4.6 Article

Induction of core symptoms of autism spectrum disorder by in vivo CRISPR/Cas9-based gene editing in the brain of adolescent rhesus monkeys

Journal

SCIENCE BULLETIN
Volume 66, Issue 9, Pages 937-946

Publisher

ELSEVIER
DOI: 10.1016/j.scib.2020.12.017

Keywords

Autism spectrum disorders; Nonhuman primate model; Disease model; Gene-editing

Funding

  1. Key-Area Research and Development Program of Guangdong Province [2019B03035001]
  2. National Natural Science Foundation of China [81941014, 31625013, 91732302, 81471312, 81771387, 81460352, 81500983, 31700897, 31700910, 31800901, 31960178]
  3. Strategic Priority Research Program of the Chinese Academy of Sciences [XDBS32060200]
  4. Shanghai Brain-Intelligence Project from the Science and Technology Commission of the Shanghai Municipality [16JC1420501]
  5. Shanghai Municipal Science and Technology Major Project [2018SHZDZX05]
  6. Applied Basic Research Programs of Science and Technology Commission Foundation of Yunnan Province [2017FB109, 2018FB052, 2018FB053, 2019FA007]
  7. China Postdoctoral Science Foundation [2018M631105]
  8. CAS Light of West China Program
  9. National Key R&D Program of China [2018YFA0801403]
  10. Key Scientific and Technological Projects of Guangdong Province [2018B030335001]

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The study induced genetic mutations in MECP2 gene in the brains of adolescent rhesus monkeys, leading to a series of autistic-like behavioral abnormalities, indicating that acute manipulation of disease-causing genes directly results in behavioral changes; Some aspects of ASD and RTT did not appear in the gene-edited monkeys, hinting that different brain areas may contribute to distinct ASD symptoms.
Although CRISPR/Cas9-mediated gene editing is widely applied to mimic human disorders, whether acute manipulation of disease-causing genes in the brain leads to behavioral abnormalities in non-human primates remains to be determined. Here we induced genetic mutations in MECP2, a critical gene linked to Rett syndrome (RTT) and autism spectrum disorders (ASD), in the hippocampus (DG and CA1?4) of adolescent rhesus monkeys (Macaca mulatta) in vivo via adeno-associated virus (AAV)-delivered Staphylococcus aureus Cas9 with small guide RNAs (sgRNAs) targeting MECP2. In comparison to monkeys injected with AAV-SaCas9 alone (n = 4), numerous autistic-like behavioral abnormalities were identified in the AAV-SaCas9-sgMECP2-injected monkeys (n = 7), including social interaction deficits, abnormal sleep patterns, insensitivity to aversive stimuli, abnormal hand motions, and defective social reward behaviors. Furthermore, some aspects of ASD and RTT, such as stereotypic behaviors, did not appear in the MECP2 gene-edited monkeys, suggesting that different brain areas likely contribute to distinct ASD symptoms. This study showed that acute manipulation of disease-causing genes via in vivo gene editing directly led to behavioral changes in adolescent primates, paving the way for the rapid generation of genetically engineered non-human primate models for neurobiological studies and therapeutic development. ? 2020 Science China Press. Published by Elsevier B.V. and Science China Press. All rights reserved.

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