Rescuing SYNGAP1 haploinsufficiency by redirecting alternative splicing

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PROJECT SUMMARY Synaptic transmission and plasticity are fundamental to neuronal functions, and dysregulations of synaptic protein expression are direct causes of neurodevelopmental disorders such as autism. Over one hundred de novo loss-of-function mutations in SYNGAP1 have been unambiguously associated with autism spectral disorders and intellectual disability. Recent success in splice-switching oligonucleotides (SSOs) suggests that redirecting splicing through genetic and SSO-mediated ablations is a promising approach to rescue haploinsufficiency. We have identified an alternative splicing event in SYNGAP1 that leads to nonsense- mediated mRNA decay (NMD) during mouse and human development. To determine whether the SYNGAP1 NMD exon is a viable therapeutic target, we investigate the regulatory mechanism and its functions using genetic approaches, and determine whether genetic deletion and SSO suppression of the SYNGAP1 NMD exon can rescue heterozygous knockout phenotypes in mouse mutants and patient-iPSC-derived neurons. Upon completion, this project will provide genetic insights into the physiological functions of this SYNGAP1 NMD exon and generate critical preclinical reagents to restore SYNGAP1 protein expression from haploinsufficiency.