Most single-gene diagnosed neurodevelopmental disorders are caused by haploinsufficiency, meaning only one of the two copies of a gene remains functional. Haploinsufficiency of the SCN2A gene is one of the most common causes of neurodevelopmental disorders, often manifesting as autism, intellectual disability, and, in some children, intractable epilepsy.
In September 2025, researchers from the University of California, San Francisco, published a research paper titled "CRISPR activation for SCN2A-related neurodevelopmental disorders" in the leading international academic journal Nature. The study applied CRISPR activation (CRISPRa) technology to treat SCN2A haploinsufficiency. In a mouse model of puberty, equivalent to 10 years in human age, the study successfully restored SCN2A levels in the brain and reversed neurodevelopmental disorders. These findings demonstrate the potential of this therapeutic approach to rescue SCN2A haploinsufficiency and suggest that rescue can improve neurodevelopmental phenotypes even during adolescence.
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As is well known, CRISPR-Cas9 gene editing technology uses guide RNA to target the Cas9 enzyme to a target DNA sequence, where it then cleaves both strands of the target DNA, creating double-strand breaks and thereby knocking out specific genes.
Qi Lei and others at Stanford University developed a dCas9 with disabled cleavage activity. This dCas9 retains the ability to bind DNA but does not cleave double-stranded DNA. Fusion of dCas9 with a transcriptional activator protein can activate specific genes and increase their expression levels. This technique is known as CRISPR activation (CRISPRa).
In this study, the research team used Scn2a haploinsufficiency as a proof-of-concept study, demonstrating that modulating the expression of existing functional gene copies through CRISPR activation (CRISPRa) is sufficient to rescue the neurological phenotypes of Scn2a haploinsufficient mice.
The research team first demonstrated that restoring Scn2a expression in a mouse model during adolescence (roughly equivalent to 10 years of age in humans) could rescue the electrophysiological defects associated with Scn2a haploinsufficiency (Scn2a+/-). Next, the team used adeno-associated virus (AAV)-delivered CRISPRa to treat adolescent mice, demonstrating that this technique could correct the intrinsic and synaptic defects in neocortical pyramidal cells, the primary cell type responsible for the neurodevelopmental disorders and epilepsy caused by SCN2A haploinsufficiency.
Figure 1. SCN2A-rAAV-CRISPRa rescues spiking properties of SCN2A+/- hESC-derived neurons. (Tamura S, et al., 2025)
Furthermore, the study found that systemic delivery of CRISPRa protected the Scn2a+/- mouse model from chemically induced seizures. Finally, the team demonstrated that AAV-CRISPRa treatment could rescue the abnormal excitability of SCN2A haploinsufficient human stem cell-derived neurons.
Collectively, these findings demonstrate the potential of CRISPRa-based therapeutic strategies to rescue SCN2A haploinsufficiency and demonstrate that intervention during adolescence can improve neurodevelopmental phenotypes. The research team stated, "We were surprised to find that, when SCN2A is insufficient, the brain's anatomy remains intact and synapses remain, albeit unable to mature. However, increasing SCN2A levels restored these synapses to normal and prevented epileptic seizures."
Reference
Tamura S, et al. CRISPR activation for SCN2A-related neurodevelopmental disorders. Nature, 2025: 1-9.