RARE DISEASE
Dravet syndrome
Dravet syndrome
Dravet syndrome
Synonyms: SMEI, Severe myoclonic epilepsy of infancy, Severe myoclonus epilepsy of infancy
Synonyms: SMEI, Severe myoclonic epilepsy of infancy, Severe myoclonus epilepsy of infancy
Synonyms: SMEI, Severe myoclonic epilepsy of infancy, Severe myoclonus epilepsy of infancy
Drug discovery
27
drugs
With orphan designations
Overview
Dravet syndrome is a severe developmental and epileptic encephalopathy caused predominantly by SCN1A mutations (85% of cases), characterized by refractory seizures onset in infancy, prolonged febrile seizures, and diverse seizure types evolving with age. Key features include developmental delays, intellectual disability, motor impairments, and comorbidities like sleep disorders and autonomic dysfunction. Treatment focuses on seizure control while avoiding sodium channel blockers, with emerging gene-targeted therapies in clinical trials [1][5][6][17].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,154 drug discovery papers about Dravet syndrome, with 2 first-in-class and 67 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,154 drug discovery papers about Dravet syndrome, with 2 first-in-class and 67 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-06 | Beyond seizures in Dravet and Lennox-Gastaut syndromes - An Italian Expert Consensus on Non-Seizure issues and the role of fenfluramine.
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies (DEEs) in which disability and family burden are driven by seizures and non-seizure issues (NSIs), including cognition, behavior, sleep, communication, motor function, and adaptive abilities. To develop practical consensus statements on NSIs in DS and LGS, integrating NSI evaluation within a DEE framework and appraising the perceived role of fenfluramine (FFA). An Italian panel of 12 epilepsy specialists spanning pediatric and adult practice developed statements using an Estimate-Talk-Estimate process. Consensus was predefined as ≥ 70% agreement (agree/strongly agree). Eleven final statements were clustered into three macro-areas, with the first two explored in greater depth: (1) the cross-cutting, lifespan impact of NSIs in DS and LGS; (2) the potential for FFA to provide clinically meaningful benefits across selected NSI domains in DS and, more variably, in LGS, with effects not always fully captured by seizure metrics; and (3) the role of other interventions on NSIs and the need for structured assessment tools. Incorporating NSI priorities into shared goal-setting and longitudinal monitoring may improve the clinical relevance of care in DS and LGS. The panel supported an NSI-informed, net-benefit approach to treatment optimization and identified FFA as a relevant option, while recognizing that evidence on NSI outcomes remains heterogeneous and should be strengthened through syndrome-specific, longitudinal assessment.
2026-07-30 | cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy.
Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.
2026-07-29 | A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Nonseizure outcomes.
A plant-derived, highly purified cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU]) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC). Improvements in nonseizure outcomes including cognition and behavior have been reported in patients with epilepsy administered CBD. This systematic literature review (SLR) evaluated studies reporting changes in nonseizure outcomes after CBD initiation in patients with developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs) other than LGS, DS, and TSC. An SLR was conducted in March 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline, and Cochrane Central Register of Controlled Trials libraries were searched for studies on TREs, CBD, nonseizure outcomes, and adverse events (AEs). Results were narratively summarized. Thirty-two studies comprising 1343 patients were included. Thirty-one studies reported improvement in nonseizure outcomes in ≥ 1 patient, including neuropsychiatric function (n = 9/9 studies), cognitive function (n = 9/9), use of concomitant antiseizure medications (n = 7/8), communication (n = 7/7), behavior (n = 7/7), motor function (n = 6/6), healthcare utilization (n = 5/5), quality of life (n = 5/5), global change (n = 4/4), sleep (n = 2/2), and development (n = 2/2). Reported AEs were consistent with the known safety profile of CBD and most commonly gastrointestinal, including diarrhea (17-34%), vomiting (5-50%), and decreased appetite (7-20%). This SLR mainly identified observational studies with moderate to high bias risk. The available evidence suggests CBD may improve various nonseizure outcomes in patients with DEEs and complex TREs, while underscoring the need for rigorous confirmatory studies.
2026-07-06 | Perampanel in Chinese patients with Dravet syndrome: Efficacy and tolerability assessed via a multicenter, prospective, real-world observational study.
As a third-generation antiseizure medication, the efficacy of perampanel in treating Dravet syndrome (DS) remains incompletely characterized. This multicenter, prospective, real-world observational study aimed to evaluate the efficacy and long-term tolerability of perampanel as adjunctive therapy in Chinese patients with DS. Patients with unresolved DS were enrolled from four participating hospitals in China between January 2019 and December 2023. All patients received perampanel as add-on therapy. Efficacy and retention rate were evaluated at 3, 6, and 12 months of perampanel treatment. Genetic screening for SCN1A mutations was performed in all enrolled patients. Fifty-six patients were enrolled, of whom 48 (85.71%) harbored SCN1A mutations. The mean treatment duration of perampanel was 25.00 ± 7.65 months, with a mean maximum daily perampanel dose of 3.94 ± 1.19 mg. The retention rates at 6 and 12 months were 69.64% and 64.29%, respectively. After 6 and 12 months of treatment, the ≥50% responder rates were 66.07% and 60.71%, while seizure-freedom rates were 21.43% and 12.50%, respectively. Seizure exacerbation occurred in three patients (5.36%). Adverse events occurred in six patients during treatment (three discontinued treatment), with no new safety concerns identified. Among 30 patients with ≥50% seizure frequency reduction throughout 12-month treatment who carried SCN1A mutations, 33.33% had truncating mutations, 46.67% had missense mutations, 13.33% had splice site mutations, 3.33% had in-frame mutations, and 3.33% had large chromosomal deletions encompassing SCN1A. No significant difference in the ≥50% seizure frequency reduction rate was observed between patients with SCN1A truncating mutations and those with missense mutations. Additionally, treatment response to perampanel did not differ significantly according to the specific mutation regions within the Nav1.1 sodium channel. Perampanel demonstrated favorable efficacy and acceptable long-term tolerability as adjunctive therapy in Chinese patients with DS. The efficacy of perampanel remained consistent regardless of the specific genotype or location of SCN1A mutations.
2026-07-05 | Prolonged fenfluramine use in open-label studies of Dravet or Lennox-Gastaut syndromes: Long-term safety, tolerability, patient global functioning, and considerations for interpreting effectiveness.
Long-term safety and global functioning are reported in patients with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS) treated with fenfluramine in an open-label extension (OLE) study after participating in a previous open-label feeder study. Patients could enroll in this international, multicenter OLE (NCT03936777) after completing one of three fenfluramine open-label studies. The latest feeder study fenfluramine dose was continued, then flexibly titrated (maximum: .7 mg/kg/day [26 mg/day] without stiripentol or .4 mg/kg/day [17 mg/day] with stiripentol), with ≥1 concomitant antiseizure medication administered. Primary endpoint was fenfluramine long-term safety/tolerability. Global functioning using caregiver- and investigator-reported Clinical Global Impression of Improvement (CGI-I) ratings, globally and for subdomains (cognition, behavior, motor function), at last visit relative to study baseline was evaluated. Overall treatment exposure and age groups were analyzed post hoc. A total of 412 patients enrolled (DS: 265 [64.3%], LGS: 147 [35.7%]); 30.8% were ≥18 years old. Median fenfluramine treatment duration in this OLE was 729.5 days (range = 8-1544), and overall median fenfluramine exposure, including feeder studies, was 1464.5 days (range = 171-2800). In this OLE, ≥1 treatment-emergent adverse event (TEAE) was reported in 311 (75.5%) patients; fenfluramine-related (per investigator) serious TEAEs were reported in five (1.2%) patients. Three patients died in this OLE (deemed unrelated to fenfluramine by investigators). After starting this OLE already receiving fenfluramine, 373 of 401 (93.0%) and 376 of 401 (93.8%) patients were rated by caregiver and investigator, respectively, as "improved or no change" on CGI-I versus this study baseline; subdomain ratings of "improved or no change" were largely consistent with global assessment. In our OLE study of patients with DS or LGS treated with fenfluramine (up to 4 years), no new or unexpected safety signals were observed; global functioning was improved or stable (vs. study baseline) in >90% of patients, supporting long-term fenfluramine use in pediatric and adult patients with DS or LGS.
cell therapies
2026-05-02 | Movement Disorders in Developmental and Epileptic Encephalopathies.
