A high-fidelity RNA-targeting Cas13 restores paternal Ube3a expression and improves motor functions in Angelman syndrome mice

文献类型： 外文期刊

第一作者： Li, Jinhui

作者： Li, Jinhui;Shen, Zhixin;Liu, Yajing;Liu, Yuanhua;Tang, Junjie;Lv, Ruimin;Geng, Guannan;Xiong, Zhi-Qi;Zhou, Changyang;Yang, Hui;Yang, Hui;Yan, Zixiang;Lin, Xiang;Lin, Xiang;Yang, Hui;Xiong, Zhi-Qi;Zhou, Changyang;Yang, Hui

作者机构：

期刊名称：MOLECULAR THERAPY （ 影响因子：12.4； 五年影响因子：12.6 ）

ISSN： 1525-0016

年卷期： 2023 年 31 卷 7 期

页码：

收录情况： SCI

摘要： Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of function mutations in maternally expressed UBE3A. No gene-specific treatment is available for patients so far. Although intact and transcriptionally active, paternally inherited UBE3A is silenced by elongation of anti - sense long noncoding RNA UBE3A-ATS in neurons. Here, we demonstrated that RNA targeting of paternal Ube3a-ATS with a high-fidelity CRISPR-Cas13 (hfCas13x.1) system could restore Ube3a expression to similar levels as that of maternal Ube3a in the cultured mouse neurons. Furthermore, injection into lateral ventricles with neuron-specific hSyn1 promoter - driven hfCas13x.1 packaged in adeno-associated virus (AAV-PHP.eb) could restore paternal Ube3a expression in cortex and hippocampus of neonatal AS mice for up to 4 months after treatment. Behavioral tests showed that expres- sion of paternal Ube3a significantly alleviated AS-related symptoms, including obesity and motor function. Our results suggested that hfCas13x.1-mediated suppression of the Ube3a-ATS lncRNA potentially serves as a promising targeted intervention for AS.

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