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Improvement of TaC9-ABE mediated correction of human SMN2 gene
  • +9
  • Min Chen,
  • Xiaohua Peng,
  • Yue Chi,
  • Jinling Wang,
  • Shuangpeng Li,
  • Yang liu,
  • Chengcheng Tang,
  • Xiaoqing Zhou,
  • Xuan Lu,
  • Yue Gao,
  • Liangxue Lai,
  • Qingjian Zou
Min Chen
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Xiaohua Peng
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Yue Chi
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Jinling Wang
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Shuangpeng Li
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Yang liu
BGI-Hangzhou
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Chengcheng Tang
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Xiaoqing Zhou
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Xuan Lu
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Yue Gao
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Liangxue Lai
South China Institute of Large Animal Models for Biomedicine Wuyi University
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Qingjian Zou
South China Institute of Large Animal Models for Biomedicine Wuyi University

Corresponding Author:zouqj@wyu.edu.cn

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Abstract

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the survival motor neuron 1 ( SMN1) gene. Gene editing technology repairs the conversion of the 6th base T to C in exon 7 of the paralogous SMN2 gene, compensating for the SMN protein expression and promoting the survival and function of motor neurons. However, low editing efficiency and unintended off-target effects limit the application of this technology. Here, we optimized a TaC9-adenine base editor (ABE) system by combining Cas9 nickase with the transcription activator-like effector (TALE)-adenosine deaminase fusion protein to effectively and precisely edit SMN2 without detectable Cas9 dependent off-target effects in human cell lines. We also generated human SMA-induced pluripotent stem cells (SMA-iPSCs) through the mutation of the splice acceptor or deletion of the exon 7 of SMN1. TaC9-R10 induced 45% SMN2 T6>C conversion in the SMA-iPSCs. The SMN2 T6>C splice-corrected SMA-iPSCs were directionally differentiated into motor neurons, exhibiting SMN protein recovery and anti-apoptosis ability. Therefore, the TaC9-ABE system with dual guides from the combination of Cas9 with TALE could be a potential therapeutic strategy for SMA with high efficacy and safety.
02 Feb 2024Submitted to Biotechnology and Bioengineering
07 Feb 2024Submission Checks Completed
07 Feb 2024Assigned to Editor
07 Feb 2024Review(s) Completed, Editorial Evaluation Pending
19 Apr 2024Editorial Decision: Revise Minor
20 May 20241st Revision Received
05 Jun 2024Editorial Decision: Revise Minor
07 Jun 20242nd Revision Received
10 Jun 2024Editorial Decision: Accept