SYNGAP1 encodes a neuronal Ras GTPase activating protein and is a significant risk gene associated with autism spectrum disorders (ASDs) and intellectual disability (ID). As many of the genetic mutations in individuals with SYNGAP1-related ID (SRID) lead to decreased SYNGAP1 expression, SRID is an ideal candidate for genetic and antisense oligonucleotide–based therapies that increase SYNGAP1 expression. Leveraging recently discovered regulatory mechanisms of SYNGAP1 expression, Richard Huganir’s team plans to design precision antisense oligonucleotides that increase SYNGAP1 expression and to validate them using human pluripotent stem cell models of SRID. These studies will help to advance the therapeutic potential of antisense oligonucleotide–based treatments for SRID as well as other monogenic forms of ID and ASD.

Neurexin-neuroligin binding is essential for appropriate synaptic development and function, and mutations in neurexins and neuroligins have been linked to autism spectrum disorder (ASD). In the current project, Peng Zhang aims to assess how enhancements to and blockade of a specific heparan sulfate moiety alters neurexin function and whether such modulations can reverse synaptic deficits in a neurexin mouse model of ASD.

Ranmal Aloka Samarasinghe is studying brain organoids derived from individuals with mutations in SCN8A. Preliminary findings suggest that these organoids display excitatory-inhibitory imbalance and a loss of gamma oscillations. The current study aims to uncover the pathophysiological changes that underlie this observation and to test novel therapeutics that can rescue key cellular and physiological phenotypes in this model.

J. Elliott Robinson plans to create gene therapies to address cognitive symptoms in neurofibromatosis type 1 (NF1) using a combination of protein engineering methods, CRISPR activation-based approaches to regulate endogenous gene expression and new systemic AAV capsids that freely cross the blood-brain barrier after intravenous administration. The resulting vectors will be tested in NF1 model mice in vivo and disseminated to the larger research community for additional validation.

In the current project, Corey Harwell and colleagues plan to examine the impact of loss of Setd2 function on the proliferation and cell fate specification of cortical progenitors. Their studies of the cellular and molecular functions of Setd2 during cortical neurogenesis may provide insights into convergent molecular mechanisms by which other chromatin-associated autism risk genes contribute to autism pathogenesis.

The UBE3A gene, encoding the ubiquitin ligase UBE3A/E6AP, is a high-confidence risk gene for autism spectrum disorder (ASD) but the downstream targets of UBE3A-mediated ubiquitination are poorly defined. In the current project, Hiroaki Kiyokawa plans to apply a novel proteomic technique called ‘orthogonal ubiquitin transfer’ to identify neuronal-specific substrates of UBE3A. Successful completion of this project is expected to provide a novel high-resolution perspective about neuronal-specific pathways downstream of UBE3A and identify potential therapeutic targets for ASD.

More than half of the genes associated with autism spectrum disorders (ASDs) encode for regulatory proteins. In the current project, Kasper Lage’s team aims to unravel the regulatory networks of transcription factors TCF4, CHD8, DYRK1A and GIGYF1 in human induced pluripotent stem cell (iPSC)-derived glutamatergic excitatory neurons using newly developed genome-wide chromatin-binding profiling methods. They then plan to use integrative computational methods to associate the identified regulatory networks with ASD genome-wide association studies and exome sequencing data to identify the subnetworks and sets of target genes most enriched in ASDs.