Gene-replacement therapy in neurodevelopmental disorders: progress and challenges

Heterozygous loss-of-function variants in the SLC6A1 gene, encoding GAT1, which is the main GABA transporter in the brain, lead to a broad spectrum of neuropsychiatric and neurodevelopmental disorders including epilepsy, developmental delay, intellectual disability, and autism. Gene-replacement strategies involving adeno-associated viruses (AAV) require the delivery of genes to specific types of neurons or areas in the brain, likely during certain developmental time points. In this issue of the JCI, Guo and colleagues from the Gray lab evaluated two promoters, three injection modalities, and various timing strategies for replacement of GAT1 via AAV type 9 in heterozygous and homozygous knockout mouse models. Intrathecal administration of vectors containing either promoter at postnatal day 5 achieved high expression and was the best tolerated approach. Notably, gene-replacement therapy failed at later disease stages, suggesting the importance of early gene reconstitution and confirming the importance of GABA metabolism in early brain development.