Enhancer-targeted CRISPR-Activation Rescues Haploinsufficient Autism Susceptibility Genes.

George T Chen, Gayatri Nair, Aubrey J Osorio,Sandra M Holley, Kimiya Ghassemzadeh, Jose Gonzalez,Congyi Lu,Neville E Sanjana,Carlos Cepeda,Daniel H Geschwind

bioRxiv : the preprint server for biology(2024)

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Abstract
Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD's genetic susceptibility is imparted by de novo mutations of major effect, most of which cause haploinsufficiency. We mapped enhancers of two high confidence autism genes - CHD8 and SCN2A and 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 in CHD8 and SCN2A expression 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.
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