AAV delivery of full-length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders.

Abstract

SYNGAP1-related disorders (SRDs) are rare neurodevelopmental conditions characterized by severe neurological symptoms, including epilepsy, motor impairment, and cognitive dysfunction. Current treatment options are limited, with patients relying on a cocktail of medications to manage the diverse symptoms but that do not address the underlying pathology. SRDs are primarily caused by haploinsufficiency of the SYNGAP1 gene, which encodes the synaptic scaffolding and signaling protein, SynGAP. We developed a gene supplementation strategy to deliver broad neuronal expression of human SYNGAP1 via an adeno-associated virus (AAV). Driven by the pan-neuronal SYNAPSIN I promoter, SYNGAP1 delivery alleviated several disease phenotypes in a Syngap1 heterozygous mouse model, including epileptiform activity, hyperactivity, and risk-taking behaviors. Notably, AAV-SYNGAP1 administration in juvenile mice, which corresponds to the typical age of diagnosis in humans, rescued behavioral deficits, highlighting its clinical relevance. Our findings provide the first evidence that AAV-mediated gene therapy can restore SYNGAP1 function and reverse key phenotypes, supporting its potential as a transformative therapeutic for SRD patients.