Towards transgenic primates: What can we learn from mouse genetics?

Abstract

Considering the great physiological and behavioral similarities with humans, monkeys represent the ideal models not only for the study of complex cognitive behavior but also for the preclinical research and development of novel therapeutics for treating human diseases. Various powerful genetic technologies initially developed for making mouse models are being explored for generating transgenic primate models. We review the latest genetic engineering technologies and discuss the potentials and limitations for systematic production of transgenic primates.

The ethics of using transgenic non-human primates to study what makes us human

“…For uniquely human sequences or genes, transgenic research using NHPs could likely be accomplished with existing techniques, either through homologous exchange of HLS sequence with homologous sequence of the transgenic host species or addition of HLS sequences to the host genome24,25,26,27. However, new advances will be required to study functional consequences of differences in expression, since precisely altering expression levels in transgenic research by increasing copy number or modifying the regulatory region of a gene remains technically challenging.…”

“…The research continuum from bench to bedside suggests that results of transgenic research may also produce clinical benefits, especially given that HLS gene variants have been found to be disproportionately enriched in genomic locations implicated in human diseases19,21. Another key factor is evidence that evolutionary mechanisms that have produced rapid genomic changes in the human lineage often produce human disease as a byproduct25. It is possible that HLS variants that affect human phenotype could provide important insights into disorders and clinically relevant phenotypes that are difficult to study by other means, including cognitive disease25, neurodegenerative disorders38, social behavior disorders such as autism39, dementia40, speech articulation defects41,21, and gene delivery systems42 for therapeutic use.…”

“…Another key factor is evidence that evolutionary mechanisms that have produced rapid genomic changes in the human lineage often produce human disease as a byproduct25. It is possible that HLS variants that affect human phenotype could provide important insights into disorders and clinically relevant phenotypes that are difficult to study by other means, including cognitive disease25, neurodegenerative disorders38, social behavior disorders such as autism39, dementia40, speech articulation defects41,21, and gene delivery systems42 for therapeutic use. Since this research is still in the early stages and the benefits still theoretical, it is appropriate to examine proactively the ethical concerns related to NHP transgenic research.…”

Advanced Circuit and Cellular Imaging Methods in Nonhuman Primates

“…NHPs are also likely to be the most suitable model for the study of many human-relevant brain functions, such as those involving foveal vision, fine manual motor control and hand-eye coordination, finger sensation, highcognition, and many psychiatric and neurological diseases. The same neural circuit analysis tools that were developed in insect and rodent models are now beginning to translate successfully to NHPs, including powerful genetic tools (Kuang et al, 2009;Okano and Mitra, 2015;He and Huang, 2018;Snyder and Chan, 2018), providing novel and exciting paths to both basic discovery and preclinical testing.…”