Cell-Selective Adeno-Associated Virus-Mediated SCN1A Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates
Open accessAbstract
Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused by monoallelic loss-of-function variants in the SCN1A gene. SCN1A encodes for the alpha subunit of the voltage-gated type I sodium channel (Na V 1.1), the primary voltage-gated sodium channel responsible for generation of action potentials in GABAergic inhibitory interneurons. In these studies, we tested the efficacy of an adeno-associated virus serotype 9 (AAV9) SCN1A gene regulation therapy, AAV9-RE GABA -eTF SCN1A , designed to target transgene expression to GABAergic inhibitory neurons and reduce off-target expression within excitatory cells, in the Scn1a +/− mouse model of DS. Biodistribution and preliminary safety were evaluated in nonhuman primates (NHPs). AAV9-RE GABA -eTF SCN1A was engineered to upregulate SCN1A expression levels within GABAergic inhibitory interneurons to correct the underlying haploinsufficiency and circuit dysfunction. A single bilateral intracerebroventricular (ICV) injection of AAV9-RE GABA -eTF SCN1A in Scn1a +/− postnatal day 1 mice led to increased SCN1A mRNA transcripts, specifically within GABAergic inhibitory interneurons, and Na V 1.1 protein levels in the brain. This was associated with a significant decrease in the occurrence of spontaneous and hyperthermia-induced seizures, and prolonged survival for over a year. In NHPs, delivery of AAV9-RE GABA -eTF SCN1A by unilateral ICV injection led to widespread vector biodistribution and transgene expression throughout the brain, including key structures involved in epilepsy and cognitive behaviors, such as hippocampus and cortex. AAV9-RE GABA -eTF SCN1A was well tolerated, with no adverse events during administration, no detectable changes in clinical observations, no adverse findings in histopathology, and no dorsal root ganglion-related toxicity. Our results support the clinical development of AAV9-RE GABA -eTF SCN1A (ETX101) as an effective and targeted disease-modifying approach to SCN1A + DS.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
New approaches include targeting regulatory elements of large genes, such as SCN1A, employing cellselective specificity.
“New approaches include targeting regulatory elements of large genes, such as SCN1A, employing cellselective specificity 235 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [235]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072 · cited 1× · see citing works
“31,32 Based on these features, candidate sequences were screened empirically for efficacy in upregulating SCN1A expression (see Fig.”
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · cited 1× · see citing works
“Referenced ENCODE datasets were accessed from the ENCODE portal (https://www.encodeproject.org/) 33 or UCSD Genome Browser 34 using the Table Browser tool (https://www.genome.ucsc.edu).”
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,949 · see citing works
Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes
Siepel, A., Bejerano, G., Pedersen, J. S., Hinrichs, A. S., Hou, M., Rosenbloom, K., Clawson, H., Spieth, J., Hillier, L. W., Richards, S., et al. (2005) · Genome Research · doi:10.1101/gr.3715005 · Cited by 4,408 · see citing works
Model of autism: increased ratio of excitation/inhibition in key neural systems
Rubenstein, J. L. R., & Merzenich, M. M. (2003) · Genes, Brain and Behavior · doi:10.1034/j.1601-183x.2003.00037.x · Cited by 2,768 · see citing works
Neocortical excitation/inhibition balance in information processing and social dysfunction
Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., O’Shea, D. J., Sohal, V. S., Goshen, I., Finkelstein, J., Paz, J. T., et al. (2011) · Nature · doi:10.1038/nature10360 · Cited by 2,454 · see citing works
Adeno-associated virus vector as a platform for gene therapy delivery
Wang, D., Tai, P. W. L., & Gao, G. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0012-9 · Cited by 2,444 · cited 2× · see citing works
“46,47 To overcome these key limitations, we developed AAV9-RE GABA -eTF S CN1A , a novel gene regulation therapy, to selectively drive upregulation of endogenous WT SCN1A in GABAergic inhibitory interneurons to rescue haploinsufficiency of SCN1A in DS (Fig.”
Detection of nonneutral substitution rates on mammalian phylogenies
Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R., & Siepel, A. (2010) · Genome Research · doi:10.1101/gr.097857.109 · Cited by 2,353 · cited 3× · see citing works
“1B), 29 accessibility data (DNase hypersensitivity), and transcription factor binding site enrichment (chromatin immuno-precipitation sequencing [ChIP-seq] clusters) (Fig.”
The UCSC Table Browser data retrieval tool
Karolchik, D. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkh103 · Cited by 2,326 · see citing works
The Encyclopedia of DNA elements (ENCODE): data portal update
Davis, C. A., Hitz, B. C., Sloan, C. A., Chan, E. T., Davidson, J. M., Gabdank, I., Hilton, J. A., Jain, K., Baymuradov, U. K., Narayanan, A. K., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gkx1081 · Cited by 1,717 · cited 1× · see citing works
“31,32 Based on these features, candidate sequences were screened empirically for efficacy in upregulating SCN1A expression (see Fig.”
Adeno-Associated Virus (AAV) as a Vector for Gene Therapy
Naso, M. F., Tomkowicz, B., Perry, W. L., & Strohl, W. R. (2017) · BioDrugs · doi:10.1007/s40259-017-0234-5 · Cited by 1,362 · cited 1× · see citing works
“62 Previously, we demonstrated that unilateral ICV administration of AAV9 in NHPs results in widespread and symmetrical distribution throughout the brain, with significantly improved transduction of forebrain structures compared to intrathecal-lumbar administration.”
Yu, F. H., Mantegazza, M., Westenbroek, R. E., Robbins, C. A., Kalume, F., Burton, K. A., Spain, W. J., McKnight, G. S., Scheuer, T., & Catterall, W. A. (2006) · Nature Neuroscience · doi:10.1038/nn1754 · Cited by 1,173 · cited 9× · see citing works
“49,53 AAV9-RE GABA -eTF S CN1A achieves GABA-specific expression of an SCN1A transcriptional activator using a single AAV vector, enabling a clinically tractable path for an AAV-mediated gene therapy for DS.”
InfluentialOgiwara, I., Miyamoto, H., Morita, N., Atapour, N., Mazaki, E., Inoue, I., Takeuchi, T., Itohara, S., Yanagawa, Y., Obata, K., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.5270-06.2007 · Cited by 879 · cited 6× · see citing works
“11 15–21 Specific deletion of SCN1A within forebrain GABAergic inhibitory interneurons is sufficient to recapitulate sensitivity to hyperthermia-induced seizures (HTS), premature death, as well as behavioral and cognitive impairments observed in global SCN1A knockouts.”
InfluentialEpigenomic Signatures of Neuronal Diversity in the Mammalian Brain
Mo, A., Mukamel, E. A., Davis, F. P., Luo, C., Henry, G. L., Picard, S., Urich, M. A., Nery, J. R., Sejnowski, T. J., Lister, R., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.018 · Cited by 739 · cited 3× · see citing works
“36,39,40 These elements were designed to capture regulatory sequence features that confer endogenous cell selectivity in compact form, enabling cell-selective expression compatible with the 4.7 kb AAV packaging capacity.”
