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Precision Engineering of the Genome, Epigenome and Transcriptome | EK24


CRISPR activation to rescue SCN2A haploinsufficiency in Autism Spectrum Disorder


Mar 8, 2021 12:00am ‐ Mar 8, 2021 12:00am

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CRISPR activation to rescue SCN2A haploinsufficiency in Autism Spectrum Disorder Authors and Affilications: Serena M. Tamura (1,2), Perry W.E. Spratt (3), Andrew Nelson (3), Navneet Matharu(1,2) ,Stephan J. Sanders (4), Kevin J. Bender (3), Nadav Ahituv(1,2) (1)Bioengineering & Therapeutic Sciences UCSF , (2) Institute for Human Genetics UCSF, (3) Dept. of Neurology UCSF, (4)Dept. of Psychiatry UCSF Abstract Body: Loss-of-function (LoF) mutations that cause haploinsufficiency (having only one of two functional gene copies) in SCN2A are one of the most frequent causes of autism spectrum disorder (ASD). Individuals with SCN2A haploinsufficiency are often comorbid with intellectual disability and developmental delay. Here, we set out to use CRISPR activation (CRISPRa) to target the promoter of SCN2A and upregulate its expression to overcome SCN2A haploinsufficiency in mice and human ESC-differentiated excitatory neurons. We injected adeno-associated virus (AAV) CRISPRa into the medial prefrontal cortex of Scn2a+/- mice and observed a rescue of the associated heterozygous cellular deficits, including action potential firing speed and synaptic maturation. In human ESC-differentiated excitatory neurons, we are currently growing these cells to maturation and plan to treat with CRISPRa to functionally assess whether we can rescue their electrophysiological properties. In summary, our project provides a potential therapeutic for one of the most significant causes of ASD and can also be adapted to treat other commonly observed haploinsufficient neurodevelopmental disorders.

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