Monogenic developmental and epileptic encephalopathies (DEE) frequently feature co-occurring movement disorders. Gene discovery has expanded epilepsy-dyskinesia syndromes (EDS) from classic associations such as stereotypies in Rett syndrome to PRRT2-related infantile seizures with paroxysmal dyskinesia and crouched gait in SCN1A-associated Dravet syndrome. To outline the movement disorders spectrum in EDS, propose a pragmatic syndrome-based clinical framework, group implicated genes into mechanistic categories, highlight selected genotype-phenotype correlations, and summarize symptomatic and precision therapeutic options. A non-systematic, structured literature review identified monogenic disorders reported with EDS, grouping publications into four tiers: multi-etiology cohorts; small series and narrative/systematic reviews; single-gene or pathway-focused reports; and mechanistic/therapeutic studies. Eight cohort studies and multiple tier 2-3 series and reviews yielded 245 single-gene associations, most mapping to ion channel and synaptic signaling pathways. Across DEE cohorts, movement disorders occurred in roughly one-quarter to over one-half of patients, were often hyperkinetic (notably dystonia and stereotypies), and frequently combined multiple phenomenologies. We grouped clinical presentations into early and late infantile-onset EDS, Rett and Rett-like syndromes, paroxysmal/episodic and relapsing-remitting disorders, disorders with severe acute motor exacerbations, and hypokinetic/progressive phenotypes. Treatments are guided by gene- and mechanism-informed strategies including sodium-channel blockers, glutamatergic modulators, ketogenic diet, agents for paroxysmal dyskinesias, and deep brain stimulation in life-threatening crises. Movement disorders are common, often severe, and genetically heterogeneous across EDS. A syndrome-based approach integrating clinical features, neuroimaging, and broad genetic testing (including copy number variants and repeat expansions) can guide symptomatic management and emerging precision therapies.
2024-04-18 | Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8
ABSTRACT Dravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed to SCN1A haploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion of Scn1a recapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier ( Dsm ) loci, Dsm2 on chromosome 7 and Dsm3 on chromosome 8, using interval-specific congenic (ISC) mapping. Dsm2 was complex and encompassed at least two separate loci, while Dsm3 was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes for Dsm2 include Nav2, Ptpn5, Ldha, Dbx1, Prmt3 and Slc6a5 , while Dsm3 has a single high priority candidate, Psd3 . This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.
2023-01-24 | The Generation of Human iPSC Lines from Three Individuals with Dravet Syndrome and Characterization of Neural Differentiation Markers in iPSC-Derived Ventral Forebrain Organoid Model.
Dravet syndrome (DRVT) is a rare form of neurodevelopmental disorder with a high risk of sudden unexpected death in epilepsy (SUDEP), caused mainly (>80% cases) by mutations in the SCN1A gene, coding the Nav1.1 protein (alfa-subunit of voltage-sensitive sodium channel). Mutations in SCN1A are linked to heterogenous epileptic phenotypes of various types, severity, and patient prognosis. Here we generated iPSC lines from fibroblasts obtained from three individuals affected with DRVT carrying distinct mutations in the SCN1A gene (nonsense mutation p.Ser1516*, missense mutation p.Arg1596His, and splicing mutation c.2589+2dupT). The iPSC lines, generated with the non-integrative approach, retained the distinct SCN1A gene mutation of the donor fibroblasts and were characterized by confirming the expression of the pluripotency markers, the three-germ layer differentiation potential, the absence of exogenous vector expression, and a normal karyotype. The generated iPSC lines were used to establish ventral forebrain organoids, the most affected type of neurons in the pathology of DRVT. The DRVT organoid model will provide an additional resource for deciphering the pathology behind Nav1.1 haploinsufficiency and drug screening to remediate the functional deficits associated with the disease.
2022-04-07 | Ameliorating Effect of Umbilical Cord Mesenchymal Stem Cells in a Human Induced Pluripotent Stem Cell Model of Dravet Syndrome.
Dravet syndrome (DS) is a form of severe childhood-onset refractory epilepsy typically caused by a heterozygous loss-of-function mutation. DS patient-derived induced pluripotent stem cells (iPSCs) are appropriate human cells for exploring disease mechanisms and testing new therapeutic strategies in vitro. Repeated spontaneous seizures can cause neuroinflammatory reactions and oxidative stress, resulting in neuronal toxicity, neuronal dysfunction, blood-brain barrier disruption, and hippocampal inflammation. Antiepileptic drug therapy does not delay the development of chronic epilepsy. The application of mesenchymal stem cells (MSCs) is one therapeutic strategy for thwarting epilepsy development. This study evaluated the effects of human umbilical cord mesenchymal stem cell-conditioned medium (HUMSC-CM) in a new in vitro model of neurons differentiated from DS patient-derived iPSCs. In the presence of HUMSC-CM, increases in superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), glutathione peroxidase (GPX), and glutathione (GSH) levels were found to contribute to a reduction in reactive oxygen species (ROS) levels. In parallel, inflammation was rescued in DS patient-derived neuronal cells via increased expression of anti-inflammatory cytokines (TGF-β, IL-6, and IL-10) and significant downregulation of tumor necrosis factor-α and interleukin-1β expression. The intracellular calcium concentration ([Ca2+]i) and malondialdehyde (MDA) and ROS levels were decreased in DS patient-derived cells. In addition, action potential (AP) firing ability was enhanced by HUMSC-CM. In conclusion, HUMSC-CM can effectively eliminate ROS, affect migration and neurogenesis, and promote neurons to enter a highly functional state. Therefore, HUMSC-CM is a promising therapeutic strategy for the clinical treatment of refractory epilepsy such as DS.
2021-07-28 | Application of induced pluripotent stem cells in epilepsy.
Epilepsy is among the most common neurological disorders, affecting approximately 50 million people worldwide. Importantly, epilepsy is genetically and etiologically heterogenous, but several epilepsy types exhibit similar clinical presentations. Epilepsy-associated genes are being identified. However, the molecular pathomechanisms remain largely unknown. Approximately one-third of epilepsy is refractory to multiple conventional anti-epileptic drugs (AEDs). Induced pluripotent stem cells (iPSCs) provide an excellent tool to study the pathomechanisms underlying epilepsy and to develop novel treatments. Indeed, disease-specific iPSCs have been established for several genetic epilepsies. In particular, the molecular mechanisms underlying certain developmental and epileptic encephalopathies, such as Dravet syndrome, have been revealed. Modeling epilepsy with iPSCs enables new drug development based on the elucidated pathomechanisms. This can also be used to evaluate conventional AEDs and drug repurposing. Furthermore, transplanting neuronal cells derived from iPSCs into the brain has great potential to treat refractory epilepsies. Recent advances in iPSC technology have enabled the generation of neuronal organoids, or "mini brains." These organoids demonstrate electrophysiological activities similar to those of the brain and have the potential for extensive epilepsy research opportunities. Thus, the application of iPSCs in epilepsy provides insight into novel treatments based on the molecular pathomechanisms of epilepsy. In this review, we comprehensively discuss the studies conducted on iPSCs established for genetic epilepsy or epilepsies without major structural dysmorphic features.
gene therapies
2026-07-14 | PV interneuron-targeted CRISPRa rescue of SCN1A haploinsufficiency in Dravet syndrome
Dravet syndrome is a severe epileptic encephalopathy caused by SCN1A haploinsufficiency, which leads to reduced Na V 1.1 expression in parvalbumin (PV)-expressing interneurons and disrupted excitatory-inhibitory balance in the brain. We developed an AAV-based CRISPR activation system (AAV9-E2-dCas9-VP64) to selectively upregulate SCN1A from its endogenous locus in PV interneurons. An in vitro saturating guide RNA (gRNA) screen across the human SCN1A promoter identified a lead guide with robust and highly specific engagement of the SCN1A locus. This lead gRNA was validated in human Dravet syndrome model GABAergic neurons, where dose-dependent and specific SCN1A upregulation was observed. Intracerebroventricular (ICV) administration in a mouse model of Dravet syndrome produced dose-dependent improvement in survival as well as reduced susceptibility to hyperthermia-induced seizures and increased Na V 1.1 protein expression, with maintained PV interneuron selectivity and minimal off-target expression. In a study in juvenile cynomolgus macaques, MRI-guided ICV administration of the vector was well tolerated, achieved broad cortical biodistribution, and maintained strong detargeting of peripheral tissues, with substantially lower peripheral dCas9 expression relative to the brain. These results support PV interneuron-selective SCN1A gene modulation via CRISPR activation as a promising therapeutic strategy for Dravet syndrome. AAV9-E2-dCas9-VP64 (RT101) is currently in preclinical development and is being advanced toward evaluation in the clinic.
2026-06-12 | Lost in Sleep Transition: Tangled Sleep and Thermoregulation in Dravet Syndrome
Original Article Citation Fadila S, Krivoshein G, Majadly H, Mavashov A, Ranen S, Brusel M, Dopeso-Reyes IG, Beucher B, Kremer EJ, Tolner EA, Rubinstein M. Disrupted temperature-sleep coupling mechanism in a Dravet syndrome mouse model. Nature Communications. 2026;17:3232. Dravet syndrome (DS) is associated with epilepsy, developmental delays, thermal dysregulation, and sleep disturbances. While seizures have been linked to hippocampal dysfunction, what drives sleep disturbances and thermal dysregulation is poorly understood. Using DS mice (Scn1aA1783V), we identified a link between sleep and thermoregulation. We found that DS mice exhibited lower core body temperature. Next, using electrocorticography, local field potential recordings, and core temperature monitoring, we showed that DS mice exhibited a lack of core temperature change during the transition from waking to non-rapid eye movement sleep. This is in contrast to wild-type (WT) mice, in which sleep onset coincided with a temperature drop. Additionally, warmth promoted sleep in WT, but not in DS mice. Vector-mediated expression of SCN1A or chemogenetic stimulation of the anterior hypothalamus restored the warmth-induced somnogenesis in DS mice. These findings highlight a connection between sleep and thermal dysregulation in DS, implicating altered neuronal activity of the hypothalamus.
2026-05-13 | In vivo adenine base editing ameliorates Dravet syndrome phenotypes in a mouse model.
Dravet syndrome (DS) is a severe neurodevelopmental disorder characterized by drug-resistant epilepsy, temperature-sensitive seizures, cognitive impairment, and a high incidence of sudden unexpected death in epilepsy (SUDEP). DS is caused by loss-of-function variants in SCN1A, which encodes the α subunit of the voltage-gated sodium channel (Nav1.1). Current approved treatments manage symptoms of DS but do not correct the root cause of the disease. Here, we describe the use of an adenine base editor (ABE) to directly correct SCN1AR613X, a recurrent variant found in patients with DS. We identified ABE strategies to efficiently correct R613X in engineered homozygous SCN1AR613X human embryonic kidney 293T and mouse Neuro-2a cells (72 and 92% correction efficiencies, respectively). We then used a dual-adeno-associated virus serotype 9 (AAV9) approach to deliver an optimized ABE system to Scn1aR613X/+ mice, which recapitulate several key DS pathologies. AAV9-ABE treatment of Scn1aR613X/+ neonates resulted in efficient DNA and mRNA editing (59 and 97%, respectively, in bulk neocortices), restoring parvalbumin-expressing inhibitory neuron excitability and sodium current to wild-type levels. This ameliorated both spontaneous and temperature-induced seizures and led to a 3.3-fold improvement in 45-day survival over vehicle-treated mice (ABE treated, 90%; and vehicle treated, 27%). Last, ABE treatment in 12-day-old mice resulted in a 3.0-fold improvement in 60-day survival over vehicle-treated mice (ABE treated, 82%; and vehicle treated, 27%). In conclusion, these data validate a strategy to correct SCN1A variants with ABE and highlight the potential of precision genome editing treatments for the treatment of DS and possibly other neurodevelopmental disorders.
2026-05-11 | Genetic medicines for epilepsy: unlocking new avenues for seizure control.
Epilepsy affects millions of people globally and is marked by unpredictable seizures due to excessive brain activity. These seizures not only vary widely in brain origin and severity but can also be associated with a range of factors - from head injuries to infections to genetic causes. Although antiseizure medications provide effective seizure control for many patients, approximately 30% experience drug-resistant epilepsy, with syndromic forms such as Lennox-Gastaut and Dravet syndrome posing significant therapeutic challenges. In addition, current pharmacological treatments are often associated with significant side effects and typically do not address the underlying pathophysiology. Gene therapies and genetic medicines are groundbreaking treatment modalities that enable direct targeting of disease mechanisms and associated genes. After FDA approval of the very first gene therapy in 2017 and the discovery of CRISPR-based gene editing, the field has rapidly expanded offering new hope for epilepsy treatment. This review highlights the latest advancements and therapeutic approaches for genetic medicines and explores their potential to transform the therapeutic landscape of epilepsy.
2026-04-25 | Bridging evidence gaps in dravet syndrome: real-world safety insights from under-reported antiseizure therapies.
Dravet syndrome is an early-onset developmental and epileptic encephalopathy in which management must extend beyond seizure control to include the monitoring and treatment of neurodevelopmental and systemic comorbidities. Well-established treatments, together with recently approved agents, are discussed alongside under-reported therapies. Safety profiles, clinically relevant pharmacokinetic interactions, and practical aspects of dose titration and monitoring are reviewed. Emerging targeted pharmacological and genetic strategies are also briefly considered as potential disease-modifying approaches. In clinical practice, valproate-based regimens remain central to seizure management, with adjunctive therapies tailored to seizure type, comorbidities, tolerability, and drug interactions. While stiripentol, clobazam, fenfluramine, and cannabidiol are supported by the strongest evidence, less frequently reported therapies, including perampanel, topiramate, levetiracetam, cenobamate, and ketogenic dietary therapies, may benefit selected patients but require cautious use due to heterogeneous efficacy and safety data. The complexity of available options highlights the need for individualized, dynamic treatment strategies. Although emerging targeted and genetic therapies may represent a future paradigm shift beyond symptomatic seizure control, their clinical impact remains to be established, warranting careful implementation and long-term safety evaluation.
oligonucleotides
2026-06-10 | At the forefront of gene-based therapies in Dravet syndrome.
Dravet syndrome (DS), a catastrophic developmental and epileptic encephalopathy primarily caused by SCN1A haploinsufficiency, remains largely refractory to current antiseizure medications. In recent years, gene-targeted therapies, including antisense oligonucleotides (ASOs)-and viral-based therapies, have emerged as promising disease-modifying strategies. Preclinical in vitro and in vivo models demonstrated that ASO-mediated modulation of SCN1A can restore transcript and protein levels, normalize interneuron excitability, and extend survival. Key advances include the discovery of deep-intronic 'poison' exons expanding actionable ASO targets and the demonstration of long-term functional rescue after early-life administration. Complementary strategies, such as SCN8A modulation, SCN1A viral delivery, and tau suppression, further broadened therapeutic options. Clinically, the ASO STK-001 trial showed favorable safety, pharmacodynamic activity, and durable seizure reduction in Phase 1/2a and open-label extension trials, alongside improvements in adaptive behavior and cognition. ASO-based modulation of SCN1A represents a pivotal advance in DS therapy, translating robust preclinical efficacy into early clinical benefit. Optimization of dosing regimens, durability, and combinatorial approaches targeting parallel molecular pathways will be critical to realize precision gene therapy for DS. Viral gene therapy approaches constitute a promising therapeutic platform, but comprehensive validation will be essential to ascertain their immunogenic safety and demonstrate clinical efficacy.
2026-05-21 | Enhanced splicing modulation by NMA-modified antisense oligonucleotides.
Aberrant RNA splicing contributes to many human diseases, and splice-switching antisense oligonucleotides are ideally suited as a therapeutic strategy to modulate splicing and restore normal gene expression. Nusinersen (Spinraza™) has revolutionized the treatment of spinal muscular atrophy. It is a splice-switching oligonucleotide (SSO) modified with 2'-O-methoxyethyl (MOE). Here, we evaluate a next-generation ribose modification, 2'-O-[2-(methylamino)-2-oxoethyl] (NMA), which enhances the pharmacological properties of SSOs. We identified a long-lasting NMA-modified human candidate SSO, salanersen, that is three to four-fold more potent than nusinersen in human SMN2 transgenic mice. To evaluate the generality of the NMA chemistry, we applied it to modulation of SCN1A exon 20N splicing, a therapeutic strategy for Dravet syndrome. An NMA-modified SSO is 3.5 -fold more potent than STK-001, a MOE-modified SSO currently in clinical trials. Our data establish the NMA chemistry as a broadly applicable ribose modification that markedly improves the pharmacological profile of SSOs, supporting its development as a next-generation platform for splicing modulation therapies.
2026-02-19 | Ameliorating Seizures in Dravet Syndrome: A Review of Newly Approved and Investigational Drugs, RNA and Gene-Based Therapies.
Dravet syndrome (DS) is a severe infantile-onset developmental and epileptic encephalopathy characterised by frequent drug-resistant seizures, cognitive and motor impairment, and an elevated risk of premature mortality, particularly from sudden unexpected death in epilepsy (SUDEP). Over 95% of cases are caused by loss-of-function pathogenic variants in SCN1A, the gene encoding the voltage-gated sodium channel alpha-1 subunit, NaV1.1. Despite advances in the understanding of DS pathophysiology, current treatments have primarily targeted seizure control without addressing the myriad of associated morbidities and the underlying molecular defect. Recent therapeutic developments include the approval of new antiseizure medications such as fenfluramine and pharmaceutical-grade cannabidiol, which have demonstrated efficacy and tolerability in randomised placebo-controlled trials. Investigational therapies, including selective serotonin receptor modulators and RNA-based and gene-based strategies, are expanding the treatment landscape. Antisense oligonucleotides (e.g., STK-001) aim to restore SCN1A expression, while emerging gene therapy approaches, including engineered AAV vectors (e.g., ETX101) and CRISPR-mediated transcriptional activation, seek to directly modify disease biology. Although challenges remain, such as long-term safety concerns, a broad spectrum of phenotypic severity, and efficacy and accessibility of advanced therapies, rapid progress in therapeutic research for DS offers new hope. Future directions include defining the most effective genetic therapies to improve outcomes, and ideally cure, all features of DS; optimal timing to deliver interventions as well as benefits derived from administration at later ages; ideal combinations of therapies; comparison of outcomes of targeted therapies with natural history studies and biomarker development. Together, these advances signal a paradigm shift in epilepsy management from symptomatic treatment to precision medicine for children and adults with DS.
2025-11-03 | More than epilepsy—a parent-initiated collaborative analysis of the research landscape and research needs in Dravet syndrome
Abstract Background Dravet syndrome (DS) is a developmental and epileptic encephalopathy associated with SCN1A mutations or deletions, significantly affecting patients and their families. Three European patient and family associations (PFAs) initiated the current analysis to advance DS research, identify unmet research needs, and propose future DS research directions. Methods A landscape analysis based on a SCOPUS and PubMed review of 3003 publications was performed, building the basis of workshops with selected stakeholders and opinion leaders. Results Advances have been made in DS epidemiology, clinical characterization, pathophysiology, and therapy. However, gaps remain in understanding the mechanisms, development, and management of cognitive, behavioral, social, motor, speech and language, and sleep problems. There is a poor understanding of DS in adulthood and sudden unexpected death in epilepsy (SUDEP) . Many patients endure difficult-to-treat seizures and side effects from polypharmacy. Disease-modifying therapies under development, including zorevunersen, ETX101, RT101, and mRNA modulators, promise causal therapy, potentially improving not only seizures but also development in behavioral, cognitive, and motor domains. Conclusion Patient and family associations emphasize that DS extends beyond epilepsy. Research on SUDEP mechanisms and non-epileptic symptoms is critical. Further studies on DS progression and treatments, involving standardized cognitive, behavioral, and motor metrics, alongside mortality rates, are necessary. More focus is needed on adult DS.
2025-10-30 | Precision medicine for sodium channelopathy-related autism and epilepsy.
Precision medicines for monogenic brain disorders are rapidly advancing. Voltage-gated sodium channel (VGSC) genes are the leading monogenic cause of severe epilepsy and profound autism spectrum disorder (ASD), most notably SCN1A, SCN2A, SCN3A, and SCN8A. Recent advances in animal and human induced pluripotent stem cell (hiPSC) disease models provide a powerful platform for advancing precision medicines. Thanks to the genomic revolution, many gene therapies are in preclinical studies and clinical trials for VGSC-related diseases, including viral vector gene replacement, clustered regularly interspaced short palindromic repeats (CRISPR) base editing, prime editing, and genetic modulation strategies including antisense oligonucleotides, engineered tRNAs, and CRISPR activation/interference (CRISPRa/i). This review highlights the latest advances in disease modeling and next-generation therapeutic development to advance precision medicine for VGSC-related brain disorders.
other
2025-11-13 | Intravenous immunoglobulin and febrile status epilepticus in children with Dravet syndrome: A retrospective multicentre study.
To assess the efficacy and tolerability of intravenous immunoglobulin (IVIG) in reducing febrile status epilepticus in children with Dravet syndrome. We conducted a retrospective multicentre study across seven French university hospitals (2005-2022). Children with genetically confirmed Dravet syndrome who received sequential IVIG were included. Clinical data were collected over two 6-month periods: before and after IVIG initiation. Fourteen individuals (six males, eight females) were included. At IVIG initiation, all were in the stormy phase, aged 10 to 92 months, and receiving a median of four antiseizure medications. IVIG was administered every 1 to 6 weeks (0.3-0.5 g/kg per infusion). Hospitalizations for status epilepticus significantly decreased, from a median of 4 (range 0-16) at baseline to 1 (range 0-6) after treatment (p = 0.002). Twelve individuals improved, two remained stable. Adverse events occurred in 6 out of 14 individuals, including infusion-related fever or seizures. Central venous access was required in six cases. IVIG was continued beyond 6 months in 11 out of 14 individuals. These series suggest a potential benefit of IVIG in reducing status epilepticus in selected children with Dravet syndrome. However, tolerability and feasibility issues were identified. A prospective controlled trial is warranted to further define the role of IVIG in this population.
2025-04-01 | COVID-19 infection and vaccination in children with Dravet syndrome or infantile epileptic spasms syndrome: An internet survey in Japan.
This study aimed to clarify the status of coronavirus disease 2019 (COVID-19) infection and vaccination among children with infantile-onset drug-resistant epilepsy through an internet survey involving Dravet syndrome (DS) and infantile epileptic spasms syndrome (IESS) family associations. A web-based survey was conducted between October and November 2023, targeting parents of children aged ≤15 years with DS or IESS who were members of the Dravet Syndrome JP or West Syndrome JP family associations, covering patient characteristics, COVID-19 infection, and vaccination. A total of 151 and 112 responses were obtained. COVID-19 infections occurred in 68.2 % and 52.7 % of DS and IESS cases, respectively. Fever-triggered seizures were reported in 61.8 % of DS and 3.6 % of IESS cases. Among DS cases, 22.8 % (8.0 % vaccinated), 36.6 % (20.0 % vaccinated), and 34.0 % (16.0 % vaccinated) required temporary visits for seizure exacerbation, emergency visits for seizure clusters/status epilepticus, and seizure-related hospitalizations, respectively. Vaccination rates were 25.3 % for DS and 17.3 % for IESS. Post-vaccination fever-triggered seizures occurred in 2.9 % and 3.5 % of DS cases after the first and second doses, respectively, and 0.0 % of IESS cases. Among DS cases, temporary visits were required in 2.9 % and 0.0 %, emergency visits in 0.0 % for both doses and hospitalizations in 2.9 % and 3.5 %, respectively. Vaccine hesitancy arising from seizure concerns was reported by 66.4 % and 23.0 % of DS and IESS caregivers, respectively. COVID-19 vaccination is well-tolerated and may lower seizure risks in children with DS. However, caregivers should monitor those with a history of fever-triggered seizures.
2023-10-20 | Epilepsy and sudden unexpected death in epilepsy in a mouse model of human SCN1B-linked developmental and epileptic encephalopathy.
Abstract Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C>T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b−/− mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C>T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in Scn1b−/− mice. β1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, β1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of β1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b−/− mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C>T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared with Scn1b−/− mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.
2023-09-29 | Potentiating NaV1.1 in Dravet syndrome patient iPSC-derived GABAergic neurons increases neuronal firing frequency and decreases network synchrony
Abstract Dravet syndrome is a developmental and epileptic encephalopathy characterized by seizures, behavioral abnormalities, developmental deficits, and elevated risk of sudden unexpected death in epilepsy (SUDEP). Most patient cases are caused by de novo loss-of-function mutations in the gene SCN1A , causing a haploinsufficiency of the alpha subunit of the voltage-gated sodium channel Na V 1.1. Within the brain, Na V 1.1 is primarily localized to the axons of inhibitory neurons, and decreased Na V 1.1 function is hypothesized to reduce GABAergic inhibitory neurotransmission within the brain, driving neuronal network hyperexcitability and subsequent pathology. We have developed a human in vitro model of Dravet syndrome using differentiated neurons derived from patient iPSC and enriched for GABA expressing neurons. Neurons were plated on high definition multielectrode arrays (HD-MEAs), permitting recordings from the same cultures over the 7-weeks duration of study at the network, single cell, and subcellular resolution. Using this capability, we characterized the features of axonal morphology and physiology. Neurons developed increased spiking activity and synchronous network bursting. Recordings were processed through a spike sorting pipeline for curation of single unit activity and to assess the effects of pharmacological treatments. At 7-weeks, the application of the GABA A R receptor agonist muscimol eliminated network bursting, indicating the presence of GABAergic neurotransmission. To identify the role of Na V 1.1 on neuronal and network activity, cultures were treated with a dose-response of the Na V 1.1 potentiator δ-theraphotoxin-Hm1a. This resulted in a strong increase in firing rates of putative GABAergic neurons, an increase in the intraburst firing rate, and eliminated network bursting. These results validate that potentiation of Na V 1.1 in Dravet patient iPSC-derived neurons results in decreased firing synchrony in neuronal networks through increased GABAergic neuron activity and support the use of human neurons and HD-MEAs as viable high-throughput electrophysiological platform to enable therapeutic discovery.
2023-07-13 | Structure-function relationship of new peptides activating human Nav1.1
Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Nav1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Nav1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.
small molecules
2026-08-06 | Beyond seizures in Dravet and Lennox-Gastaut syndromes - An Italian Expert Consensus on Non-Seizure issues and the role of fenfluramine.
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies (DEEs) in which disability and family burden are driven by seizures and non-seizure issues (NSIs), including cognition, behavior, sleep, communication, motor function, and adaptive abilities. To develop practical consensus statements on NSIs in DS and LGS, integrating NSI evaluation within a DEE framework and appraising the perceived role of fenfluramine (FFA). An Italian panel of 12 epilepsy specialists spanning pediatric and adult practice developed statements using an Estimate-Talk-Estimate process. Consensus was predefined as ≥ 70% agreement (agree/strongly agree). Eleven final statements were clustered into three macro-areas, with the first two explored in greater depth: (1) the cross-cutting, lifespan impact of NSIs in DS and LGS; (2) the potential for FFA to provide clinically meaningful benefits across selected NSI domains in DS and, more variably, in LGS, with effects not always fully captured by seizure metrics; and (3) the role of other interventions on NSIs and the need for structured assessment tools. Incorporating NSI priorities into shared goal-setting and longitudinal monitoring may improve the clinical relevance of care in DS and LGS. The panel supported an NSI-informed, net-benefit approach to treatment optimization and identified FFA as a relevant option, while recognizing that evidence on NSI outcomes remains heterogeneous and should be strengthened through syndrome-specific, longitudinal assessment.
2026-07-30 | cGAS-mediated type I IFN signaling contributes to disease progression in drug-refractory epilepsy.
Epilepsy is a prevalent neurological disease, with one-third of individuals becoming nonresponsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we identify activation of cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN) signaling, in human DRE brain tissue. Microglia from individuals with DRE exhibit a robust type I IFN signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we similarly detect activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS attenuates seizure phenotypes, reduces glial inflammatory signatures and normalizes neuronal transcriptomic changes in mice with Dravet syndrome. Together, these findings identify cGAS-mediated neuroimmune signaling as a contributor to seizure pathology in Dravet syndrome and highlight this pathway as a potential therapeutic target.
2026-07-29 | A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Nonseizure outcomes.
A plant-derived, highly purified cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU]) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC). Improvements in nonseizure outcomes including cognition and behavior have been reported in patients with epilepsy administered CBD. This systematic literature review (SLR) evaluated studies reporting changes in nonseizure outcomes after CBD initiation in patients with developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs) other than LGS, DS, and TSC. An SLR was conducted in March 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline, and Cochrane Central Register of Controlled Trials libraries were searched for studies on TREs, CBD, nonseizure outcomes, and adverse events (AEs). Results were narratively summarized. Thirty-two studies comprising 1343 patients were included. Thirty-one studies reported improvement in nonseizure outcomes in ≥ 1 patient, including neuropsychiatric function (n = 9/9 studies), cognitive function (n = 9/9), use of concomitant antiseizure medications (n = 7/8), communication (n = 7/7), behavior (n = 7/7), motor function (n = 6/6), healthcare utilization (n = 5/5), quality of life (n = 5/5), global change (n = 4/4), sleep (n = 2/2), and development (n = 2/2). Reported AEs were consistent with the known safety profile of CBD and most commonly gastrointestinal, including diarrhea (17-34%), vomiting (5-50%), and decreased appetite (7-20%). This SLR mainly identified observational studies with moderate to high bias risk. The available evidence suggests CBD may improve various nonseizure outcomes in patients with DEEs and complex TREs, while underscoring the need for rigorous confirmatory studies.
2026-07-06 | Perampanel in Chinese patients with Dravet syndrome: Efficacy and tolerability assessed via a multicenter, prospective, real-world observational study.
As a third-generation antiseizure medication, the efficacy of perampanel in treating Dravet syndrome (DS) remains incompletely characterized. This multicenter, prospective, real-world observational study aimed to evaluate the efficacy and long-term tolerability of perampanel as adjunctive therapy in Chinese patients with DS. Patients with unresolved DS were enrolled from four participating hospitals in China between January 2019 and December 2023. All patients received perampanel as add-on therapy. Efficacy and retention rate were evaluated at 3, 6, and 12 months of perampanel treatment. Genetic screening for SCN1A mutations was performed in all enrolled patients. Fifty-six patients were enrolled, of whom 48 (85.71%) harbored SCN1A mutations. The mean treatment duration of perampanel was 25.00 ± 7.65 months, with a mean maximum daily perampanel dose of 3.94 ± 1.19 mg. The retention rates at 6 and 12 months were 69.64% and 64.29%, respectively. After 6 and 12 months of treatment, the ≥50% responder rates were 66.07% and 60.71%, while seizure-freedom rates were 21.43% and 12.50%, respectively. Seizure exacerbation occurred in three patients (5.36%). Adverse events occurred in six patients during treatment (three discontinued treatment), with no new safety concerns identified. Among 30 patients with ≥50% seizure frequency reduction throughout 12-month treatment who carried SCN1A mutations, 33.33% had truncating mutations, 46.67% had missense mutations, 13.33% had splice site mutations, 3.33% had in-frame mutations, and 3.33% had large chromosomal deletions encompassing SCN1A. No significant difference in the ≥50% seizure frequency reduction rate was observed between patients with SCN1A truncating mutations and those with missense mutations. Additionally, treatment response to perampanel did not differ significantly according to the specific mutation regions within the Nav1.1 sodium channel. Perampanel demonstrated favorable efficacy and acceptable long-term tolerability as adjunctive therapy in Chinese patients with DS. The efficacy of perampanel remained consistent regardless of the specific genotype or location of SCN1A mutations.
2026-07-05 | Prolonged fenfluramine use in open-label studies of Dravet or Lennox-Gastaut syndromes: Long-term safety, tolerability, patient global functioning, and considerations for interpreting effectiveness.
Long-term safety and global functioning are reported in patients with Dravet syndrome (DS) or Lennox-Gastaut syndrome (LGS) treated with fenfluramine in an open-label extension (OLE) study after participating in a previous open-label feeder study. Patients could enroll in this international, multicenter OLE (NCT03936777) after completing one of three fenfluramine open-label studies. The latest feeder study fenfluramine dose was continued, then flexibly titrated (maximum: .7 mg/kg/day [26 mg/day] without stiripentol or .4 mg/kg/day [17 mg/day] with stiripentol), with ≥1 concomitant antiseizure medication administered. Primary endpoint was fenfluramine long-term safety/tolerability. Global functioning using caregiver- and investigator-reported Clinical Global Impression of Improvement (CGI-I) ratings, globally and for subdomains (cognition, behavior, motor function), at last visit relative to study baseline was evaluated. Overall treatment exposure and age groups were analyzed post hoc. A total of 412 patients enrolled (DS: 265 [64.3%], LGS: 147 [35.7%]); 30.8% were ≥18 years old. Median fenfluramine treatment duration in this OLE was 729.5 days (range = 8-1544), and overall median fenfluramine exposure, including feeder studies, was 1464.5 days (range = 171-2800). In this OLE, ≥1 treatment-emergent adverse event (TEAE) was reported in 311 (75.5%) patients; fenfluramine-related (per investigator) serious TEAEs were reported in five (1.2%) patients. Three patients died in this OLE (deemed unrelated to fenfluramine by investigators). After starting this OLE already receiving fenfluramine, 373 of 401 (93.0%) and 376 of 401 (93.8%) patients were rated by caregiver and investigator, respectively, as "improved or no change" on CGI-I versus this study baseline; subdomain ratings of "improved or no change" were largely consistent with global assessment. In our OLE study of patients with DS or LGS treated with fenfluramine (up to 4 years), no new or unexpected safety signals were observed; global functioning was improved or stable (vs. study baseline) in >90% of patients, supporting long-term fenfluramine use in pediatric and adult patients with DS or LGS.
cell therapies
2026-05-02 | Movement Disorders in Developmental and Epileptic Encephalopathies.
Monogenic developmental and epileptic encephalopathies (DEE) frequently feature co-occurring movement disorders. Gene discovery has expanded epilepsy-dyskinesia syndromes (EDS) from classic associations such as stereotypies in Rett syndrome to PRRT2-related infantile seizures with paroxysmal dyskinesia and crouched gait in SCN1A-associated Dravet syndrome. To outline the movement disorders spectrum in EDS, propose a pragmatic syndrome-based clinical framework, group implicated genes into mechanistic categories, highlight selected genotype-phenotype correlations, and summarize symptomatic and precision therapeutic options. A non-systematic, structured literature review identified monogenic disorders reported with EDS, grouping publications into four tiers: multi-etiology cohorts; small series and narrative/systematic reviews; single-gene or pathway-focused reports; and mechanistic/therapeutic studies. Eight cohort studies and multiple tier 2-3 series and reviews yielded 245 single-gene associations, most mapping to ion channel and synaptic signaling pathways. Across DEE cohorts, movement disorders occurred in roughly one-quarter to over one-half of patients, were often hyperkinetic (notably dystonia and stereotypies), and frequently combined multiple phenomenologies. We grouped clinical presentations into early and late infantile-onset EDS, Rett and Rett-like syndromes, paroxysmal/episodic and relapsing-remitting disorders, disorders with severe acute motor exacerbations, and hypokinetic/progressive phenotypes. Treatments are guided by gene- and mechanism-informed strategies including sodium-channel blockers, glutamatergic modulators, ketogenic diet, agents for paroxysmal dyskinesias, and deep brain stimulation in life-threatening crises. Movement disorders are common, often severe, and genetically heterogeneous across EDS. A syndrome-based approach integrating clinical features, neuroimaging, and broad genetic testing (including copy number variants and repeat expansions) can guide symptomatic management and emerging precision therapies.
2024-04-18 | Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8
ABSTRACT Dravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed to SCN1A haploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion of Scn1a recapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier ( Dsm ) loci, Dsm2 on chromosome 7 and Dsm3 on chromosome 8, using interval-specific congenic (ISC) mapping. Dsm2 was complex and encompassed at least two separate loci, while Dsm3 was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes for Dsm2 include Nav2, Ptpn5, Ldha, Dbx1, Prmt3 and Slc6a5 , while Dsm3 has a single high priority candidate, Psd3 . This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.
2023-01-24 | The Generation of Human iPSC Lines from Three Individuals with Dravet Syndrome and Characterization of Neural Differentiation Markers in iPSC-Derived Ventral Forebrain Organoid Model.
Dravet syndrome (DRVT) is a rare form of neurodevelopmental disorder with a high risk of sudden unexpected death in epilepsy (SUDEP), caused mainly (>80% cases) by mutations in the SCN1A gene, coding the Nav1.1 protein (alfa-subunit of voltage-sensitive sodium channel). Mutations in SCN1A are linked to heterogenous epileptic phenotypes of various types, severity, and patient prognosis. Here we generated iPSC lines from fibroblasts obtained from three individuals affected with DRVT carrying distinct mutations in the SCN1A gene (nonsense mutation p.Ser1516*, missense mutation p.Arg1596His, and splicing mutation c.2589+2dupT). The iPSC lines, generated with the non-integrative approach, retained the distinct SCN1A gene mutation of the donor fibroblasts and were characterized by confirming the expression of the pluripotency markers, the three-germ layer differentiation potential, the absence of exogenous vector expression, and a normal karyotype. The generated iPSC lines were used to establish ventral forebrain organoids, the most affected type of neurons in the pathology of DRVT. The DRVT organoid model will provide an additional resource for deciphering the pathology behind Nav1.1 haploinsufficiency and drug screening to remediate the functional deficits associated with the disease.
2022-04-07 | Ameliorating Effect of Umbilical Cord Mesenchymal Stem Cells in a Human Induced Pluripotent Stem Cell Model of Dravet Syndrome.
Dravet syndrome (DS) is a form of severe childhood-onset refractory epilepsy typically caused by a heterozygous loss-of-function mutation. DS patient-derived induced pluripotent stem cells (iPSCs) are appropriate human cells for exploring disease mechanisms and testing new therapeutic strategies in vitro. Repeated spontaneous seizures can cause neuroinflammatory reactions and oxidative stress, resulting in neuronal toxicity, neuronal dysfunction, blood-brain barrier disruption, and hippocampal inflammation. Antiepileptic drug therapy does not delay the development of chronic epilepsy. The application of mesenchymal stem cells (MSCs) is one therapeutic strategy for thwarting epilepsy development. This study evaluated the effects of human umbilical cord mesenchymal stem cell-conditioned medium (HUMSC-CM) in a new in vitro model of neurons differentiated from DS patient-derived iPSCs. In the presence of HUMSC-CM, increases in superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), glutathione peroxidase (GPX), and glutathione (GSH) levels were found to contribute to a reduction in reactive oxygen species (ROS) levels. In parallel, inflammation was rescued in DS patient-derived neuronal cells via increased expression of anti-inflammatory cytokines (TGF-β, IL-6, and IL-10) and significant downregulation of tumor necrosis factor-α and interleukin-1β expression. The intracellular calcium concentration ([Ca2+]i) and malondialdehyde (MDA) and ROS levels were decreased in DS patient-derived cells. In addition, action potential (AP) firing ability was enhanced by HUMSC-CM. In conclusion, HUMSC-CM can effectively eliminate ROS, affect migration and neurogenesis, and promote neurons to enter a highly functional state. Therefore, HUMSC-CM is a promising therapeutic strategy for the clinical treatment of refractory epilepsy such as DS.
2021-07-28 | Application of induced pluripotent stem cells in epilepsy.
Epilepsy is among the most common neurological disorders, affecting approximately 50 million people worldwide. Importantly, epilepsy is genetically and etiologically heterogenous, but several epilepsy types exhibit similar clinical presentations. Epilepsy-associated genes are being identified. However, the molecular pathomechanisms remain largely unknown. Approximately one-third of epilepsy is refractory to multiple conventional anti-epileptic drugs (AEDs). Induced pluripotent stem cells (iPSCs) provide an excellent tool to study the pathomechanisms underlying epilepsy and to develop novel treatments. Indeed, disease-specific iPSCs have been established for several genetic epilepsies. In particular, the molecular mechanisms underlying certain developmental and epileptic encephalopathies, such as Dravet syndrome, have been revealed. Modeling epilepsy with iPSCs enables new drug development based on the elucidated pathomechanisms. This can also be used to evaluate conventional AEDs and drug repurposing. Furthermore, transplanting neuronal cells derived from iPSCs into the brain has great potential to treat refractory epilepsies. Recent advances in iPSC technology have enabled the generation of neuronal organoids, or "mini brains." These organoids demonstrate electrophysiological activities similar to those of the brain and have the potential for extensive epilepsy research opportunities. Thus, the application of iPSCs in epilepsy provides insight into novel treatments based on the molecular pathomechanisms of epilepsy. In this review, we comprehensively discuss the studies conducted on iPSCs established for genetic epilepsy or epilepsies without major structural dysmorphic features.
gene therapies
2026-07-14 | PV interneuron-targeted CRISPRa rescue of SCN1A haploinsufficiency in Dravet syndrome
Dravet syndrome is a severe epileptic encephalopathy caused by SCN1A haploinsufficiency, which leads to reduced Na V 1.1 expression in parvalbumin (PV)-expressing interneurons and disrupted excitatory-inhibitory balance in the brain. We developed an AAV-based CRISPR activation system (AAV9-E2-dCas9-VP64) to selectively upregulate SCN1A from its endogenous locus in PV interneurons. An in vitro saturating guide RNA (gRNA) screen across the human SCN1A promoter identified a lead guide with robust and highly specific engagement of the SCN1A locus. This lead gRNA was validated in human Dravet syndrome model GABAergic neurons, where dose-dependent and specific SCN1A upregulation was observed. Intracerebroventricular (ICV) administration in a mouse model of Dravet syndrome produced dose-dependent improvement in survival as well as reduced susceptibility to hyperthermia-induced seizures and increased Na V 1.1 protein expression, with maintained PV interneuron selectivity and minimal off-target expression. In a study in juvenile cynomolgus macaques, MRI-guided ICV administration of the vector was well tolerated, achieved broad cortical biodistribution, and maintained strong detargeting of peripheral tissues, with substantially lower peripheral dCas9 expression relative to the brain. These results support PV interneuron-selective SCN1A gene modulation via CRISPR activation as a promising therapeutic strategy for Dravet syndrome. AAV9-E2-dCas9-VP64 (RT101) is currently in preclinical development and is being advanced toward evaluation in the clinic.
2026-06-12 | Lost in Sleep Transition: Tangled Sleep and Thermoregulation in Dravet Syndrome
Original Article Citation Fadila S, Krivoshein G, Majadly H, Mavashov A, Ranen S, Brusel M, Dopeso-Reyes IG, Beucher B, Kremer EJ, Tolner EA, Rubinstein M. Disrupted temperature-sleep coupling mechanism in a Dravet syndrome mouse model. Nature Communications. 2026;17:3232. Dravet syndrome (DS) is associated with epilepsy, developmental delays, thermal dysregulation, and sleep disturbances. While seizures have been linked to hippocampal dysfunction, what drives sleep disturbances and thermal dysregulation is poorly understood. Using DS mice (Scn1aA1783V), we identified a link between sleep and thermoregulation. We found that DS mice exhibited lower core body temperature. Next, using electrocorticography, local field potential recordings, and core temperature monitoring, we showed that DS mice exhibited a lack of core temperature change during the transition from waking to non-rapid eye movement sleep. This is in contrast to wild-type (WT) mice, in which sleep onset coincided with a temperature drop. Additionally, warmth promoted sleep in WT, but not in DS mice. Vector-mediated expression of SCN1A or chemogenetic stimulation of the anterior hypothalamus restored the warmth-induced somnogenesis in DS mice. These findings highlight a connection between sleep and thermal dysregulation in DS, implicating altered neuronal activity of the hypothalamus.
2026-05-13 | In vivo adenine base editing ameliorates Dravet syndrome phenotypes in a mouse model.
Dravet syndrome (DS) is a severe neurodevelopmental disorder characterized by drug-resistant epilepsy, temperature-sensitive seizures, cognitive impairment, and a high incidence of sudden unexpected death in epilepsy (SUDEP). DS is caused by loss-of-function variants in SCN1A, which encodes the α subunit of the voltage-gated sodium channel (Nav1.1). Current approved treatments manage symptoms of DS but do not correct the root cause of the disease. Here, we describe the use of an adenine base editor (ABE) to directly correct SCN1AR613X, a recurrent variant found in patients with DS. We identified ABE strategies to efficiently correct R613X in engineered homozygous SCN1AR613X human embryonic kidney 293T and mouse Neuro-2a cells (72 and 92% correction efficiencies, respectively). We then used a dual-adeno-associated virus serotype 9 (AAV9) approach to deliver an optimized ABE system to Scn1aR613X/+ mice, which recapitulate several key DS pathologies. AAV9-ABE treatment of Scn1aR613X/+ neonates resulted in efficient DNA and mRNA editing (59 and 97%, respectively, in bulk neocortices), restoring parvalbumin-expressing inhibitory neuron excitability and sodium current to wild-type levels. This ameliorated both spontaneous and temperature-induced seizures and led to a 3.3-fold improvement in 45-day survival over vehicle-treated mice (ABE treated, 90%; and vehicle treated, 27%). Last, ABE treatment in 12-day-old mice resulted in a 3.0-fold improvement in 60-day survival over vehicle-treated mice (ABE treated, 82%; and vehicle treated, 27%). In conclusion, these data validate a strategy to correct SCN1A variants with ABE and highlight the potential of precision genome editing treatments for the treatment of DS and possibly other neurodevelopmental disorders.
2026-05-11 | Genetic medicines for epilepsy: unlocking new avenues for seizure control.
Epilepsy affects millions of people globally and is marked by unpredictable seizures due to excessive brain activity. These seizures not only vary widely in brain origin and severity but can also be associated with a range of factors - from head injuries to infections to genetic causes. Although antiseizure medications provide effective seizure control for many patients, approximately 30% experience drug-resistant epilepsy, with syndromic forms such as Lennox-Gastaut and Dravet syndrome posing significant therapeutic challenges. In addition, current pharmacological treatments are often associated with significant side effects and typically do not address the underlying pathophysiology. Gene therapies and genetic medicines are groundbreaking treatment modalities that enable direct targeting of disease mechanisms and associated genes. After FDA approval of the very first gene therapy in 2017 and the discovery of CRISPR-based gene editing, the field has rapidly expanded offering new hope for epilepsy treatment. This review highlights the latest advancements and therapeutic approaches for genetic medicines and explores their potential to transform the therapeutic landscape of epilepsy.
2026-04-25 | Bridging evidence gaps in dravet syndrome: real-world safety insights from under-reported antiseizure therapies.
Dravet syndrome is an early-onset developmental and epileptic encephalopathy in which management must extend beyond seizure control to include the monitoring and treatment of neurodevelopmental and systemic comorbidities. Well-established treatments, together with recently approved agents, are discussed alongside under-reported therapies. Safety profiles, clinically relevant pharmacokinetic interactions, and practical aspects of dose titration and monitoring are reviewed. Emerging targeted pharmacological and genetic strategies are also briefly considered as potential disease-modifying approaches. In clinical practice, valproate-based regimens remain central to seizure management, with adjunctive therapies tailored to seizure type, comorbidities, tolerability, and drug interactions. While stiripentol, clobazam, fenfluramine, and cannabidiol are supported by the strongest evidence, less frequently reported therapies, including perampanel, topiramate, levetiracetam, cenobamate, and ketogenic dietary therapies, may benefit selected patients but require cautious use due to heterogeneous efficacy and safety data. The complexity of available options highlights the need for individualized, dynamic treatment strategies. Although emerging targeted and genetic therapies may represent a future paradigm shift beyond symptomatic seizure control, their clinical impact remains to be established, warranting careful implementation and long-term safety evaluation.
oligonucleotides
2026-06-10 | At the forefront of gene-based therapies in Dravet syndrome.
Dravet syndrome (DS), a catastrophic developmental and epileptic encephalopathy primarily caused by SCN1A haploinsufficiency, remains largely refractory to current antiseizure medications. In recent years, gene-targeted therapies, including antisense oligonucleotides (ASOs)-and viral-based therapies, have emerged as promising disease-modifying strategies. Preclinical in vitro and in vivo models demonstrated that ASO-mediated modulation of SCN1A can restore transcript and protein levels, normalize interneuron excitability, and extend survival. Key advances include the discovery of deep-intronic 'poison' exons expanding actionable ASO targets and the demonstration of long-term functional rescue after early-life administration. Complementary strategies, such as SCN8A modulation, SCN1A viral delivery, and tau suppression, further broadened therapeutic options. Clinically, the ASO STK-001 trial showed favorable safety, pharmacodynamic activity, and durable seizure reduction in Phase 1/2a and open-label extension trials, alongside improvements in adaptive behavior and cognition. ASO-based modulation of SCN1A represents a pivotal advance in DS therapy, translating robust preclinical efficacy into early clinical benefit. Optimization of dosing regimens, durability, and combinatorial approaches targeting parallel molecular pathways will be critical to realize precision gene therapy for DS. Viral gene therapy approaches constitute a promising therapeutic platform, but comprehensive validation will be essential to ascertain their immunogenic safety and demonstrate clinical efficacy.
2026-05-21 | Enhanced splicing modulation by NMA-modified antisense oligonucleotides.
Aberrant RNA splicing contributes to many human diseases, and splice-switching antisense oligonucleotides are ideally suited as a therapeutic strategy to modulate splicing and restore normal gene expression. Nusinersen (Spinraza™) has revolutionized the treatment of spinal muscular atrophy. It is a splice-switching oligonucleotide (SSO) modified with 2'-O-methoxyethyl (MOE). Here, we evaluate a next-generation ribose modification, 2'-O-[2-(methylamino)-2-oxoethyl] (NMA), which enhances the pharmacological properties of SSOs. We identified a long-lasting NMA-modified human candidate SSO, salanersen, that is three to four-fold more potent than nusinersen in human SMN2 transgenic mice. To evaluate the generality of the NMA chemistry, we applied it to modulation of SCN1A exon 20N splicing, a therapeutic strategy for Dravet syndrome. An NMA-modified SSO is 3.5 -fold more potent than STK-001, a MOE-modified SSO currently in clinical trials. Our data establish the NMA chemistry as a broadly applicable ribose modification that markedly improves the pharmacological profile of SSOs, supporting its development as a next-generation platform for splicing modulation therapies.
2026-02-19 | Ameliorating Seizures in Dravet Syndrome: A Review of Newly Approved and Investigational Drugs, RNA and Gene-Based Therapies.
Dravet syndrome (DS) is a severe infantile-onset developmental and epileptic encephalopathy characterised by frequent drug-resistant seizures, cognitive and motor impairment, and an elevated risk of premature mortality, particularly from sudden unexpected death in epilepsy (SUDEP). Over 95% of cases are caused by loss-of-function pathogenic variants in SCN1A, the gene encoding the voltage-gated sodium channel alpha-1 subunit, NaV1.1. Despite advances in the understanding of DS pathophysiology, current treatments have primarily targeted seizure control without addressing the myriad of associated morbidities and the underlying molecular defect. Recent therapeutic developments include the approval of new antiseizure medications such as fenfluramine and pharmaceutical-grade cannabidiol, which have demonstrated efficacy and tolerability in randomised placebo-controlled trials. Investigational therapies, including selective serotonin receptor modulators and RNA-based and gene-based strategies, are expanding the treatment landscape. Antisense oligonucleotides (e.g., STK-001) aim to restore SCN1A expression, while emerging gene therapy approaches, including engineered AAV vectors (e.g., ETX101) and CRISPR-mediated transcriptional activation, seek to directly modify disease biology. Although challenges remain, such as long-term safety concerns, a broad spectrum of phenotypic severity, and efficacy and accessibility of advanced therapies, rapid progress in therapeutic research for DS offers new hope. Future directions include defining the most effective genetic therapies to improve outcomes, and ideally cure, all features of DS; optimal timing to deliver interventions as well as benefits derived from administration at later ages; ideal combinations of therapies; comparison of outcomes of targeted therapies with natural history studies and biomarker development. Together, these advances signal a paradigm shift in epilepsy management from symptomatic treatment to precision medicine for children and adults with DS.
2025-11-03 | More than epilepsy—a parent-initiated collaborative analysis of the research landscape and research needs in Dravet syndrome
Abstract Background Dravet syndrome (DS) is a developmental and epileptic encephalopathy associated with SCN1A mutations or deletions, significantly affecting patients and their families. Three European patient and family associations (PFAs) initiated the current analysis to advance DS research, identify unmet research needs, and propose future DS research directions. Methods A landscape analysis based on a SCOPUS and PubMed review of 3003 publications was performed, building the basis of workshops with selected stakeholders and opinion leaders. Results Advances have been made in DS epidemiology, clinical characterization, pathophysiology, and therapy. However, gaps remain in understanding the mechanisms, development, and management of cognitive, behavioral, social, motor, speech and language, and sleep problems. There is a poor understanding of DS in adulthood and sudden unexpected death in epilepsy (SUDEP) . Many patients endure difficult-to-treat seizures and side effects from polypharmacy. Disease-modifying therapies under development, including zorevunersen, ETX101, RT101, and mRNA modulators, promise causal therapy, potentially improving not only seizures but also development in behavioral, cognitive, and motor domains. Conclusion Patient and family associations emphasize that DS extends beyond epilepsy. Research on SUDEP mechanisms and non-epileptic symptoms is critical. Further studies on DS progression and treatments, involving standardized cognitive, behavioral, and motor metrics, alongside mortality rates, are necessary. More focus is needed on adult DS.
2025-10-30 | Precision medicine for sodium channelopathy-related autism and epilepsy.
Precision medicines for monogenic brain disorders are rapidly advancing. Voltage-gated sodium channel (VGSC) genes are the leading monogenic cause of severe epilepsy and profound autism spectrum disorder (ASD), most notably SCN1A, SCN2A, SCN3A, and SCN8A. Recent advances in animal and human induced pluripotent stem cell (hiPSC) disease models provide a powerful platform for advancing precision medicines. Thanks to the genomic revolution, many gene therapies are in preclinical studies and clinical trials for VGSC-related diseases, including viral vector gene replacement, clustered regularly interspaced short palindromic repeats (CRISPR) base editing, prime editing, and genetic modulation strategies including antisense oligonucleotides, engineered tRNAs, and CRISPR activation/interference (CRISPRa/i). This review highlights the latest advances in disease modeling and next-generation therapeutic development to advance precision medicine for VGSC-related brain disorders.
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2025-11-13 | Intravenous immunoglobulin and febrile status epilepticus in children with Dravet syndrome: A retrospective multicentre study.
