Wednesday, September 17, 2025
No menu items!
HomeNatureCRISPR activation for SCN2A-related neurodevelopmental disorders

CRISPR activation for SCN2A-related neurodevelopmental disorders

  • Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sanders, S. J. et al. Progress in understanding and treating SCN2A-mediated disorders. Trends Neurosci. https://doi.org/10.1016/j.tins.2018.03.011 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maenner, M. J. et al. Prevalence of autism spectrum disorder among children aged 8 years – Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2016. MMWR Surveill. Summ. https://doi.org/10.15585/MMWR.SS6904A1 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fu, J. M. et al. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat. Genet. 54, 1320–1331 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Epi25 Collaborative Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes. Nat. Neurosci. 27, 1864–1879 (2024).

    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • Wang, D., Tai, P. W. L. & Gao, G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug Discov. 18, 358–378 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, Z., Yang, H. & Colosi, P. Effect of genome size on AAV vector packaging. Mol. Ther. 18, 80–86 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Howe, K. L. et al. Ensembl 2021. Nucleic Acids Res. 49, D884–D891 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Matharu, N. & Ahituv, N. Modulating gene regulation to treat genetic disorders. Nat. Rev. Drug Discov. 19, 757–775 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Werling, D. M. et al. Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex. Cell Rep. 31, 107489 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jenkins, P. M. & Bender, K. J. Axon initial segment structure and function in health and disease. Physiol. Rev. 105, 765–801 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Spratt, P. W. E. et al. The autism-associated gene Scn2a contributes to dendritic excitability and synaptic function in the prefrontal cortex. Neuron 103, 673–685 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nelson, A. D. et al. Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites. Neuron 112, 1133–1149 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lu, C. et al. Overexpression of NEUROG2 and NEUROG1 in human embryonic stem cells produces a network of excitatory and inhibitory neurons. FASEB J. 33, 5287–5299 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, T. et al. Action potential initiation in neocortical inhibitory interneurons. PLoS Biol. https://doi.org/10.1371/journal.pbio.1001944 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Matharu, N. et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363, eaau0629 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Grimm, D. et al. In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses. J. Virol. 82, 5887–5911 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bae, S., Park, J. & Kim, J.-S. Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases. Bioinformatics 30, 1473–1475 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, W. et al. PTPN14 is required for the density-dependent control of YAP1. Genes Dev. 26, 1959–1971 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Correia, J. C. et al. Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling. Proc. Natl Acad. Sci. USA 121, e2319724121 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Busse, D. C. et al. Interferon-induced protein 44 and interferon-induced protein 44-like restrict replication of respiratory syncytial virus. J. Virol. 94, e00297–20 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baum, M. L. et al. CSMD1 regulates brain complement activity and circuit development. Brain Behav. Immun. 119, 317–332 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Spratt, P. W. E. et al. Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells. Cell Rep. 36, 109483 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chung, J. H., Larsen, A. R., Chen, E. & Bunz, F. A PTCH1 homolog transcriptionally activated by p53 suppresses hedgehog signaling. J. Biol. Chem. 289, 33020–33031 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liang, L. et al. Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain. Genome Med. 13, 135 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yuan, Y. et al. Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model. Brain 147, 1231–1246 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Zhang, J. et al. Severe deficiency of the voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice. Cell Rep. 36, 109495 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Miyamoto, H. et al. Impaired cortico-striatal excitatory transmission triggers epilepsy. Nat. Commun. 10, 1917 (2019).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reynolds, C., King, M. D. & Gorman, K. M. The phenotypic spectrum of SCN2A-related epilepsy. Eur. J. Paediatr. Neurol. 24, 117–122 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Colasante, G. et al. dCas9-based Scn1a gene activation restores inhibitory interneuron excitability and attenuates seizures in Dravet syndrome mice. Mol. Ther. 28, 235–253 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Colasante, G. et al. In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy. Brain 143, 891–905 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yamagata, T. et al. CRISPR/dCas9-based Scn1a gene activation in inhibitory neurons ameliorates epileptic and behavioral phenotypes of Dravet syndrome model mice. Neurobiol. Dis. 141, 104954 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chang, H.-C. et al. rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith–Magenis syndrome mice. J. Biol. Chem. 299, 102728 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, G. et al. Multiplexed activation of endogenous genes by CRISPRa elicits potent antitumor immunity. Nat. Immunol. 20, 1494–1505 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liao, H.