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

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

来源：Molecular Therapy, 2023, 31(7): 2286-2295.

DOI：10.1016/j.ymthe.2023.02.015

• ANTISENSE RNA
• UBE3A
• MODEL
• DEGRADATION
• TRANSCRIPT
• DEFICITS
• P53

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.

• 单位
  中国科学院; 1