Elise Robinson and colleagues plan to develop and deploy the statistical methods needed to interpret genomic data from SPARK and other large autism spectrum disorder (ASD) datasets. They aim to identify causal variants, genes and pathways from ASD genome-wide association study (GWAS) results and characterize how they differ or converge with those that have been identified using exome sequencing data. Lastly, they plan to contrast the molecular basis of ASD with and without co-occurring intellectual disability.

In the current project, Nael Nadif Kasri aims to establish an all-human iPSC-based neuronal network platform to rigorously and multiparametrically assess the consequences of specific mutations in ASD risk genes on neuronal network function. The platform will be used to assess selected ASD gene variants of unknown significance and as a first-tier in vitro selection platform for testing genetic strategies for the amelioration of neuropathological phenotypes associated with genetically defined ASDs.

Rett syndrome (RTT) is a currently incurable neurodevelopmental disorder in urgent need of novel therapies capable of correcting its underlying genetic causes. To accomplish this critical objective, Pablo Perez-Pinera and Thomas Gaj plan to develop a gene therapy for reverting RTT mutations in vivo using CRISPR base editing technology. They anticipate that this work will provide key preclinical data for advancing a cure for this condition.

In the current project, Amy Ramsey and colleagues aim to develop gene therapy for a group of syndromic autism conditions called GRIN disorders. They plan to use a gene replacement strategy where GRIN1 or GRIN2B genes are delivered by adeno-associated viruses. They plan to test different virus capsids, promoters and routes of administration in three mouse models of patient variants. Studies are designed to measure liver and brain toxicity, vector and cargo distribution, and molecular, cellular and behavioral aspects of efficacy.