Autism Spectrum Disorder (ASD) affects 1-2% of children in the United States. The etiology(ies) and neurobiological underpinnings of autism remains unclear and hence targets for effective medical treatments are rare. While myriad genetic mouse models have been created, and many demonstrate some phenotypic features of autism, there is growing concern that rodent models may not be the best approach for creating phenocopies of childhood disorders, such as autism, that have cognitive and social disabilities as their core features. Over the last 5 years, through the use of techniques such as CRISPR/Cas9, there has been a revolution in genetically modifying organisms that can be applied to large species such as nonhuman primates (NHP). A first goal of this application is to develop a nonhuman primate model of ASD through loss of function modifications to the CHD8 gene. The gene encoding the chromatin remodeler CHD8 is among the most frequently mutated genes in individuals with ASD. The CHD8 form of autism is unique in being both highly penetrant and having a behavioral and neurobiological phenotype. Individuals with loss of function of this gene not only have autism but typically demonstrate macrocephaly/megalencephaly. We have selected this gene as a starting point because UC Davis Co-investigators on this application have been developing mouse models with Chd8 mutations and analysis of megalencephaly is a major focus of a recently funded Autism Center of Excellence at the MIND Institute. A second goal of the application is to build capacity and expertise in generating genetically modified nonhuman primate models of neurodevelopmental disorders. We argue that UC Davis, with its California National Primate Research Center that houses over 4000 rhesus monkeys, the Mouse Biology Program that has expertise in genetic manipulations leading to hundreds of clinically significant mouse models, and the MIND Institute which houses expertise on all facets of neurodevelopmental disorders research from genetics to clinical trials, is extraordinarily well-positioned to generate and comprehensively evaluate these animal models. We will establish a Leadership Group that will guide this program to successful development of valuable nonhuman primate models of neurodevelopmental disorders. For this initial phase of studies we propose 1) to implement strategies for gene editing of the nonhuman primate, validation of gene editing and efficient production of embryos for later implantation 2) to produce up to ten live rhesus monkeys with Chd8 loss of function mutations 3) to determine normal and abnormal trajectories of structural and functional brain development for rhesus monkeys with Chd8 loss of function mutations and 4) to carry out behavioral analyses of the genetically modified offspring. While the proximal goal of this application is to develop a valuable NHP model to facilitate understanding of the neurobiological underpinnings of autism, a long-term goal is to establish infrastructure to enable the generation of genetically modified monkeys for translational biomedical research more globally - which we believe to be in the national interest.
To better understand the neurobiological and molecular underpinnings of autism spectrum disorder, a first goal of this application is to develop a nonhuman primate model through genetic modification of the CHD8 gene. This gene is among the most frequently mutated genes in individuals with ASD. A long- term goal is to establish infrastructure to enable the generation of genetically modified monkeys for translational biomedical research - which we believe to be in the national interest.
