Kavli Affiliate: Kevin Bender, Jeanne Tamar Paz
| Authors: Serena Tamura, Andrew D Nelson, Perry WE Spratt, Henry Kyoung, Xujia Zhou, Zizheng Li, Jingjing Zhao, Stephanie S Holden, Atehsa Sahagun, Caroline M Keeshen, Congyi Lu, Elizabeth C Hamada, Roy Ben-Shalom, Jen Q Pan, Jeanne T Paz, Stephan J Sanders, Navneet Matharu, Nadav Ahituv and Kevin J Bender
| Summary:
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.