Enhancer-targeted CRISPR-Activation Rescues Haploinsufficient Autism Susceptibility Genes

Abstract

AbstractAutism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD’s genetic susceptibility is imparted byde novomutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes –CHD8andSCN2Aand used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons and cerebral forebrain organoids to correct the effects of haploinsufficiency, taking advantage of the presence of a wildtype allele of each gene and endogenous gene regulation. We found that CRISPR-A induced a sustained increase inCHD8andSCN2Aexpression in treated neurons and organoids, with rescue of gene expression levels and mutation-associated phenotypes, including gene expression and physiology. These data support gene activation via targeting enhancers of haploinsufficient genes, as a therapeutic intervention in ASD and other neurodevelopmental disorders.