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.

Mark Zylka plans to evaluate the extent to which molecular phenotypes worsen with age in Chd8^V986*/+ heterozygous mice, which harbor a loss-of-function autism-linked mutation. Results from this study are expected to highlight the importance of expanding the age range over which autism model mice are evaluated, with the ultimate aim of better understanding neuropathological changes in older individuals with ASD.