CRISPR activation for SCN2A-related neurodevelopmental disorders
Serena Tamura1,2, Andrew D Nelson3,4, Perry W E Spratt3,4
1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Nature
|September 17, 2025
Summary
CRISPR activation therapy can upregulate the functional SCN2A gene copy, rescuing neurological deficits in mouse models of SCN2A haploinsufficiency. This approach shows promise for treating neurodevelopmental disorders caused by gene haploinsufficiency.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Most neurodevelopmental disorders stem from single gene defects, often acting through haploinsufficiency.
- SCN2A haploinsufficiency is a common genetic cause of neurodevelopmental disorders, including autism, intellectual disability, and epilepsy.
Purpose of the Study:
- To investigate CRISPR activation (CRISPRa) as a therapeutic strategy to upregulate the functional gene copy in SCN2A haploinsufficiency.
- To assess the efficacy of CRISPRa in rescuing neurological phenotypes in mouse models and human neurons.
Main Methods:
- Utilized CRISPR activation (CRISPRa) to upregulate the existing functional copy of the SCN2A gene.
- Employed adeno-associated virus (AAV) delivery of CRISPRa in adolescent Scn2a haploinsufficient mice.
- Assessed electrophysiological and synaptic deficits in neocortical pyramidal cells.
- Evaluated seizure protection against chemoconvulsants.
- Tested CRISPRa in human stem-cell-derived neurons.
Main Results:
- Restoring Scn2a expression in adolescent mice rescued electrophysiological deficits.
- CRISPRa treatment corrected intrinsic and synaptic deficits in neocortical pyramidal cells.
- Systemic CRISPRa delivery protected mice against seizures.
- CRISPRa treatment rescued neuronal excitability in human stem-cell-derived neurons.
Conclusions:
- CRISPR activation is a potential therapeutic approach for SCN2A haploinsufficiency.
- Therapeutic intervention, even in adolescent stages, can ameliorate neurodevelopmental phenotypes associated with SCN2A haploinsufficiency.
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