InfluentialA general and flexible method for signal extraction from single-cell RNA-seq data
Risso, D., Perraudeau, F., Gribkova, S., Dudoit, S., & Vert, J.-P. (2018) · Nature Communications · doi:10.1038/s41467-017-02554-5 · Cited by 718 · see citing works
Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission
Han, S., Tai, C., Westenbroek, R. E., Yu, F. H., Cheah, C. S., Potter, G. B., Rubenstein, J. L., Scheuer, T., de la Iglesia, H. O., & Catterall, W. A. (2012) · Nature · doi:10.1038/nature11356 · Cited by 643 · see citing works
The core Dravet syndrome phenotype
Dravet, C. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.02994.x · Cited by 630 · see citing works
ENCODE data at the ENCODE portal
Sloan, C. A., Chan, E. T., Davidson, J. M., Malladi, V. S., Strattan, J. S., Hitz, B. C., Gabdank, I., Narayanan, A. K., Ho, M., Lee, B. T., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv1160 · Cited by 549 · cited 1× · see citing works
“Referenced ENCODE datasets were accessed from the ENCODE portal (https://www.encodeproject.org/) 33 or UCSD Genome Browser 34 using the Table Browser tool (https://www.genome.ucsc.edu).”
The clinical landscape for AAV gene therapies
Kuzmin, D. A., Shutova, M. V., Johnston, N. R., Smith, O. P., Fedorin, V. V., Kukushkin, Y. S., van der Loo, J. C. M., & Johnstone, E. C. (2021) · Nature Reviews Drug Discovery · doi:10.1038/d41573-021-00017-7 · Cited by 503 · cited 1× · see citing works
“46,47 To overcome these key limitations, we developed AAV9-RE GABA -eTF S CN1A , a novel gene regulation therapy, to selectively drive upregulation of endogenous WT SCN1A in GABAergic inhibitory interneurons to rescue haploinsufficiency of SCN1A in DS (Fig.”
How introns enhance gene expression
Shaul, O. (2017) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2017.06.016 · Cited by 500 · cited 2× · see citing works
“36,39,40 These elements were designed to capture regulatory sequence features that confer endogenous cell selectivity in compact form, enabling cell-selective expression compatible with the 4.7 kb AAV packaging capacity.”
InfluentialSymonds, J. D., Zuberi, S. M., Stewart, K., McLellan, A., O‘Regan, M., MacLeod, S., Jollands, A., Joss, S., Kirkpatrick, M., Brunklaus, A., et al. (2019) · Brain · doi:10.1093/brain/awz195 · Cited by 459 · see citing works
Prognostic, clinical and demographic features in SCN1A mutation-positive Dravet syndrome
Brunklaus, A., Ellis, R., Reavey, E., Forbes, G. H., & Zuberi, S. M. (2012) · Brain · doi:10.1093/brain/aws151 · Cited by 366 · see citing works
Han, Z., Chen, C., Christiansen, A., Ji, S., Lin, Q., Anumonwo, C., Liu, C., Leiser, S. C., Meena, Aznarez, I., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz6100 · Cited by 341 · cited 1× · see citing works
“…selective, antisense oligonucleotide-based therapy has been reported to be well tolerated in DS patients at multiple monthly doses of up to 20 mg. 66,69 The safety, pharmacokinetic profile, and effi-594 cacy of higher doses under placebo-controlled conditions will determine the frequency of…”
Cheah, C. S., Yu, F. H., Westenbroek, R. E., Kalume, F. K., Oakley, J. C., Potter, G. B., Rubenstein, J. L., & Catterall, W. A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1211591109 · Cited by 336 · see citing works
Design of polydactyl zinc-finger proteins for unique addressing within complex genomes
Liu, Q., Segal, D. J., Ghiara, J. B., & Barbas, C. F. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.11.5525 · Cited by 327 · cited 2× · see citing works
“1A), 26,28 and was designed to selectively bind a conserved regulatory region upstream of the SCN1A transcription start site (NM_001202435) (see Experimental Procedures section).”
Cooper, M. S., McIntosh, A. M., Crompton, D. E., McMahon, J. M., Schneider, A., Farrell, K., Ganesan, V., Gill, D. S., Kivity, S., Lerman‐Sagie, T., et al. (2016) · Epilepsy Research · doi:10.1016/j.eplepsyres.2016.10.006 · Cited by 320 · see citing works
Redefining the cerebellar cortex as an assembly of non-uniform Purkinje cell microcircuits
Cerminara, N. L., Lang, E. J., Sillitoe, R. V., & Apps, R. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn3886 · Cited by 315 · see citing works
Glutamatergic pre-ictal discharges emerge at the transition to seizure in human epilepsy
Huberfeld, G., de la Prida, L. M., Pallud, J., Cohen, I., Quyen, M. L. V., Adam, C., Clémenceau, S., Baulac, M., & Miles, R. (2011) · Nature Neuroscience · doi:10.1038/nn.2790 · Cited by 314 · see citing works
Zinc Finger Tools: custom DNA-binding domains for transcription factors and nucleases
Mandell, J. G., & Barbas, C. F. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl209 · Cited by 313 · cited 2× · see citing works
“27 We designed several candidate target sequences based on conservation (PhyloP) 29,30 and genomic regulatory markers surrounding the distal SCN1A promoter (NM_001202435), including species sequence conservation (Fig.”
Mendell, J. R., Al-Zaidy, S. A., Lehman, K. J., McColly, M., Lowes, L. P., Alfano, L. N., Reash, N. F., Iammarino, M. A., Church, K. R., Kleyn, A., et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2021.1272 · Cited by 295 · see citing works
Wirrell, E. C., Laux, L., Donner, E. J., Jetté, N., Knupp, K. G., Meskis, M. A., Miller, I., Sullivan, J. E., Welborn, M., & Berg, A. T. (2017) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2017.01.025 · Cited by 287 · see citing works
Sudden unexpected death in a mouse model of Dravet syndrome
Kalume, F. K., Westenbroek, R. E., Cheah, C. S., Yu, F. H., Oakley, J. C., Scheuer, T., & Catterall, W. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66220 · Cited by 285 · see citing works
Tai, C., Abe, Y., Westenbroek, R. E., Scheuer, T., & Catterall, W. A. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1411131111 · Cited by 266 · see citing works
Hussman, J. P. (2001) · Journal of Autism and Developmental Disorders · doi:10.1023/a:1010715619091 · Cited by 263 · see citing works
Incidence of Dravet Syndrome in a US Population
Wu, Y. W., Sullivan, J., McDaniel, S. S., Meisler, M. H., Walsh, E. M., Li, S. X., & Kuzniewicz, M. W. (2015) · Pediatrics · doi:10.1542/peds.2015-1807 · Cited by 248 · see citing works
Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy
Oakley, J. C., Kalume, F. K., Yu, F. H., Scheuer, T., & Catterall, W. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0813330106 · Cited by 239 · see citing works
Colasante, G., Lignani, G., Brusco, S., Berardino, C. D., Carpenter, J. C., Giannelli, S. G., Valassina, N., Bido, S., Ricci, R., Castoldi, V., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.08.018 · Cited by 236 · cited 2× · see citing works
“Several potential disease-modifying therapies for DS are under various stages of development, 64–69 which differ in their approaches and neuronal cell types targeted.”
Chen, C.-L., Bharucha, V., Chen, Y., Westenbroek, R., Brown, A. M., Malhotra, J., Jones, D. M., Avery, C., Gillespie, P., Kazen-Gillespie, K., et al. (2002) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.212638099 · Cited by 203 · cited 1× · see citing works
“48,49 Our strategy regulates endogenous SCN1A transcription upstream of these intrinsic regulatory mechanisms, which may provide additional physiological control, and safeguards against overexpression.”
Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy
Nabbout, R., Chémaly, N., Chipaux, M., Barcia, G., Bouis, C., Dubouch, C., Leunen, D., Jambaqué, I., Dulac, O., Dellatolas, G., et al. (2013) · Orphanet Journal of Rare Diseases · doi:10.1186/1750-1172-8-176 · Cited by 196 · see citing works
Mapping genetic modifiers of survival in a mouse model of Dravet syndrome
Miller, A. R., Hawkins, N. A., McCollom, C. E., & Kearney, J. A. (2013) · Genes Brain & Behavior · doi:10.1111/gbb.12099 · Cited by 185 · see citing works
Self-citationDravet syndrome: Characteristics, comorbidities, and caregiver concerns
Villas, N., Meskis, M. A., & Goodliffe, S. (2017) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2017.06.031 · Cited by 184 · see citing works
Genetics and Function of Neocortical GABAergic Interneurons in Neurodevelopmental Disorders
Rossignol, E. (2011) · Neural Plasticity · doi:10.1155/2011/649325 · Cited by 183 · see citing works
Ogiwara, I., Iwasato, T., Miyamoto, H., Iwata, R., Yamagata, T., Mazaki, E., Yanagawa, Y., Tamamaki, N., Hensch, T. K., Itohara, S., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt331 · Cited by 183 · see citing works
Al-Zaidy, S. A., & Mendell, J. R. (2019) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2019.06.007 · Cited by 183 · cited 1× · see citing works
“72 AAV-delivered transgenes form stable, nonreplicating circular episomal DNA, which is gradually lost in dividing cells, but persists in postmitotic cells, such as neurons, due to the very low cellular turnover.”
From genotype to phenotype in Dravet disease
Gataullina, S., & Dulac, O. (2016) · Seizure · doi:10.1016/j.seizure.2016.10.014 · Cited by 179 · see citing works
Schuster, D. J., Dykstra, J. A., Riedl, M. S., Kitto, K. F., Belur, L. R., McIvor, R. S., Elde, R. P., Fairbanks, C. A., & Vulchanova, L. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00042 · Cited by 177 · cited 1× · see citing works
“54 By emulating endogenous expression patterns and gene regulation mechanisms, we can avoid supraphysiological protein expression and improve safety and potency of gene therapies.”
Skluzacek, J. V., Watts, K. P., Parsy, O., Wical, B., & Camfield, P. (2011) · Epilepsia · doi:10.1111/j.1528-1167.2011.03012.x · Cited by 170 · see citing works
The contribution of GABAergic dysfunction to neurodevelopmental disorders
Ramamoorthi, K., & Lin, Y. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.03.003 · Cited by 169 · cited 1× · see citing works
“59 Thus, targeted gene delivery to GABAergic inhibitory interneurons may have the potential to address the neu-rocircuitry deficits observed across multiple neurodevelopmental and epileptic encephalopathies.”
Intracerebroventricular Delivery as a Safe, Long-Term Route of Drug Administration
Cohen-Pfeffer, J. L., Gururangan, S., Lester, T. L., Lim, D. A., Shaywitz, A. J., Westphal, M., & Slavc, I. (2016) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2016.10.022 · Cited by 161 · cited 1× · see citing works
“63 Here, we show that a one-time, unilateral ICV injection of AAV9-RE GABA -eTF SCN1A in NHPs was well tolerated and led to widespread vector biodistribution and robust transgene expression throughout the brain.”
Lenk, G. M., Jafar‐Nejad, P., Hill, S. F., Huffman, L. D., Smolen, C., Wagnon, J. L., Petit, H. J., Yu, W., Ziobro, J. M., Bhatia, K., et al. (2020) · Annals of Neurology · doi:10.1002/ana.25676 · Cited by 145 · see citing works
Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids
Chamberlain, K., Riyad, J. M., & Weber, T. (2016) · Human Gene Therapy Methods · doi:10.1089/hgtb.2015.140 · Cited by 141 · cited 3× · see citing works
“72 AAV-delivered transgenes form stable, nonreplicating circular episomal DNA, which is gradually lost in dividing cells, but persists in postmitotic cells, such as neurons, due to the very low cellular turnover.”
InfluentialSun, Y., Paşca, S. P., Portmann, T., Goold, C., Worringer, K. A., Guan, W., Chan, K. C., Gai, H., Vogt, D., Chen, Y.-J. J., et al. (2016) · eLife · doi:10.7554/elife.13073 · Cited by 141 · see citing works
Yamagata, T., Raveau, M., Kobayashi, K., Miyamoto, H., Tatsukawa, T., Ogiwara, I., Itohara, S., Hensch, T. K., & Yamakawa, K. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104954 · Cited by 135 · cited 1× · see citing works
“64,68 However, GABA-selective expression of these described transgenes is required for therapeutic efficacy, and the size of these effector transgenes precludes packaging within a single AAV particle.”
A human Dravet syndrome model from patient induced pluripotent stem cells
Higurashi, N., Uchida, T., Lossin, C., Misumi, Y., Okada, Y., Akamatsu, W., Imaizumi, Y., Zhang, B., Nabeshima, K., Mori, M. X., et al. (2013) · Molecular Brain · doi:10.1186/1756-6606-6-19 · Cited by 134 · see citing works
Gersbach, C. A., Gaj, T., & Barbas, C. F. (2014) · Accounts of Chemical Research · doi:10.1021/ar500039w · Cited by 132 · see citing works
Screening of conventional anticonvulsants in a genetic mouse model of epilepsy
Hawkins, N. A., Anderson, L. L., Gertler, T. S., Laux, L., George, A. L., & Kearney, J. A. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.413 · Cited by 115 · cited 2× · see citing works
“60 In contrast, we demonstrate that a single bilateral ICV administration of AAV9-RE GABA -eTF S CN1A at PND1 leads to both a significant reduction in HTS sensitivity and extended survival in two distinct genetic mouse models of DS ( Scn1a + / - and Scn1a + /R1407X ).”
Self-citationIto, S., Ogiwara, I., Yamada, K., Miyamoto, H., Hensch, T. K., Ōsawa, M., & Yamakawa, K. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2012.08.003 · Cited by 113 · cited 2× · see citing works
“Similarly, treatment with AAV9-RE GABA -eTF SCN1A also significantly increased resistance to HTS in an alternative mouse model of DS, 11,25 where a nonsense mutation (R1407X) was introduced in the reading frame of one copy of SCN1A (Supplementary Fig.”
SCN1A gain of function in early infantile encephalopathy
Berecki, G., Bryson, A., Terhag, J., Maljevic, S., Gazina, E. V., Hill, S., & Petrou, S. (2019) · Annals of Neurology · doi:10.1002/ana.25438 · Cited by 94 · cited 2× · see citing works
“53 Accordingly, we designed an expression cassette (collectively referred to as RE GABA ) to drive potent expression in multiple subtypes of GABAergic interneurons, with minimal expression in excitatory neurons, by utilizing optimized human genomic regulatory sequences surrounding the GAD1 gene…”
Goff, K. M., & Goldberg, E. M. (2019) · eLife · doi:10.7554/elife.46846 · Cited by 93 · see citing works
Valassina, N., Brusco, S., Salamone, A., Serra, L., Luoni, M., Giannelli, S. G., Bido, S., Massimino, L., Ungaro, F., Mazzara, P. G., et al. (2022) · Nature Communications · doi:10.1038/s41467-021-27837-w · Cited by 78 · cited 1× · see citing works
“61 Together, these data suggest that disease phenotype may be reversed and strongly support continued development of AAV9-RE GABA -eTF S CN1A as a novel gene therapy with the potential to durably rescue multiple phenotypes in DS patients.”
