UCSF

Haploinsufficiency, having only one functional gene copy, is associated with close to 100 autism spectrum disorder (ASD) risk genes. Here, using SCN2A haploinsufficiency, a major ASD risk condition, we show that CRISPR activation (CRISPRa) of the existing functional copy at adolescent stages provides a viable therapeutic approach. First, we demonstrate the potential for a therapeutic to rescue electrophysiological deficits in mice by utilizing heterozygous Scn2a conditional knockin mice. Next, using an AAV-based CRISPRa approach, we rescue these electrophysiological deficits in Scn2a heterozygous mice and human SCN2A heterozygous excitatory neurons. Our results provide a novel therapeutic approach for numerous ASD-associated genes and also suggest that rescue Scn2a function, even in relatively mature developmental stages, could ameliorate neurodevelopmental phenotypes.