数字农科院2.0

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

作者： Li G.;Jin M.;Li Z.;Xiao Q.;Lin J.;Yang D.;Liu Y.;Wang X.;Xie L.;Ying W.;Wang H.;Zuo E.;Shi L.;Wang N.;Chen W.;Xu C.;Yang H.

作者机构：

关键词： Gene therapy;Monogenic diseases;Muscle;Therapeutics

期刊名称： The Journal of clinical investigation

ISSN： 1558-8238

年卷期： 2023 年 133 卷 3 期

页码：

收录情况： SCIE（2023版）

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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