NatureSep 17, 2025

Using CRISPR to Boost SCN2A Gene Activity in Neurodevelopmental Disorders

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 3, 2026

Abstract

Upregulation of the functional SCN2A gene copy can rescue neurological phenotypes in Scn2a haploinsufficient mice.

SCN2A haploinsufficiency may lead to autism spectrum disorder, intellectual disability, and refractory epilepsy.
Restoring Scn2a expression in adolescent mice rescues electrophysiological deficits linked to haploinsufficiency.
Adeno-associated virus CRISPR activation treatment can correct intrinsic and synaptic deficits in neocortical pyramidal cells.
Systemic delivery of CRISPRa shows protective effects against seizures induced by chemoconvulsants in Scn2a mice.
CRISPRa treatment has been shown to rescue excitability in human neurons derived from SCN2A haploinsufficient stem cells.

Simplified

Most neurodevelopmental disorders with single gene diagnoses act via haploinsufficiency, in which only one of the two gene copies is functional. SCN2A haploinsufficiency is one of the most frequent causes of neurodevelopmental disorder, often presenting with autism spectrum disorder, intellectual disability and, in a subset of children, refractory epilepsy. Here, using SCN2A haploinsufficiency as a proof-of-concept, we show that upregulation of the existing functional gene copy through CRISPR activation (CRISPRa) can rescue neurological-associated phenotypes in Scn2a haploinsufficient mice. We first show that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency (Scn2a). Next, using an adeno-associated virus CRISPRa-based treatment in adolescent mice, we show that we can correct intrinsic and synaptic deficits in neocortical pyramidal cells, a major cell type that contributes to neurodevelopmental disorders and seizure aetiology in SCN2A haploinsufficiency. Furthermore, we find that systemic delivery of CRISPRa protects Scn2amice against chemoconvulsant-induced seizures. Finally, we also show that adeno-associated virus CRISPRa treatment rescues excitability in SCN2A haploinsufficient human stem-cell-derived neurons. Our results showcase the potential of this therapeutic approach to rescue SCN2A haploinsufficiency and demonstrates that rescue even at adolescent stages can ameliorate neurodevelopmental phenotypes. 1 2 +/-+/-

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Using CRISPR to Boost SCN2A Gene Activity in Neurodevelopmental Disorders

Abstract

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