Cell class-specific AAV gene therapy for SLC6A1-related neurodevelopmental disorder

About This Grant

PROJECT SUMMARY SLC6A1-related disorder is a severe developmental epileptic encephalopathy with an urgent need for an innovative disease-modifying therapy. All patients lack one functional copy of SLC6A1, the gene encoding the primary GABA transporter in the brain, GAT1. The average age of diagnosis is two years of life, characterized by seizures, motor impairment, language delay, developmental regression, social impairment, and intellectual disability. The monogenic nature of this disease suggests SLC6A1 upregulation or replacement as an obvious treatment strategy; yet despite considerable efforts, we still lack an FDA-approved drug to induce endogenous SLC6A1 expression and there are no clinical trials to provide a supplemental copy of the gene. Adeno-associated virus (AAV)-mediated gene delivery of SLC6A1 could provide a one-time curative treatment to patients that suffer from this disease, but the importance of targeting expression to defined brain cell types is unknown. A critical complication of SLC6A1 is its cell class selectivity, being enriched in inhibitory neurons and astrocytes that remove GABA from extracellular spaces. These data suggest the most effective therapy will elevate SLC6A1 gene expression in inhibitory neurons or astrocytes of the brain. Our work has demonstrated proof-of-concept that SLC6A1 gene replacement to inhibitory cells or astrocytes is a viable therapeutic approach for SLC6A1-related disorder. Moreover, expression of SLC6A1 in all neurons is neither effective nor safe. Our circuit-selective gene replacement strategy could ultimately produce a first-in- class therapeutic. In this R44, our Allen Institute-spinout company, EpiCure Therapeutics Inc, will identify the minimal biodistribution required for targeting inhibitory neurons, assess co-targeting inhibitory neurons and astrocytes, determine the impact of next-generation capsids on cell type specificity, and combine genetic regulatory elements with the optimal capsid to test transgene expression and safety in macaques and ultimately arrive at a clinical developmental candidate.