Genetic Strategies for Neurodevelopmental Research

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.

Grant Number: 5R01MH121447-05
NIH Institute/Center: NIH
Principal Investigator: David Amaral