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Improvement of TaC9-ABE mediated correction of human SMN2 gene.

Authors :
Peng X
Chi Y
Wang J
Li S
Liu Y
Tang C
Zhou X
Lu X
Gao Y
Lai L
Chen M
Zou Q
Source :
Biotechnology and bioengineering [Biotechnol Bioeng] 2024 Oct; Vol. 121 (10), pp. 3059-3067. Date of Electronic Publication: 2024 Jun 24.
Publication Year :
2024

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 antiapoptosis 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.<br /> (© 2024 Wiley Periodicals LLC.)

Details

Language :
English
ISSN :
1097-0290
Volume :
121
Issue :
10
Database :
MEDLINE
Journal :
Biotechnology and bioengineering
Publication Type :
Academic Journal
Accession number :
38923503
Full Text :
https://doi.org/10.1002/bit.28780