Transgenic Neuroscience Research Exploring the Scientific Opportunities Afforded by New Nonhuman Primate Models: Proceedings of a Workshop (2019) / Chapter Skim
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3 State of the Science of Transgenic Nonhuman Primate Models for Nervous System Disorders
3 State of the Science of Transgenic Nonhuman Primate Models for Nervous System Disorders
Pages 15-26
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From page 15... ...
. • A successful gene therapy using a viral vector achieved for a rare form of genetic blindness was made possible, in part, by safety studies conducted in nonhuman primates (Bennett)
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When combined with genetic modification -- either through transgenesis, viral gene delivery, genome editing, or cloning -- scientists have a wide array of tools with which to study how gene disruptions affect brain function and explore potential interventions. Deverman added that in mouse models, the large number of transgenic lines has facilitated the development of these tools by restricting the expression of transgenes to specific cell types and brain regions.
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GENETICALLY MODIFIED NONHUMAN PRIMATE MODELS OF DISEASE Throughout the workshop, several participants discussed the state of science of genetically modified nonhuman primate models and their potential usefulness to enhance understanding of nervous system disorders and advance therapeutic development for PD, Huntington's disease (HD) , autism spectrum disorder (ASD)
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probe, which Okano and colleagues are evaluating in the PD transgenic marmosets. Transgenic Rhesus Macaque Models of Huntington's Disease Anthony Chan and colleagues at the Yerkes National Primate Research Center and the Emory University School of Medicine developed a transgenic rhesus macaque primate model of HD, a complex autosomal dominant neurodegenerative disorder that affects about 40,000 people in North America with motor, cognitive, and psychiatric manifestations (Yang et al., 2008)
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Given this large number of genes, nonhuman primate models are likely to play an increasingly important role in autism research. For example, in developing gene therapy approaches, Spiro suggested that a nonhuman primate model might be a critical step before moving to human trials.
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. Feng's lab at MIT has collaborated with a group in China to develop viable cynomolgus macaque monkeys with both homozygous and heterozygous mutations, and has shown that these animals show reduced motor activity, dramatic sleep disruption similar to what is seen in humans, and impaired social interaction, including lack of reciprocal play and vocalizations.
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His group is using somatic cell nuclear transfer, where they fuse fetal fibroblast cells with enucleated oocytes to produce embryos expressing the genome of the animal from which the fibroblasts were obtained. These embryos are then implanted into surrogates to produce genetically uniform
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. Poo added that he hopes that future manipulations, screening, and gene editing can be carried out in primary cultures before performing somatic cell nuclear transfer.
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GENE MODIFICATION AS THERAPY Nonhuman primate models have proven valuable not only as models to advance understanding of human diseases and discover new therapeutic approaches, but also to ensure that treatments can be delivered safely to humans (Friedman et al., 2017)
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While the nonhuman primate models have been predictive of safety, Bennett noted that few retinal diseases occur naturally in nonhuman primates, perhaps because they are selected against in the wild. One exception is that male squirrel monkeys have an incidence of color blindness similar to that of the X-linked form of red–green color blindness seen in
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STATE OF THE SCIENCE OF TRANSGENIC NONHUMAN PRIMATE MODELS 25 human men. A gene therapy approach to treating red–green color blindness has been developed in the monkeys (Mancuso et al., 2009)
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