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

Abstract

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.

Ethical and Welfare Implications of Genetically Altered Non-Human Primates for Biomedical Research

“…Despite these advances, the widespread adoption of GA NHP models appeared impractical until recently, given the paucity of methods for making precise genetic changes in NHP embryos ( Vermeire et al, 2017 ). Tools such as ZFNS (zinc finger nucleases), TALENS (transcription activatorlike effector nucleases), and CRISPR (clustered regularly interspaced short palindromic repeats, with RNA-guided nucleases such as Cas9) have made possible this once out-of-reach goal ( Park & Silva, 2019 ). This has led to calls for the creation of lines of GA NHPS and arguments for their necessity to biomedical science ( Jennings et al, 2016 ; Scaduto, 2016 ; Kishi & Okano, 2017 ).…”

Generation of Common Marmoset Model Lines of Spinocerebellar Ataxia Type 3

“…To create a non-human primate model that accurately reproduces human disease pathology, it is important to develop advanced genetic modification techniques such as genome editing. Precise and complicated genome modifications, such as targeted gene knock-in and making or repairing point mutations without occurrence of genetic mosaicism, remain impractical in non-human primates, largely due to the low efficiency of these techniques (Park and Silva, 2019). Knockout marmosets produced by genome editing technologies were reported recently (Sato et al, 2016;Kumita et al, 2019), and the application of these technologies has been much faster compared with previous transgene introduction methods.…”

“…Therefore, it is necessary to apply not only genome editing techniques but also conventional gene modification techniques developed in mice to non-human primates to develop various models suitable for each study. Besides, marmosets offer several advantages such as reduced intergeneration time which allows the establishment of transgenic lines two-three times faster than in macaques (Park and Silva, 2019), a transgenic marmoset model will be a powerful tool for the preclinical study of neurodegenerative diseases, and continuous efforts for the development of efficient genetic tools adapted to them will be important. Now, novel findings are being discovered that cannot be obtained with any model animals other than nonhuman primates, and we are confident that those findings from our marmoset model can contribute to overcoming neurodegenerative diseases.…”

Problems and outlooks of optogenetic technologies in the 21st century

“…In this case, a solution with DNA encoding opsin is injected in utero on certain days of embryo development, and then it is exposed to a high-voltage electric discharge for short duration, which allows to selective effect on specific cell types and brain regions. Unlike viral methods, electroporation can introduce more copies of a gene and deliver DNA of any size with large promoter segments to achieve higher cell specificity [32].…”