authors and AffiliationsHuidaGene Therapeutics Inc., Shanghai, ChinaDong Yang, Xiaoqing Wu, Mengsi Duan, Xing Wang, Guoling Li, Aiguo Guo, Meixian Wu, Jin Zheng, Tong Li, Alvin Luk, Xuan Yao, Linyu Shi & Hui YangInstitute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, ChinaYinan Yao, Yuanhua Liu, Renxia Zhang & Hui YangLingang Laboratory, Shanghai, ChinaChunlong XuShanghai Research Center for Brain Science and Brain-Inspired Technology, Shanghai, ChinaChunlong Xu & Hui YangAuthorsDong YangView author publicationsYou can also search for this author in.

22QA1412300）。十、 王由中国博士后科学基金会（批准号2023M741325）资助。作者信息作者注意到这些作者做出了同样的贡献：杨东，吴晓青，姚一楠，段梦思。作者和所属单位上海水大基因治疗有限公司，杨东东，吴晓青，段梦思，王兴，李国玲，郭爱国，吴梅贤，金正，李彤，卢阿尔文，姚轩，杨林宇，中国科学院脑科学与智能技术卓越中心神经科学研究所，上海，姚中国，刘元华，张仁霞，杨林岗实验室，上海，徐春龙上海脑科学与脑启发技术研究中心，上海，徐春龙，杨惠阳作者董阳维作者出版物您也可以在中搜索这位作者。

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PubMed Google ScholarContributionsD.Y., L.S., C.X. and H.Y. conceived the project and experiments. D.Y., X. Wu, Y.Y., M.D., X. Wang, G.L., A.G., M.W., J.Z. and R.Z. performed the experiments and analyzed the data. Y.L. performed the bioinformatic analyses. D.Y., Y.Y., C.X., A.L., T.L.

PubMed谷歌学术贡献SD。Y、 ，L.S.，C.X.和H.Y.构思了该项目和实验。D、 Y.，X.Wu，Y.Y.，M.D.，X.Wang，G.L.，A.G.，M.W.，J.Z.和R.Z.进行了实验并分析了数据。Y、 L.进行了生物信息学分析。D、 Y.，Y.Y.，C.X.，A.L.，T.L。

and H.Y. wrote the manuscript with input from all authors. H.Y. and X.Y. supervised research and acquired funding.Corresponding authorsCorrespondence to.

H.Y.在所有作者的意见下撰写了手稿。H、 Y.和X.Y.监督研究并获得资金。通讯作者通讯。

Xuan Yao, Linyu Shi, Chunlong Xu or Hui Yang.Ethics declarations

宣尧、石林玉、徐春龙或杨辉。道德宣言

Competing interests

相互竞争的利益

H.Y. is the founder of HuidaGene Therapeutics Inc. The other authors declare no competing interests.

H、 Y.是HuidaGene Therapeutics Inc.的创始人。其他作者声明没有利益冲突。

Peer review

同行评审

Peer review information

同行评审信息

Nature Neuroscience thanks Bence György, Huda Zoghbi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

自然神经科学感谢Bence György，Huda Zoghbi和其他匿名审稿人对这项工作的同行评议做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InformationSupplementary Figs. 1–17, Tables 1–5, Results 1–3, Discussion, Methods and References.Reporting SummarySupplementary Data 1Supplementary Data 1.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息补充信息补充图1-17，表1-5，结果1-3，讨论，方法和参考文献。报告摘要补充数据1补充数据1。

Statistical source data and unprocessed western blot for the supplementary figures.Source dataSource Data Figs. 1–7Source Data Fig. 1. Statistical source data and unprocessed western blot. Source Data Fig. 2. Statistical source data and unprocessed western blot. Source Data Fig. 3. Statistical source data.

补充数字的统计源数据和未经处理的蛋白质印迹。源数据源数据图1-7源数据图1。统计源数据和未经处理的蛋白质印迹。源数据图2。统计源数据和未经处理的蛋白质印迹。源数据图3。统计源数据。

Source Data Fig. 4. Statistical source data. Source Data Fig. 5. Statistical source data. Source Data Fig. 6. Statistical source data and unprocessed western blot. Source Data Fig. 7. Statistical source data and unprocessed western blot.Rights and permissionsSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsAbout this articleCite this articleYang, D., Wu, X., Yao, Y.

源数据图4。统计源数据。源数据图5。统计源数据。源数据图6。统计源数据和未经处理的蛋白质印迹。源数据图7。统计源数据和未经处理的蛋白质印迹。权利和许可Pringer Nature或其许可人（例如协会或其他合作伙伴）根据与作者或其他权利持有人的出版协议对本文拥有专有权；本文接受稿件版本的作者自行存档仅受此类出版协议和适用法律的条款管辖。转载和许可本文引用本文Yang，D.，Wu，X.，Yao，Y。

et al. An RNA editing strategy rescues gene duplication in a mouse model of MECP2 duplication syndrome and nonhuman primates..

RNA编辑策略可以挽救MECP2复制综合征和非人灵长类动物小鼠模型中的基因复制。。

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