A China-U.S. joint research team reported the generation of germline-transmittable cynomolgus macaques with Shank3 mutations, known to cause a form of autism.
The study, published in Nature, was conducted by scientists from the Shenzhen Institutes of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS), Massachusetts Institute of Technology, Sun Yat-Sen University and South China Agricultural University.
Through the genome-editing system CRISPR, they engineered macaque monkeys to express a gene mutation linked to autism and other neurodevelopmental disorders in humans. These monkeys showed some behavioral traits and brain connectivity patterns similar to those in humans with these conditions.
Autism Spectrum Disorders (ASD) is complex developmental disorders with a strong genetic basis. Scientists have identified hundreds of genetic variants associated with ASD, many of which individually confer only a small degree of risk. In this study, the researchers focused on one gene with a strong association, known as Shank3.
"The new type of model, however, could help scientists to develop better treatment options for some neurodevelopmental disorders," said FENG Guoping, who is the James W. and Patricia Poitras Professor of Neuroscience, a member of MIT's McGovern Institute for Brain Research, and one of the senior authors of the study.
Mouse models of ASD, due to their neural and behavioral differences from primates, haven't worked out very well. The reported behavioral and neural traits of Shank3 mutant primates provide new insights into the circuit-based pathophysiological model of ASD.
The primate model is close to humans in evolution and has many similarities to humans in brain structure. For example, the prefrontal cortex in nonhuman primates is well developed, which plays important roles in decision-making, attention and social interactions. Deficits in these cognitive functions have been associated with brain disorders including autism. Therefore, "nonhuman primates are hopeful to become an ideal animal model for simulating some human brain diseases," said Prof. ZHOU Huihui from SIAT.
The Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) is a private, nonprofit organization that promotes the humane treatment of animals in science through voluntary accreditation and assessment programs. SIAT received AAALAC accreditation in 2018 for its primate experiment platform, which laid a foundation for collaboration with international pharmaceutical companies to pursue new treatments of brain disorders in the future.
"We urgently need new treatment options for autism spectrum disorder, and treatments developed in mice have so far been disappointing. While the mouse research remains very important, we believe that primate genetic models will help us to develop better medicines and possibly even gene therapies for some severe forms of autism," says Robert Desimone, the director of MIT's McGovern Institute for Brain Research, the Doris and Don Berkey Professor of Neuroscience, and an author of the paper.
Reference: Zhou et al. 2019. Atypical behaviour and connectivity in SHANK3-mutant macaques. Nature. https://doi.org/10.1038/s41586-019-1278-0.
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