Liautard, C., Scalmani, P., Carriero, G., de Curtis, M., Franceschetti, S., & Mantegazza, M. (2013) · Epilepsia · doi:10.1111/epi.12213 · Cited by 76 · see citing works
Clinical Applications Involving CNS Gene Transfer
Kantor, B., McCown, T., Leone, P., & Gray, S. J. (2014) · Advances in Genetics · doi:10.1016/b978-0-12-800149-3.00002-0 · Cited by 74 · cited 1× · see citing works
“22 However, as the SCN1A gene (cDNA * 6 kb) exceeds the packaging capacity of AAV (4.7 kb DNA), 23 AAV-mediated gene replacement therapy for SCN1A + DS is not a viable approach.”
InfluentialNiibori, Y., Lee, S. J., Minassian, B. A., & Hampson, D. R. (2019) · Human Gene Therapy · doi:10.1089/hum.2019.225 · Cited by 71 · cited 1× · see citing works
“65 Conditional Cas9-based transcriptional activators, combined with GABA-specific Cre mouse lines or code-livery of a targeting vector emphasize the potential for a GABA-targeted SCN1A gene regulation in treating cognitive and behavioral effects, improving survival rate, and reducing seizure…”
Recent advances in gene therapy for neurodevelopmental disorders with epilepsy
Turner, T. J., Zourray, C., Schorge, S., & Lignani, G. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15168 · Cited by 71 · cited 1× · see citing works
“70,71 Importantly, AAV9-mediated gene therapies have shown transgene persistence after a single administration.”
Stein, R. E., Kaplan, J. S., Li, J., & Catterall, W. A. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1906833116 · Cited by 68 · cited 1× · see citing works
“44 The mean VCN and eTF SCN1A mRNA transcripts in the forebrain regions, including frontal cortex, temporal cortex, parietal cortex, occipital cortex and hippocampus, were measured at 1.73 copies per diploid genome and 1.71E4 transcripts per microgram RNA, respectively.”
InfluentialSelf-citationWengert, E. R., Wagley, P. K., Strohm, S. M., Reza, N., Wenker, I. C., Gaykema, R. P. A., Christiansen, A., Liau, G., & Patel, M. K. (2021) · Brain Research · doi:10.1016/j.brainres.2021.147743 · Cited by 60 · cited 2× · see citing works
“Several potential disease-modifying therapies for DS are under various stages of development, 64–69 which differ in their approaches and neuronal cell types targeted.”
Vacher, H., & Trimmer, J. S. (2012) · Epilepsia · doi:10.1111/epi.12032 · Cited by 57 · see citing works
Synergistic GABA-Enhancing Therapy against Seizures in a Mouse Model of Dravet Syndrome
Oakley, J. C., Cho, A. R., Cheah, C. S., Scheuer, T., & Catterall, W. A. (2013) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.113.203331 · Cited by 56 · cited 2× · see citing works
“…GABAergic inhibitory interneurons due to Na V 1.1 haploinsufficiency as fundamental in driving key DS phenotypes, and suggest that enhancement of GABA signaling may improve seizure control and other manifestations associated with DS. 12,13,15–21 On the contrary, pan-neuronal overexpression of Nav1.”
InfluentialA MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex
Keaveney, M. K., Tseng, H.-A., Ta, T. L., Gritton, H. J., Man, H., & Han, X. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.049 · Cited by 55 · cited 3× · see citing works
“36,39,40 These elements were designed to capture regulatory sequence features that confer endogenous cell selectivity in compact form, enabling cell-selective expression compatible with the 4.7 kb AAV packaging capacity.”
InfluentialTatsukawa, T., Ogiwara, I., Mazaki, E., Shimohata, A., & Yamakawa, K. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.01.009 · Cited by 47 · see citing works
Hawkins, N. A., Lewis, M., Hammond, R., Doherty, J., & Kearney, J. A. (2017) · Scientific Reports · doi:10.1038/s41598-017-15609-w · Cited by 32 · see citing works
Self-citationScn1a missense mutation impairs GABAA receptor-mediated synaptic transmission in the rat hippocampus
Ohno, Y., Sofue, N., Ishihara, S., Mashimo, T., Sasa, M., & Serikawa, T. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.08.021 · Cited by 11 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
AAV-based in vivo gene therapy for neurological disorders
Ling, Q., Herstine, J. A., Bradbury, A. M., & Gray, S. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00766-7 · Cited by 206 · see citing works
Developmental and epileptic encephalopathies
Scheffer, I. E., Zuberi, S., Mefford, H. C., Guerrini, R., & McTague, A. (2024) · Nature Reviews Disease Primers · doi:10.1038/s41572-024-00546-6 · Cited by 128 · see citing works
“New approaches include targeting regulatory elements of large genes, such as SCN1A , employing cell-selective specificity 235 .”
Neumann, E. N., Bertozzi, T. M., Wu, E., Serack, F. E., Harvey, J. W., Brauer, P. P., Pirtle, C. P., Coffey, A. A., Howard, M., Kamath, N., et al. (2024) · Science · doi:10.1126/science.ado7082 · Cited by 120 · see citing works
Dravet syndrome: A systematic literature review of the illness burden
Strzelczyk, A., Lagae, L. G., Wilmshurst, J. M., Brunklaus, A., Striano, P., Rosenow, F., & Schubert‐Bast, S. (2023) · Epilepsia Open · doi:10.1002/epi4.12832 · Cited by 71 · see citing works
Voltage-gated sodium channels in excitable cells as drug targets
Alsaloum, M., Dib‐Hajj, S. D., Page, D. A., Ruben, P. C., Krainer, A. R., & Waxman, S. G. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01108-x · Cited by 69 · see citing works
“In pre-clinical studies, ETX101 has been shown to increase Na V 1.1 expression in the brain, and subsequently reduce the frequency of seizures and improve survival in a murine model of Dravet syndrome 61 .”
InfluentialWidespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition
Martins Custodio, H., Clayton, L. M., Bellampalli, R., Pagni, S., Silvennoinen, K., Caswell, R., Genomics England Research Consortium, Ambrose, J. C., Arumugam, P., Bevers, R., et al. (2023) · Brain · doi:10.1093/brain/awad111 · Cited by 62 · see citing works
Genetic therapeutic advancements for Dravet Syndrome
Chilcott, E. M., Diaz, J. F. A., Bertram, C., Berti, M., & Karda, R. (2022) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2022.108741 · Cited by 60 · see citing works
Perucca, E., White, H. S., & Bialer, M. (2023) · CNS Drugs · doi:10.1007/s40263-023-01025-4 · Cited by 56 · see citing works
“injection was found to be well tolerated and to be associated with widespread distribution of the vector and efficient transgene expression throughout the brain [35, 36].”
BackgroundYe, D., Chukwu, C., Yang, Y., Hu, Z., & Chen, H. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115363 · Cited by 58 · see citing works
Established and emerging GABAA receptor pharmacotherapy for epilepsy
Richardson, R. J., Petrou, S., & Bryson, A. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1341472 · Cited by 44 · see citing works
Mich, J. K., Ryu, J., Wei, A. D., Gore, B. B., Guo, R., Bard, A. M., Martinez, R. A., Luber, E. M., Liu, J., Bishaw, Y. M., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adn5603 · Cited by 61 · see citing works
Fadila, S., Beucher, B., Dopeso‐Reyes, I. G., Mavashov, A., Brusel, M., Anderson, K., Ismeurt, C., Goldberg, E. M., Ricobaraza, A., Hernández-Alcoceba, R., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci159316 · Cited by 37 · see citing works
“Similarly, epileptic spikes and spontaneous seizures were detected following neonatal dCas9-based Scn1a activation (5), Scn1a upregulation in interneurons (8), and SUDEP (despite improved survival) was still evident following vector-mediated overexpression of Scn1b (9).”
InfluentialThe ice age – A review on formulation of Adeno-associated virus therapeutics
Grossen, P., Skaripa-Koukelli, I., van Haasteren, J., Machado, A. H. E., & Dürr, C. (2023) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2023.07.002 · Cited by 36 · see citing works
Current and Emerging Precision Therapies for Developmental and Epileptic Encephalopathies
Samanta, D., Bhatia, S., Hunter, S. E., Rao, C. K., Xiong, K., Karakas, C., Reeders, P. C., Erdemir, G., Sattar, S., Axeen, E. T., et al. (2025) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2025.04.010 · Cited by 37 · see citing works
Specchio, N., Trivisano, M., Aronica, E., Balestrini, S., Arzimanoglou, A. A., Colasante, G., Cross, J. H., Jóźwiak, S., Wilmshurst, J. M., Vigevano, F., et al. (2024) · The Lancet Child & Adolescent Health · doi:10.1016/s2352-4642(24)00196-2 · Cited by 35 · see citing works
“They achieved relevant decrease in hyperthermic-induced seizures when delivered in the pre-symptomatic stage in DS mice 81,82 .”
Epilepsy in Dravet Syndrome—Current and Future Therapeutic Opportunities
Gao, C., Pielas, M., Jiao, F., Mei, D., Wang, X., Kotulska, K., & Jóźwiak, S. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12072532 · Cited by 34 · see citing works
“1 protein levels in the brain, leading to a reduction of spontaneous and thermal-induced seizure frequency and elongated survival [82].”
BackgroundRecent Advances in Pharmacologic Treatments of Drug-Resistant Epilepsy: Breakthrough in Sight
Klein, P., Friedman, D. J., & Kwan, P. (2024) · CNS Drugs · doi:10.1007/s40263-024-01130-y · Cited by 32 · see citing works
Bialer, M., Johannessen, S. I., Koepp, M. J., Perucca, E., Perucca, P., Tomson, T., & White, H. S. (2024) · Epilepsia · doi:10.1111/epi.18056 · Cited by 31 · see citing works
Dwivedi, R., Kaushik, M., Tripathi, M., Dada, R., & Tiwari, P. (2024) · Brain Research · doi:10.1016/j.brainres.2024.149120 · Cited by 30 · see citing works
Epigenetic editing: from concept to clinic
Heller, E. A., Bintu, L., & Rots, M. G. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01323-0 · Cited by 31 · see citing works
Fahoum, F., & Eyal, S. (2023) · Epilepsia · doi:10.1111/epi.17625 · Cited by 28 · see citing works
Samanta, D. (2024) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2024.110171 · Cited by 27 · see citing works
Neurosurgical gene therapy for central nervous system diseases
Patel, R. V., Nanda, P., & Richardson, R. M. (2024) · Neurotherapeutics · doi:10.1016/j.neurot.2024.e00434 · Cited by 23 · see citing works
“In a murine model of Dravet syndrome, intraventricular injection of this construct led to increased SCN1A expression and voltage gated sodium channels in GABA interneurons with low off target expression in excitatory neurons [216].”
BackgroundAre Genetic Therapies for Epilepsy Ready for the Clinic?
Street, J. S., Qiu, Y., & Lignani, G. (2023) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597231176234 · Cited by 23 · see citing works
“In parallel, with the demonstration of a sufficient safety profile of the transcriptional activator ETX101 in NHPs, 6 the ENDEAVOR trial is a phase I/II clinical trial (NCT05419492) aiming to assess the safety and efficacy of ETX101 in infants and children with Dravet syndrome and is due to begin…”
InfluentialFan, H., Yang, M., Lin, L., Chiang, K.-L., & Chen, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010031 · Cited by 26 · see citing works
“The therapy has been shown to be effective in decreasing the frequency and intensity of seizures during postnatal days 26–28 and extended survival up to 470 days after treatment in a mouse model of DS [16].”
BackgroundState-of-the-art gene therapy in epilepsy
Walker, M. C. (2025) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001349 · Cited by 21 · see citing works
“This was effective in animal models and has been shown to be safe in nonhuman primates [31] This therapy is now entering clinical trials”
Boff, M. O., Xavier, F. A. C., Diz, F. M., Gonçalves, J. B., Ferreira, L. O., Zambeli, J., Pazzin, D. B., Previato, T. T. R., Erwig, H. S., Gonçalves, J. I. B., et al. (2025) · Cells · doi:10.3390/cells14090662 · Cited by 21 · see citing works
“AAVs can package around ~4.7 kb of DNA [122], whereas lentiviruses can carry larger amounts of genetic material, approximately ~9.8 kb [123].”
InfluentialBadonyi, M., & Marsh, J. A. (2025) · Nature Communications · doi:10.1038/s41467-025-63234-3 · Cited by 19 · see citing works
“Similar allele-speci fi c targeting approaches offer hope for treating DN conditions, such as collagen-related dystrophy 8 and long QT syndrome 9 .”
Mavashov, A., Brusel, M., Liu, J., Woytowicz, V., Bae, H., Chen, Y.-H., Dani, V. S., Cardenal‐Muñoz, E., Spinosa, V., Aibar, J. Á., et al. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1149391 · Cited by 17 · see citing works
“Multiple studies have used DS mice models to examine the therapeutic potential of current and novel drug treatments (Hawkins et al., 2017; Han et al., 2020; Isom and Knupp, 2021; Pernici et al., 2021; Tanenhaus et al., 2022).”
BackgroundRecent advances and current status of gene therapy for epilepsy
Cai, A., Gao, K., Zhang, F., & Jiang, Y. (2024) · World Journal of Pediatrics · doi:10.1007/s12519-024-00843-w · Cited by 17 · see citing works
“Preclinical studies in a Dravet syndrome model showed that an AAV9 vector expressing ETX101 reduces spontaneous seizures and extends survival, confirming the distribution and safety of this delivery sys-tem [142].”
Zhang, G., Huang, S., Wei, M., Wu, Y., Xie, Z., & Wang, J. (2025) · Frontiers in Neuroscience · doi:10.3389/fnins.2025.1634718 · Cited by 15 · see citing works
Viral Vector-Based Gene Therapy for Epilepsy: What Does the Future Hold?
Bettegazzi, B., Cattaneo, S., Simonato, M., Zucchini, S., & Soukupovà, M. (2023) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-023-00687-6 · Cited by 15 · see citing works
A hyperthermic seizure unleashes a surge of spreading depolarizations in Scn1a-deficient mice
Aiba, I., Ning, Y. Y., & Noebels, J. L. (2023) · JCI Insight · doi:10.1172/jci.insight.170399 · Cited by 15 · see citing works
Howell, K. B., White, S. M., McTague, A., D’Gama, A. M., Costain, G., Poduri, A., Scheffer, I. E., Chau, V., Smith, L., Stephenson, S. E. M., et al. (2025) · npj Genomic Medicine · doi:10.1038/s41525-025-00474-8 · Cited by 14 · see citing works
“Clinical trials of novel therapies for Dravet syndrome ( SCN1A loss-of-function phenotype), including AAV9 gene therapy and an antisense oligonucleotide, are underway 136,156 .”
Dravet Syndrome as an Example of Precision Medicine in Epilepsy
Sullivan, J. E., & Wirrell, E. C. (2022) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597221106281 · Cited by 14 · see citing works
Chou, S.-W., Mortberg, M. A., Marlen, K., Ojala, D. S., Parman, T., Howard, M., DeSouza-Lenz, K., Lian, Y., Mehrabian, M., Tiffany, M. R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.05.636713 · Cited by 14 · see citing works
Ricobaraza, A., Buñuales, M., González-Aparicio, M., Fadila, S., Rubinstein, M., Vides-Urrestarazu, I., Banderas, J., Sola-Sevilla, N., Sánchez-Carpintero, R., Lanciego, J. L., et al. (2023) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02383-8 · Cited by 13 · see citing works
Tang, S., Stamberger, H., Calhoun, J. D., Weckhuysen, S., & Carvill, G. L. (2025) · JCI Insight · doi:10.1172/jci.insight.188014 · Cited by 13 · see citing works
Temporal manipulation of the Scn1a gene reveals its essential role in adult brain function
Berardino, C. D., Mainardi, M., Brusco, S., Benvenuto, E., Broccoli, V., & Colasante, G. (2023) · Brain · doi:10.1093/brain/awad350 · Cited by 13 · see citing works
“7-9 We have previously reported that Scn1a gene reactivation after symptom onset in a Dravet genetic background can recover most symptoms, 10 indicating that efficient gene/genetic therapies aiming at re-establishing physiological levels of Na v 1.1 in different brain regions can be effective as a…”
BackgroundInfluentialAeran, R., Tanenhaus, A., Sears, S. M. S., Moerke, N. J., Miller, A., Artur, C., Bouhlal, Y., Bove, P. F., de Arce, A. J. D., Shimizu, S., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.05.011 · Cited by 12 · see citing works
“38 For mouse studies, rAAV9 vectors were produced in an adherent HEK293 system and purified by CsCl centrifugation or iodixanol gradient.”
InfluentialSelf-citationPharmacotherapeutic strategies for drug-resistant epilepsy in children
Auvin, S., & Specchio, N. (2024) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2024.110139 · Cited by 12 · see citing works
A novel rat model of Dravet syndrome recapitulates clinical hallmarks
Li, M., Yang, L., Qian, W., Ray, S., Lu, Z., Liu, T., Zou, Y., Naumann, R. K., & Wang, H. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106193 · Cited by 13 · see citing works
“Another type of strategy is to selectively target interneurons and enhance their activity with the assistance of viral vectors (Tanenhaus et al., 2022).”
BackgroundAAV-mediated interneuron-specific gene replacement for Dravet syndromePreprint
Mich, J. K., Ryu, J., Wei, A. D., Gore, B. B., Guo, R., Bard, A. M., Martinez, R. A., Bishaw, Y. M., Luber, E. M., Oliveira, L. M., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.15.571820 · Cited by 12 · see citing works
Kumagai, S., Nakajima, T., & Muramatsu, S. (2024) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2024.2386339 · Cited by 11 · see citing works
Therapeutic development approaches to treat haploinsufficiency diseases: restoring protein levels
Evans, E. F., Shyr, Z. A., Traynor, B. J., & Zheng, W. (2024) · Drug Discovery Today · doi:10.1016/j.drudis.2024.104201 · Cited by 13 · see citing works
SCN1A as a therapeutic target for Dravet syndrome
Myers, K. A. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2230364 · Cited by 11 · see citing works
“described a similar but more targeted AAV-mediated approach to achieve SCN1A replacement in both mice and non-human primates [47].”
BackgroundBarker‐Haliski, M. L., & Hawkins, N. A. (2024) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2024.2384455 · Cited by 10 · see citing works
“Additionally, gene therapies are providing exciting advancements to reduce SRS and mortality in Scn1a mice [56,57].”
Gene therapy for epilepsy: An emerging, promising approach for a serious neurological disorder
Ledri, M., & Kokaia, M. (2025) · Journal of Internal Medicine · doi:10.1111/joim.70059 · Cited by 9 · see citing works
“Transcriptional activation of SCN1A by either engineered transcription factors or CRISPRa has also demonstrated therapeutic potential in Dravet syndrome [33–35].”
Metabolic aspects of genetic ion channel epilepsies
Neal, E. S., Xu, W., & Borges, K. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15938 · Cited by 9 · see citing works
“Increasing SCN1A expression with antisense oligonucleotides or with AAV- 9-based gene therapy has been successful in mouse models of Dravet syndrome (Han et al., 2020 ; Lim et al., 2020; Tanenhaus et al., 2022 ), and trials in humans are underway (Sullivan & Wirrell, 2023 ).”
Sudden Unexpected Death in Epilepsy: Central Respiratory Chemoreception
Dereli, A. S., Apaire, A., & Tahry, R. E. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26041598 · Cited by 8 · see citing works
“1 protein levels [260,261].”
Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome
Shao, W., Liu, L., Gu, J., Yang, Y., Wu, Y., Zhang, Z., Xu, Q. Y., Wang, Y., Shen, Y. L., Gu, L., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03304-8 · Cited by 8 · see citing works
“The ef fi cacy of ETX101 has also been validated in preclinical studies: ETX101 administration reduced seizures and the risk of sudden death in DS mice and was well tolerated in nonhuman primates, and this medicine will probably start clinical trials soon [170].”
Precision medicine for sodium channelopathy-related autism and epilepsy
Robinson, M. J., Wettschurack, K. W., Halurkar, M. S., Chen, X., Zhang, Z., Zhang, J., & Yang, Y. (2025) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2025.09.007 · Cited by 8 · see citing works
“1 expression and alleviates seizures [87].”
Guo, J., Min, D., Farrell, E. K., Zhou, Y., Faingold, C. L., Cotten, J. F., & Feng, H. (2024) · Epilepsia · doi:10.1111/epi.17966 · Cited by 8 · see citing works
Potential for Therapeutic Alteration of the Underlying Biology of Epilepsy
Sperling, M. R., Peters, J. M., Wu, Q., Guignet, M. A., White, H. S., Shih, E. K., Ngo, L. Y., Carrazana, E. J., & Rabinowicz, A. L. (2025) · Biomedicines · doi:10.3390/biomedicines13092258 · Cited by 7 · see citing works
“Multiple phase 1/2 studies are currently examining ETX101, an AAV serotype 9 (AAV9) gene therapy designed to express voltage-gated sodium channels (Na V 1.1) in GABAergic inhibitory interneurons [64] in children with SCN1A -positive Dravet syndrome [148–150].”
InfluentialTchaicha, S., Auvin, S., Beniczky, S., Brunklaus, A., Lagae, L., Perucca, E., Surges, R., Adler, S., Helmstaedter, C., Jansen, F. E., et al. (2026) · Epilepsia Open · doi:10.1002/epi4.70210 · Cited by 7 · see citing works
Adeno-Associated Viral Vectors in the Treatment of Epilepsy
Mullagulova, A. I., Евгеньевна, Т. Е., Solovyeva, V. V., Yakimov, A. M., Ibrahim, A., Дмитренко, Д. В., Sufianov, A. A., Суфианова, Г. З., & Rizvanov, A. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212081 · Cited by 10 · see citing works
Sullivan, J. E., Perry, M. S., Scheffer, I. E., Wheless, J. W., Boronat, S., Brunklaus, A., Laux, L., Patel, A. D., Roberts, C. M., Dlugos, D., et al. (2025) · Epilepsia · doi:10.1111/epi.70015 · Cited by 6 · see citing works
“31,32 34 Preliminary clinical data indicate benefits on cognition and behavior, as measured by VABS-3.”
Self-citationGene therapy for Dravet syndrome: promises and impact on disease trigger and secondary modifications
Berardino, C. D., Massimino, L., Ungaro, F., & Colasante, G. (2024) · Rare Disease and Orphan Drugs Journal · doi:10.20517/rdodj.2024.07 · Cited by 6 · see citing works
McTague, A., Scheffer, I. E., Kullmann, D. M., & Sisodiya, S. M. (2024) · Handbook of clinical neurology · doi:10.1016/b978-0-323-90820-7.00016-1 · Cited by 6 · see citing works
Sang, Y., Xu, L., & Bao, Z. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.10.029 · Cited by 7 · see citing works
From Symptomatic Therapies to Disease-Modifying Approaches for Neuronal Sodium Channel Disorders
Dinoi, G., Canfora, I., D’Agnano, D., Boccanegra, B., Conte, E., Luca, A. D., Liantonio, A., Sciruicchio, V., & Imbrici, P. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms27010032 · Cited by 5 · see citing works
“No relevant adverse clinical or histopathological findings were reported [5,27].”
InfluentialBalestrini, S., & Scheffer, I. E. (2026) · CNS Drugs · doi:10.1007/s40263-026-01276-x · Cited by 8 · see citing works
Veltra, D., Theodorou, V., Katsalouli, M., Vorgia, P., Niotakis, G., Tsaprouni, T., Pons, R. M., Kosma, K., Kampouraki, A., Tsoutsou, I., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25115644 · Cited by 5 · see citing works
“Antisense oligonucleotides restoring functional SCN1A mRNA, adeno-associated virus delivered gene regulation and dCas9-based SCN1A gene activation are some of the genomics-driven therapies focusing on seizure control in SCN1A-related therapies [49–51].”
BackgroundRecent progress and challenges in gene therapy for pharmacoresistant focal epilepsy
Kullmann, D. M. (2025) · Revue Neurologique · doi:10.1016/j.neurol.2025.02.008 · Cited by 5 · see citing works
Hammer, M. F. (2025) · Bioscience Reports · doi:10.1042/bsr20253356 · Cited by 5 · see citing works
Novel pharmacological therapies in development
Perucca, P., & Perucca, E. (2026) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001456 · Cited by 4 · see citing works
Voltage-Gated Sodium Channels as Drug Targets in Epilepsy-Related Sodium Channelopathies
Wengert, E. R., Miralles, R. M., & Patel, M. K. (2024) · Springer eBooks · doi:10.1007/978-3-031-52197-3_4 · Cited by 4 · see citing works
A crash course in genomics for epilepsy clinicians
Moloney, P. B., & Delanty, N. (2025) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2025.110553 · Cited by 3 · see citing works
Li, N., Yan, L., Peng, A., Fu, X., Qin, H., & Yao, K. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00260 · Cited by 3 · see citing works
“1 expression can significantly improve clinical symptoms (Tanenhaus et al., 2022; Gao et al., 2023).”
Gallucci, A., Potet, F., Santos, S., Lin, Z., Theile, J. W., Yoger, K., Ren, W., Wang, L., Lebreton, S., Attinost, I., et al. (2025) · Molecular Pharmacology · doi:10.1016/j.molpha.2025.100072 · Cited by 3 · see citing works
Genetic therapies for neurological diseases
Rahim, A. A., Kurian, M. A., Zhou, H., Ferguson, R., Tabrizi, S. J., Lignani, G., Aquilina, K., & Waddington, S. N. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100093 · Cited by 4 · see citing works
Dravet syndrome therapeutics: where are we, what works, and what’s next?
Bagchi, V. A., Ziobro, J. M., & Isom, L. L. (2025) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2025.2576608 · Cited by 3 · see citing works
“1 protein, restored interneuron function, reduced spontaneous and hyperther-mia-induced seizures, and improved survival [93].”
Engineering a human-based translational activator for targeted protein expression restoration
Sinnott, R. W., Solanki, A., Govind, A. P., Green, W. N., & Dickinson, B. C. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag113 · Cited by 3 · see citing works
“Genomic-level technologies include gene supplementation us-ing dual-AAVs or adenovirus due to SCN1a ’s large size, or gene activation with CRISPR/dCas9 or zinc finger transcriptional activator fusions [ 27 , 66 –69 ].”
Novel epilepsy treatments in clinical development
Mesraoua, B., Abou-Khalil, B. W., Lattanzi, S., Asadi‐Pooya, A. A., Hail, H. A., AbuAlrob, M. A., & Perucca, E. (2026) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2026.110970 · Cited by 3 · see citing works
Dopamine Dilemma Overexcites the Hippocampus in Alzheimer's Disease
Wong, J. C. (2024) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597241280475 · Cited by 3 · see citing works
“11 Further research into the clinical use of D2 receptor agonists for the treatment of epilepsy is therefore warranted.”
BackgroundInvestigational new drugs for the treatment of Dravet syndrome: an update
Јаnkovic, S., Janković, S. V., Vojinovic, R. H., & Lukić, S. (2023) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2023.2193680 · Cited by 2 · see citing works
“significant side effects, and a good distribution of the vector in the brain and transgene expression were recorded [22].”
BackgroundCore Features Differentiate Dravet Syndrome from Febrile Seizures
Nordli, D. R., Nordli, D. R., & Galán, F. (2023) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2023.113416 · Cited by 3 · see citing works
Fine, A. L. (2024) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597241280687 · Cited by 3 · see citing works
“VABS-III showed similar fi ndings in the <2 years group; mean receptive raw scores increased from 27.5 ( SD = 16.4) at baseline to 38.3 ( SD = 16.1) at Month 12 (95% CI = 5.7 – 13.9) while expressive scores increased from 23.7 ( SD = 11.5) to 35.5 ( SD = 17.0, mean delta = 11.8, 95% CI = 6.8 – 16.7).”
MethodInfluentialChilcott, E. M., Diaz, J. F. A., Almacellas‐Barbanoj, A., Moore, M., Keegan, A., Waddington, Z., Fang, V., Schorge, S., Lignani, G., Waddington, S. N., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.18.664895 · Cited by 3 · see citing works
“S2E), consistent with previous studies (21, 27, 29) .”
Sakla, M., Breitinger, U., Breitinger, H., Mansour, S., & Tammam, S. N. (2023) · Current Pharmaceutical Design · doi:10.2174/1381612829666230601122846 · Cited by 2 · see citing works
Emerging Genetic Therapies in Epilepsy
Sullivan, J. E., & Hood, V. L. (2025) · Seminars in Neurology · doi:10.1055/a-2544-1530 · Cited by 2 · see citing works
“13 Given the preclinical validation of the TANGO platform in amousemodel of Dravetsyndromedemonstratingreduction in seizures and improved survival, the next step was to bring this platform into a human clinical trial.”
