ABSTRACT
The majority of autism spectrum disorder (ASD) risk genes are associated with ASD due to haploinsufficiency, where only one gene copy is functional. Here, using SCN2A haploinsufficiency, a major risk factor for ASD, we show that increasing the expression of the existing functional SCN2A allele with CRISPR activation (CRISPRa) can provide a viable therapeutic approach. We first demonstrate therapeutic potential by showing that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency. Next, using an rAAV-CRISPRa based treatment, we restore electrophysiological deficits in both Scn2a heterozygous mice and human stem-cell-derived neurons. Our results provide a novel therapeutic approach for numerous ASD-associated genes and demonstrate that rescue of Scn2a haploinsufficiency, even at adolescent stages, can ameliorate neurodevelopmental phenotypes.
Competing Interest Statement
NM is the cofounder, board member and CSO of Regel Therapeutics Inc and NA is the cofounder and on the scientific advisory board, Regel Tx. PWES is a scientist at Regel Tx. NM and NA are the inventors on patent "Gene therapy for haploinsufficiency" WO2018148256A9. NA, KJB, and SJS receive funding from BioMarin Pharmaceutical Incorporated.