Abstract

ABSTRACTOwing to their high similarity to humans, non-human primates (NHPs) provide an exceedingly suitable model for the study of human disease. In this Review, we summarize the history of transgenic NHP models and the progress of CRISPR/Cas9-mediated genome editing in NHPs, from the first proof-of-principle green fluorescent protein-expressing monkeys to sophisticated NHP models of human neurodegenerative disease that accurately phenocopy several complex disease features. We discuss not only the breakthroughs and advantages, but also the potential shortcomings of the application of the CRISPR/Cas9 system to NHPs that have emerged from the expanded understanding of this technology in recent years. Although off-target and mosaic mutations are the main concerns in CRISPR/Cas9-mediated NHP modeling, recent progress in genome editing techniques make it likely that these technical limitations will be overcome soon, bringing excellent prospects to human disease studies.

Highlights

  • Laboratory animals have long played a useful role in biomedical and medical research

  • Possibly owing to the complexity of DNA repair mechanisms (Luo et al, 2016), KI by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 in nonhuman primates (NHPs) was only achieved in January 2018, when our lab, concurrently with the Huang and Yang groups, reported KI cynomolgus monkeys with a reporter gene generated via CRISPR/ Cas9-assisted homologous recombination (HR) and homology-mediated end joining (HMEJ) (Cui et al, 2018; Yao et al, 2018)

  • Mosaic mutations introduced by CRISPR/Cas9 In addition to off-target effects, genetic mosaicism, in which cells within an organism have different genomes, is another issue that may hinder the application of genome editing for disease modeling, as components of the CRISPR/Cas9 system can repeatedly edit target genes at different stages of embryonic development

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Summary

Introduction

Laboratory animals have long played a useful role in biomedical and medical research. In 2014, our group generated KO cynomolgus monkeys by targeting one-cell embryos with CRISPR/Cas9 (Fig. 2B), which for the first time demonstrated the feasibility of this genome editing system in NHPs (Niu et al, 2014).

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