-K. et al. In vivo target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation. Cell 171, 1495–1507 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Böhm, S. et al. A gene therapy for inherited blindness using dCas9-VPR-mediated transcriptional activation. Sci. Adv. 6, eaba5614 (2020).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kemaladewi, D. U. et al. A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene. Nature 572, 125–130 (2019).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Mich, J. K. et al. Interneuron-specific dual-AAV SCN1A gene replacement corrects epileptic phenotypes in mouse models of Dravet syndrome. Sci. Transl. Med. 17, eadn5603 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Waszkielewicz, A. M. et al. Ion channels as drug targets in central nervous system disorders. Curr. Med. Chem. 20, 1241–1285 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Johnson, J. P. et al. NBI-921352, a first-in-class, NaV1.6 selective, sodium channel inhibitor that prevents seizures in Scn8a gain-of-function mice, and wild-type mice and rats. eLife 11, e72468 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ferdosi, S. R. et al. Multifunctional CRISPR-Cas9 with engineered immunosilenced human T cell epitopes. Nat. Commun. 10, 1842 (2019).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mehta, A. & Merkel, O. M. Immunogenicity of Cas9 protein. J. Pharm. Sci. 109, 62–67 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gaj, T., Sirk, S. J., Shui, S.-L. & Liu, J. Genome-editing technologies: principles and applications. Cold Spring Harb. Perspect. Biol. 8, a023754 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Levy, G. & Barak, B. Postnatal therapeutic approaches in genetic neurodevelopmental disorders. Neural Regen. Res. 16, 414–422 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Markati, T., Duis, J. & Servais, L. Therapies in preclinical and clinical development for Angelman syndrome. Expert Opin. Investig. Drugs 30, 709–720 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Silva-Santos, S. et al. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model. J. Clin. Invest. 125, 2069–2076 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wolter, J. M. et al. Cas9 gene therapy for Angelman syndrome traps Ube3a-ATS long non-coding RNA. Nature 587, 281–284 (2020).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Berg, A. T. et al. Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders. Brain 147, 2761–2774 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eaton, M. et al. Generation and basic characterization of a gene-trap knockout mouse model of Scn2a with a substantial reduction of voltage-gated sodium channel Nav 1.2 expression. Genes Brain Behav. 20, e12725 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tatsukawa, T. et al. Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity. Mol. Autism 10, 15 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shin, W. et al. Scn2a haploinsufficiency in mice suppresses hippocampal neuronal excitability, excitatory synaptic drive, and long-term potentiation, and spatial learning and memory. Front. Mol. Neurosci. 12, 145 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Léna, I. & Mantegazza, M. NaV1.2 haploinsufficiency in Scn2a knock-out mice causes an autistic-like phenotype attenuated with age. Sci. Rep. 9, 12886 (2019).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schamiloglu, S., Wu, H., Zhou, M., Kwan, A. C. & Bender, K. J. Dynamic foraging behavior performance is not affected by Scn2a haploinsufficiency. eNeuro 10, ENEURO.0367-23.2023 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goertsen, D. et al. AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset. Nat. Neurosci. 25, 106–115 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Keiser, M. S. et al. Toxicity after AAV delivery of RNAi expression constructs into nonhuman primate brain. Nat. Med. 27, 1982–1989 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hordeaux, J. et al. The GPI-linked protein LY6A drives AAV-PHP.B transport across the blood-brain barrier. Mol. Ther. 27, 912–921 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yao, Y. et al. Variants of the adeno-associated virus serotype 9 with enhanced penetration of the blood-brain barrier in rodents and primates. Nat. Biomed. Eng. 6, 1257–1271 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Blesa, J. et al. BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: targeted AAV vector delivery and PET imaging. Sci. Adv. 9, eadf4888 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ewels, P. A. et al. The nf-core framework for community-curated bioinformatics pipelines. Nat. Biotechnol. 38, 276–278 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fang, Z., Liu, X. & Peltz, G. GSEApy: a comprehensive package for performing gene set enrichment analysis in Python. Bioinformatics 39, btac757 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Planells-Cases, R. et al. Neuronal death and perinatal lethality in voltage-gated sodium channel αII-deficient mice. Biophys. J. 78, 2878–2891 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Van Erum, J., Van Dam, D. & De Deyn, P. P. PTZ-induced seizures in mice require a revised Racine scale. Epilepsy Behav. 95, 51–55 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Markram, H. et al. Reconstruction and simulation of neocortical microcircuitry. Cell 163, 456–492 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ben-Shalom, R. et al. Opposing effects on NaV1.2 function underlie differences between SCN2A variants observed in individuals with autism spectrum disorder or infantile seizures. Biol. Psychiatry 82, 224–232 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ruden, J. B., Dixit, M., Zepeda, J. C., Grueter, B. A. & Dugan, L. L. Robust expression of functional NMDA receptors in human induced pluripotent stem cell-derived neuronal cultures using an accelerated protocol. Front. Mol. Neurosci. 14, 777049 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments