Mini-dCas13X-mediated RNA editing restores dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy

文献类型： 外文期刊

第一作者： Li, Guoling

作者： Li, Guoling;Yang, Dong;Wang, Xing;Wang, Haoqiang;Shi, Linyu;Yang, Hui;Li, Guoling;Xiao, Qingquan;Yang, Dong;Liu, Yuanhua;Ying, Wenqin;Yang, Hui;Jin, Ming;Lin, Jiajia;Wang, Ning;Chen, Wanjin;Li, Zhifang;Xu, Chunlong;Xie, Long;Zuo, Erwei;Xu, Chunlong;Yang, Hui;Wang, Ning;Chen, Wanjin;Xu, Chunlong;Yang, Hui

作者机构：

期刊名称：JOURNAL OF CLINICAL INVESTIGATION （ 影响因子：15.9； 五年影响因子：16.7 ）

ISSN： 0021-9738

年卷期： 2023 年 133 卷 3 期

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收录情况： SCI

摘要： Approximately 10% of monogenic diseases are caused by nonsense point mutations that generate premature termination codons (PTCs), resulting in a truncated protein and nonsense-mediated decay of the mutant mRNAs. Here, we demonstrate a mini-dCas13X-mediated RNA adenine base editing (mxABE) strategy to treat nonsense mutation-related monogenic diseases via A-to-G editing in a genetically humanized mouse model of Duchenne muscular dystrophy (DMD). Initially, we identified a nonsense point mutation (c.4174C>T, p.Gln1392*) in the DMD gene of a patient and validated its pathogenicity in humanized mice. In this model, mxABE packaged in a single adeno-associated virus (AAV) reached A-to-G editing rates up to 84% in vivo, at least 20-fold greater than rates reported in previous studies using other RNA editing modalities. Furthermore, mxABE restored robust expression of dystrophin protein to over 50% of WT levels by enabling PTC read-through in multiple muscle tissues. Importantly, systemic delivery of mxABE by AAV also rescued dystrophin expression to averages of 37%, 6%, and 54% of WT levels in the diaphragm, tibialis anterior, and heart muscle, respectively, as well as rescued muscle function. Our data strongly suggest that mxABE-based strategies may be a viable new treatment modality for DMD and other monogenic diseases.

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