Potschka, H., & Pérez‐Pérez, D. (2025) · Epilepsia · doi:10.1111/epi.18581 · Cited by 2 · see citing works
“7,8 In this critical review, we provide an overview of pre-clinical studies that have assessed antiseizure medications (ASMs) already licensed as orphan drugs for DEEs.”
Depolarization block induction via slow NaV1.1 inactivation in Dravet syndrome
Lemaire, L., Desroches, M., Rodrigues, S., & Campillo, F. (2025) · Scientific Reports · doi:10.1038/s41598-025-17468-2 · Cited by 2 · see citing works
“Despite partially effective drugs such as stiripentol 10 , fenfluramine 11,12 or cannabidiol 13 and promising novel approaches like disease-modifying and genetic therapies 14–17 , DS remains drug resistant for most patients 18,19 .”
Yang, K., Geng, Y., Zhou, W., Zhang, L., Xu, Z., Wang, J., Li, F., & Qiu, Z. (2026) · Biological Psychiatry · doi:10.1016/j.biopsych.2026.03.999 · Cited by 2 · see citing works
Prime editing of a pathogenic Scn1a allele ameliorates seizure phenotypes in a GEFS + mouse model
Kissling, L., Pietrafesa, F., Ranucci, M., Böck, D., Mathis, N., Kulcsár, P. I., Ioannidi, E. I., Schmidheini, L., Tálas, A., Villiger, E. A., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.adz2557 · Cited by 2 · see citing works
Targeted Treatments for Genetic Epilepsies, Part 1: Channelopathies
Hunter, S. E., Cardwell, E. B., Lea, J. K., Rao, C. K., Samanta, D., Karamian, A. G. S., Karakas, C., Erdemir, G., Fan, Z., Xiong, K., et al. (2026) · Current Treatment Options in Neurology · doi:10.1007/s11940-026-00873-x · Cited by 2 · see citing works
Gentherapien für Epilepsie: Klinische Studien sind auf dem Weg
Müller, P., & Lerche, H. (2023) · Fortschritte der Neurologie · Psychiatrie · doi:10.1055/a-1995-5405 · Cited by 2 · see citing works
“In einem Mausmodell für das Dravet-Syndrom reduzierte dies die Anfallsrate um etwa 70 % und nach 90 Tagen lebten noch 100 % der behandelten Tiere, im Gegensatz zu 50 % der unbehandelten [28].”
BackgroundSilva-Cardoso, G. K., & N’Gouemo, P. (2023) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2023.2248375 · Cited by 2 · see citing works
Mahesan, A., Kamila, G., & Gulati, S. (2024) · Annals of Indian Academy of Neurology · doi:10.4103/aian.aian_49_24 · Cited by 3 · see citing works
Regulatory Elements for Gene Therapy of Epilepsy
Chesnokova, E., Bal, N. V., Alhalabi, G., & Balaban, P. M. (2025) · Cells · doi:10.3390/cells14030236 · Cited by 2 · see citing works
Scott, R. C., Hsieh, J., McTague, A., Mahoney, J. M., & Christian, C. A. (2025) · Epiliepsy currents/Epilepsy currents · doi:10.1177/15357597251320142 · Cited by 2 · see citing works
Zhu, L., Demetriou, Y., Barden, J., Disla, J., Zhao, M., & Mattis, J. (2025) · Epilepsia · doi:10.1111/epi.18532 · Cited by 2 · see citing works
Mavashov, A., Turk, S., Sarusi, Y., Brusel, M., Perry, R. B., Quinn, S., Almog, Y., Vilian, K., Ulitsky, I., & Rubinstein, M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.03.18.643778 · Cited by 2 · see citing works
Dravet Syndrome: Past, Present, and Future
Liu, Y.-H., Kuo, C., Chou, I., Hsu, T., Lin, K., & Society for Neurological Rare Disorders-Taiwan (2025) · Acta Neurologica Taiwanica · doi:10.4103/ant.ant-d-25-00005 · Cited by 1 · see citing works
Uncovering targets and molecular pathways for personalizing treatment in epilepsy
Rosa, F., & Lerche, H. (2026) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2026.2638746 · Cited by 1 · see citing works
“…(e.g. using Targeted Augmentation of Nuclear Gene Output (TANGO) technology) [23,24,59,60] or by activating SCN1A expression via viral delivery of either a specific SCN1A transcription factor (ETX101) [25] or a CRISPRa [33] that lacks nuclease function but recruits transcription factors.”
Mir, M. Y., Seh, B. A., Rafiq, K., & Légrádi, Á. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27062845 · Cited by 1 · see citing works
“An AAV9-delivered engineered transcription factor designed to selectively enhance Scn1a transcription in GABAergic neurons significantly reduced spontaneous seizures and improved survival in mouse models of Dravet syndrome [56].”
Genetic medicines for epilepsy: unlocking new avenues for seizure control
Wee, I. C., Przybyla, M., Touma, J., Ittner, L. M., & van Eersel, J. (2026) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2026.1768550 · Cited by 1 · see citing works
“A variety of strategies have been applied to reduce expression of the UBE3A antisense transcript, including the use of ASOs, Cas9, zinc finger nucleases and a chemically modified-gapmer ASO (single-stranded RNA-DNA-RNA molecules designed to induce cleavage of a target RNA) (Milazzo et al., 2021; Meng et al., 2015; Baz…”
InfluentialZhang, L., Ma, R., Meng, X., & Tao, Y. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.106802 · Cited by 1 · see citing works
Bialer, M., Landmark, C. J., Koepp, M. J., Perucca, E., Perucca, P., Tomson, T., White, H. S., & Wirrell, E. C. (2026) · Epilepsia · doi:10.1002/epi.70346 · Cited by 1 · see citing works
Wang, X., Lin, X., He, H., & Peng, J. (2023) · PubMed Central · doi:10.11817/j.issn.1672-7347.2023.220639 · Cited by 1 · see citing works
- Authors
- Tanenhaus, A., Stowe, T., Young, A., McLaughlin, J., Aeran, R., Lin, I. W., Li, J., Hosur, R., Chen, M., Leedy, J., Chou, T., Pillay, S., Vila, M. C., Kearney, J. A., Moorhead, M., Belle, A., & Tagliatela, S.
- Affiliations
- Encoded Therapeutics, Inc., South San Francisco, California, USA.
- Northwestern University (US)
- Corresponding author
- Tagliatela, Stephanie
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2022-06
- Volume
- 33
- Issue
- 11-12
- Pages
- 579-597
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- PMC
- PMC9242722
- OpenAlex
- W4224133987
- Cited by
- 124
- References
- 72
- Citations by year
- 2026: 26 · 2025: 39 · 2024: 27 · 2023: 28 · 2022: 4
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Human Gene Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Dravet syndrome, SCN1A, AAV9, haploinsufficiency, seizures, developmental and epileptic encephalopathy, vector biodistribution, intracerebroventricular administration, mouse model
- MeSH terms
- Epileptic Syndromes, Dependovirus, Animals, Disease Models, Animal, Epilepsies, Myoclonic, gamma-Aminobutyric Acid, Phenotype, Primates, Seizures, Spasms, Infantile, Tissue Distribution, Mice, NAV1.1 Voltage-Gated Sodium Channel
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
