SMN1型
脊髓性肌萎缩
形状记忆合金*
基因组编辑
生物
表型
突变
运动神经元
遗传学
癌症研究
基因
神经科学
基因组
脊髓
计算机科学
算法
作者
Mandana Arbab,Żaneta Matuszek,K. Corlett,Ailing Du,Gregory A. Newby,Anton J. Blatnik,Aditya Raguram,Michelle F. Richter,Kevin T. Zhao,Jonathan M. Levy,Max W. Shen,W. David Arnold,Dan Wang,Jun Xie,Guangping Gao,Arthur H.M. Burghes,David R. Liu
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2023-04-21
卷期号:380 (6642)
被引量:63
标识
DOI:10.1126/science.adg6518
摘要
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, arises from survival motor neuron (SMN) protein insufficiency resulting from SMN1 loss. Approved therapies circumvent endogenous SMN regulation and require repeated dosing or may wane. We describe genome editing of SMN2 , an insufficient copy of SMN1 harboring a C6>T mutation, to permanently restore SMN protein levels and rescue SMA phenotypes. We used nucleases or base editors to modify five SMN2 regulatory regions. Base editing converted SMN2 T6>C, restoring SMN protein levels to wild type. Adeno-associated virus serotype 9–mediated base editor delivery in Δ7SMA mice yielded 87% average T6>C conversion, improved motor function, and extended average life span, which was enhanced by one-time base editor and nusinersen coadministration (111 versus 17 days untreated). These findings demonstrate the potential of a one-time base editing treatment for SMA.
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