To assess the efficacy and tolerability of intravenous immunoglobulin (IVIG) in reducing febrile status epilepticus in children with Dravet syndrome. We conducted a retrospective multicentre study across seven French university hospitals (2005-2022). Children with genetically confirmed Dravet syndrome who received sequential IVIG were included. Clinical data were collected over two 6-month periods: before and after IVIG initiation. Fourteen individuals (six males, eight females) were included. At IVIG initiation, all were in the stormy phase, aged 10 to 92 months, and receiving a median of four antiseizure medications. IVIG was administered every 1 to 6 weeks (0.3-0.5 g/kg per infusion). Hospitalizations for status epilepticus significantly decreased, from a median of 4 (range 0-16) at baseline to 1 (range 0-6) after treatment (p = 0.002). Twelve individuals improved, two remained stable. Adverse events occurred in 6 out of 14 individuals, including infusion-related fever or seizures. Central venous access was required in six cases. IVIG was continued beyond 6 months in 11 out of 14 individuals. These series suggest a potential benefit of IVIG in reducing status epilepticus in selected children with Dravet syndrome. However, tolerability and feasibility issues were identified. A prospective controlled trial is warranted to further define the role of IVIG in this population.
2025-04-01 | COVID-19 infection and vaccination in children with Dravet syndrome or infantile epileptic spasms syndrome: An internet survey in Japan.
This study aimed to clarify the status of coronavirus disease 2019 (COVID-19) infection and vaccination among children with infantile-onset drug-resistant epilepsy through an internet survey involving Dravet syndrome (DS) and infantile epileptic spasms syndrome (IESS) family associations. A web-based survey was conducted between October and November 2023, targeting parents of children aged ≤15 years with DS or IESS who were members of the Dravet Syndrome JP or West Syndrome JP family associations, covering patient characteristics, COVID-19 infection, and vaccination. A total of 151 and 112 responses were obtained. COVID-19 infections occurred in 68.2 % and 52.7 % of DS and IESS cases, respectively. Fever-triggered seizures were reported in 61.8 % of DS and 3.6 % of IESS cases. Among DS cases, 22.8 % (8.0 % vaccinated), 36.6 % (20.0 % vaccinated), and 34.0 % (16.0 % vaccinated) required temporary visits for seizure exacerbation, emergency visits for seizure clusters/status epilepticus, and seizure-related hospitalizations, respectively. Vaccination rates were 25.3 % for DS and 17.3 % for IESS. Post-vaccination fever-triggered seizures occurred in 2.9 % and 3.5 % of DS cases after the first and second doses, respectively, and 0.0 % of IESS cases. Among DS cases, temporary visits were required in 2.9 % and 0.0 %, emergency visits in 0.0 % for both doses and hospitalizations in 2.9 % and 3.5 %, respectively. Vaccine hesitancy arising from seizure concerns was reported by 66.4 % and 23.0 % of DS and IESS caregivers, respectively. COVID-19 vaccination is well-tolerated and may lower seizure risks in children with DS. However, caregivers should monitor those with a history of fever-triggered seizures.
2023-10-20 | Epilepsy and sudden unexpected death in epilepsy in a mouse model of human SCN1B-linked developmental and epileptic encephalopathy.
Abstract Voltage-gated sodium channel β1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding β1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C>T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b−/− mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C>T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in Scn1b−/− mice. β1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, β1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of β1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b−/− mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C>T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared with Scn1b−/− mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.
2023-09-29 | Potentiating NaV1.1 in Dravet syndrome patient iPSC-derived GABAergic neurons increases neuronal firing frequency and decreases network synchrony
Abstract Dravet syndrome is a developmental and epileptic encephalopathy characterized by seizures, behavioral abnormalities, developmental deficits, and elevated risk of sudden unexpected death in epilepsy (SUDEP). Most patient cases are caused by de novo loss-of-function mutations in the gene SCN1A , causing a haploinsufficiency of the alpha subunit of the voltage-gated sodium channel Na V 1.1. Within the brain, Na V 1.1 is primarily localized to the axons of inhibitory neurons, and decreased Na V 1.1 function is hypothesized to reduce GABAergic inhibitory neurotransmission within the brain, driving neuronal network hyperexcitability and subsequent pathology. We have developed a human in vitro model of Dravet syndrome using differentiated neurons derived from patient iPSC and enriched for GABA expressing neurons. Neurons were plated on high definition multielectrode arrays (HD-MEAs), permitting recordings from the same cultures over the 7-weeks duration of study at the network, single cell, and subcellular resolution. Using this capability, we characterized the features of axonal morphology and physiology. Neurons developed increased spiking activity and synchronous network bursting. Recordings were processed through a spike sorting pipeline for curation of single unit activity and to assess the effects of pharmacological treatments. At 7-weeks, the application of the GABA A R receptor agonist muscimol eliminated network bursting, indicating the presence of GABAergic neurotransmission. To identify the role of Na V 1.1 on neuronal and network activity, cultures were treated with a dose-response of the Na V 1.1 potentiator δ-theraphotoxin-Hm1a. This resulted in a strong increase in firing rates of putative GABAergic neurons, an increase in the intraburst firing rate, and eliminated network bursting. These results validate that potentiation of Na V 1.1 in Dravet patient iPSC-derived neurons results in decreased firing synchrony in neuronal networks through increased GABAergic neuron activity and support the use of human neurons and HD-MEAs as viable high-throughput electrophysiological platform to enable therapeutic discovery.
2023-07-13 | Structure-function relationship of new peptides activating human Nav1.1
Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Nav1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Nav1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.
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Drug Discovery Landscape
27 orphan drug designations for Dravet syndrome, including 5 approved therapies.
27 orphan drug designations for Dravet syndrome, including 5 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
chemically modified oligonucleotide designed as an ADAR-recruiting guide RNA | oligonucleotides | FDA | 2025-04-16 | — | RecoRNA (Guangzhou) Biotechnology Co., Ltd. |
(R)-N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide | small molecules | FDA | 2025-01-16 | — | iQure Pharma Inc |
bexicaserin hydrochloride (bexicaserin) | small molecules | FDA | 2024-09-17 | — | Longboard Pharmaceuticals, Inc. |
Adeno-associated virus serotype 9 expressing a transcription factor for the SCN1A gene | gene therapies | EMA | 2023-05-22 | — | Pharma Gateway AB |
small molecule agonist of 5-hydroxytryptamine serotonergic receptors | small molecules | FDA | 2022-07-27 | — | Xenon Pharmaceuticals Inc. |
18‐mer antisense oligonucleotide complementary to SCN1A mRNA, sodium salt | oligonucleotides | EMA | 2022-02-24 | — | Biogen Netherlands B.V. |
2-[(3-Methylbutyl)amino]-1,4-naphthalenedione | small molecules | FDA | 2021-10-12 | — | Neuroene Therapeutics |
Lorcaserin hydrochloride | small molecules | EMA | 2021-03-26 | — | Premier Research Group S.L. |
Lorcaserin | small molecules | FDA | 2020-08-31 | — | Eisai Inc. |
non-replicating recombinant adeno associated viral vector, serotype 9, designed to promote increased transcription of SCN1A gene | gene therapies | FDA | 2020-05-14 | — | Encoded Therapeutics |
18-mer antisense oligonucleotide complementary to SCN1A mRNA | oligonucleotides | FDA | 2019-08-05 | — | Stoke Therapeutics, Inc. |
diazepam | small molecules | FDA | 2018-05-23 | — | Xeris Pharmaceutical, Inc. |
cannabidiol | small molecules | FDA | 2017-12-21 | — | AXIUM Pharmaceuticals, Inc. |
cholesterol 24S-hydroxylase inhibitor | small molecules | FDA | 2017-11-29 | — | Takeda Development Center Americas, Inc. |
trazodone | small molecules | FDA | 2017-08-18 | — | Epygenix Therapeutics, Inc. |
clemizole | small molecules | FDA | 2017-04-19 | — | Epygenix Therapeutics, Inc. |
lorcaserin | small molecules | FDA | 2017-04-17 | — | Epygenix Therapeutics, Inc. |
Huperzine A | small molecules | FDA | 2017-04-12 | — | Supernus Pharmaceuticals, Inc. |
synthetic, single stranded, fully phosphorothioated 2¿-OMethyl-RNA and DNA mixmer oligonucleotide-based compound targeted against natural antisense transcripts (NATs) | oligonucleotides | FDA | 2017-03-16 | — | Camp4 Therapeutics |
26 base synthetic single-stranded fully phosphorothioated 2'-O-methyl-RNA and DNA mixmer oligonucleotide-based compound | oligonucleotides | EMA | 2017-02-27 | — | S-cubed Pharmaceutical Services ApS |
Cannabidiol [Epidyolex] | small molecules | EMA | 2014-10-15 | 2019-09-23 | Jazz Pharmaceuticals Ireland Limited |
cannabidiol | small molecules | FDA | 2014-07-01 | — | Insys Development Company, Inc. |
fenfluramine HCI [Fintepla] | small molecules | FDA | 2013-12-20 | 2020-06-25 | UCB, Inc. |
Fenfluramine hydrochloride [Fintepla] | small molecules | EMA | 2013-12-18 | 2020-12-21 | UCB Pharma |
cannabidiol [Epidiolex] | small molecules | FDA | 2013-11-14 | 2018-09-28 | Jazz Pharmaceuticals Research UK Limited |
stiripentol [Diacomit] | small molecules | FDA | 2008-10-30 | 2018-08-20 | Biocodex |
Clonazepam Intranasal Spray | small molecules | FDA | 2007-12-19 | — | Jazz Pharmaceuticals, Inc. |
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