TALEN-based generation of a cynomolgus monkey disease model for human microcephaly

Qin, Ke; Li, Weiqiang; Lai, Xiaomin; Chen, Hong; Hu, Lihua; Kang, Zhuang; Li, Kai; Ren, Jie; Lin, Xiaofeng; Zheng, Huiru; Huang, Weijun; Ma, Yunhan; Xu, Dongdong; Chen, Zheng; Song, Xin-Ming; Lin, Xinyi; Zhuang, Min; Wang, Tao; Zhuang, Fang‐Dong; Xi, Jianzhong; Mao, Frank Fuxiang; Xia, Huimin; Lahn, Bruce T.; Zhou, Qi; Yang, Shihua; Xiang, Andy Peng

doi:10.1038/cr.2016.93

Cited by 40 publications

(34 citation statements)

References 55 publications

(88 reference statements)

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“…The development of breeding and technology centers in China and Japan is a more recent phenomenon that is impacting translational research (Cyranoski 2014(Cyranoski , 2016. These nations have made major efforts to increase the supply of NHPs available to researchers in their domestic institutions and to enhance infrastructure to breed animals and perform large scale investigations, including genomic analysis (see Harding 2017 for selected references) and development of new NHP disease models using Assisted Reproductive Technologies (see, e.g., Chen et al 2016;Ke et al 2016;Sasaki 2015;Sasaki et al 2009). China has also increased its capacity to perform contract research that can be outsourced to pharmaceutical companies (Xia and Gautam 2015).…”

Section: The Critical Role Of Nhps In Translational Researchmentioning

confidence: 99%

Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges

Harding

2017

ILAR Journal

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Nonhuman primates (NHPs) are the closest animal models to humans regarding genetics, physiology and behavior. Therefore, NHPs are usually a critical component in translational research projects aimed at developing therapeutics, vaccines, devices or other interventions aimed at preventing, curing or ameliorating human disease. NHPs are often used in conjunction with other animal models, such as rodents, and results obtained using NHPs must often be used as the final criterion for establishing the potential efficacy of a pharmaceutical or vaccine before transition to human clinical trails. In some cases, NHPs may be the only relevant animal models for a particlular translational study. This issue of the ILAR journal brings together, in one place, articles that discuss the use of NHP models for studying human diseases that are highly prevalent and that cause extraordinary human suffering and financial and social burdens. Topics covered in detail include: tuberculosis; viral hepatitis; HIV/AIDS; neurodegenerative disorders; Substance abuse disorders; vision and prevention of blindness; disorder associated with psychosocial processes, such as anxiety, depression and loneliness; cardiovascular disease; metabolic disease, such as obesity and metabolic syndrome; respiratory disease; and female reproduction, prenatal development and women's health. Proper husbandry of NHPs that reduces stress and maintains animal health is critical for the development of NHP models. This issue of the journal includes a review of procedures for environmental enrichment, which helps assure animal health and wellbeing. Taken together, these articles provide detailed reviews of the use of NHP models for translational investigations and discuss successes, limitations, challenges and opportunities associated with this research.Translational studies using NHPs depend on the availability and characterization of animals, high-quality animal husbandry and welfare, and the development of assays and technologies. These necessary components of NHP-based research usually require housing animals in large centers, each of which can harbor more than 1000 (often 4000-5000 or more) animals because of

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Section: The Critical Role Of Nhps In Translational Researchmentioning

confidence: 99%

Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges

Harding

2017

ILAR Journal

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“…TALEN-mediated gene editing has been an effective tool to induce loss of function mutations in rhesus, cynomolgus monkeys and marmosets (Y. Chen et al, 2017; Ke et al, 2016; H. Liu et al, 2014; Z.…”

Section: Introductionmentioning

confidence: 99%

“…The MCPH1 gene was successfully targeted by TALENs mRNA injection into embryos (Ke et al, 2016). One live monkey carrying biallelic MCPH1 mutation was obtained in a single step and reduced MCPH1 expression was confirmed by western blot.…”

Section: Introductionmentioning

confidence: 99%

Generation of genetically engineered non‐human primate models of brain function and neurological disorders

Park

Silva

2018

American J Primatol

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Research with non-human primates (NHP) has been essential and effective in increasing our ability to find cures for a large number of diseases that cause human suffering and death. Extending the availability and use of genetic engineering techniques to NHP will allow the creation and study of NHP models of human disease, as well as broaden our understanding of neural circuits in the primate brain. With the recent development of efficient genetic engineering techniques that can be used for NHP, there’s increased hope that NHP will significantly accelerate our understanding of the etiology of human neurological and neuropsychiatric disorders. In this article, we review the present state of genetic engineering tools used in NHP, from the early efforts to induce exogeneous gene expression in macaques and marmosets, to the latest results in producing germline transmission of different transgenes and the establishment of knockout lines of specific genes. We conclude with future perspectives on the further development and employment of these tools to generate genetically engineered NHP.

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“…Subsequently, Chen et al used CRISPR/Cas9 to target the monkey dystrophin gene to mimic Duchenne muscular dystrophy (DMD) [Chen et al, ], while Zhao et al, generated three mutant offspring containing deleterious SHANK3 mutations by using CRISPR/Cas9 [Zhao et al, ]. In other studies, MECP2 (methyl‐CpG binding protein 2) and MCPH1 ( Microcephalin 1 ) were targeted by TALEN in cynomolgus monkeys to model Rett syndrome and microcephaly, respectively [Liu et al, ; Liu et al, ; Ke et al, ].…”

Section: Introductionmentioning

confidence: 99%

Modeling autism in non‐human primates: Opportunities and challenges

Zhao

Jiang

2018

Autism Research

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication deficits and restricted, repetitive patterns of behavior. For more than a decade, genetically-modified, risk factor-induced, as well as naturally occurring rodent models for ASD have been used as the most predominant tools to dissect the molecular and circuitry mechanisms underlying ASD. However, the apparent evolutionary differences in terms of social behavior and brain anatomy between rodents and humans have become an issue of debate regarding the translational value of rodent models for studying ASD. More recently, genome manipulation of non human primates using lentivirus-based gene expression, TALEN and CRISPR/Cas9 mediated gene editing techniques, has been reported. Genetically modified non-human primate models for ASD have been produced and characterized. While the feasibility, value, and exciting opportunities provided by the non-human primate models have been clearly demonstrated, many challenges still remain. Here, we review current progress, discuss the remaining challenges, and highlight the key issues in the development of non-human primate models for ASD research and drug development.

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TALEN-based generation of a cynomolgus monkey disease model for human microcephaly

Cited by 40 publications

References 55 publications

Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges

Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges

Generation of genetically engineered non‐human primate models of brain function and neurological disorders

Modeling autism in non‐human primates: Opportunities and challenges

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