Efficacy and long-term safety of CRISPR/Cas9 genome editing in the SOD1-linked mouse models of ALS

Han Xiang Deng*, Hong Zhai, Yong Shi, Guoxiang Liu, Jessica Lowry, Bin Liu, Éanna B. Ryan, Jianhua Yan, Yi Yang, Nigel Zhang, Zhihua Yang, Erdong Liu, Yongchao C. Ma, Teepu Siddique

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


CRISPR/Cas9-mediated genome editing provides potential for therapeutic development. Efficacy and long-term safety represent major concerns that remain to be adequately addressed in preclinical studies. Here we show that CRISPR/Cas9-mediated genome editing in two distinct SOD1-amyotrophic lateral sclerosis (ALS) transgenic mouse models prevented the development of ALS-like disease and pathology. The disease-linked transgene was effectively edited, with rare off-target editing events. We observed frequent large DNA deletions, ranging from a few hundred to several thousand base pairs. We determined that these large deletions were mediated by proximate identical sequences in Alu elements. No evidence of other diseases was observed beyond 2 years of age in these genome edited mice. Our data provide preclinical evidence of the efficacy and long-term safety of the CRISPR/Cas9 therapeutic approach. Moreover, the molecular mechanism of proximate identical sequences-mediated recombination provides mechanistic information to optimize therapeutic targeting design, and to avoid or minimize unintended and potentially deleterious recombination events.

Original languageEnglish (US)
Article number396
JournalCommunications Biology
Issue number1
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)


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