379
Views
1
CrossRef citations to date
0
Altmetric
Review

Current and promising therapeutic options for Dravet syndrome

, , , , , , , & ORCID Icon show all
Pages 1727-1736 | Received 31 Mar 2022, Accepted 17 Sep 2022, Published online: 21 Sep 2022

References

  • Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia. 2017;58(4):512–521.
  • Dravet C. The core Dravet syndrome phenotype. Epilepsia. 2011 Apr;52 Suppl 2:3–9.
  • Zuberi SM, Wirrell E, Yozawitz E, et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE task force on nosology and definitions. Epilepsia. 2022;63(6):1349–1397.
  • Hurst DL. Epidemiology of severe myoclonic epilepsy of infancy. Epilepsia. 1990 Jul-Aug;31(4):397–400.
  • Rosander C, Hallböök T. Dravet syndrome in Sweden: a population-based study. Dev Med Child Neurol. 2015;57(7):628–633.
  • Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet syndrome in a US Population. Pediatrics. 2015;136(5):1310–1315.
  • Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet. 2009;46(3):183–191.
  • Li W, Schneider AL, Scheffer IE. Defining Dravet syndrome: an essential pre-requisite for precision medicine trials. Epilepsia. 2021;62(9):2205–2217.
  • Cooper MS, Mcintosh A, Crompton DE, et al. Mortality in Dravet syndrome. Epilepsy Res. 2016;128:43–47.
  • Chemaly N, Kuchenbuch M, Teng T, et al. A European pilot study in Dravet syndrome to delineate what really matters for the patients and families. Epilepsia Open. 2021. DOI:10.1002/epi4.12557.
  • Mei D, Cetica V, Marini C, et al. Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies. Epilepsia. 2019;60 Suppl 3:S2–S7.
  • Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia. 2011;52(Suppl 2):24–29.
  • Catterall WA. Sodium channel mutations and epilepsy. In: editors, Noebels JL, Avoli M, Rogawski MA, et al. Jasper’s basic mechanisms of the epilepsies [Internet]. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012.
  • Patino GA, Claes LR, Lopez-Santiago LF, et al. A functional null mutation of SCN1B in a patient with Dravet syndrome. J Neurosci. 2009;29(34):10764–10778.
  • Ogiwara I, Nakayama T, Yamagata T, et al. A homozygous mutation of voltage-gated sodium channel β I gene SCN1B in a patient with Dravet syndrome. Epilepsia. 2012;53(12):200–203.
  • de Lera Ruiz M, Kraus RL. Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications. J Med Chem. 2015;58(18):7093–7118.
  • SCN1A gene [Internet]. Available at: https://www.genecards.org/cgi-bin/carddisp.pl?gene=SCN1A
  • Bender AC, Morse RP, Scott RC, et al. SCN1A mutations in Dravet syndrome: impact of interneuron dysfunction on neural networks and cognitive outcome. Epilepsy Behav. 2012;23(3):177–186.
  • Zuberi SM, Brunklaus A, Birch R, et al. Genotype-phenotype associations in SCN1A-related epilepsies. Neurology. 2011;76(7):594–600.
  • Scheffer IE, Zhang YH, Jansen FE, et al. Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus? Brain Dev. 2009;31(5):394–400.
  • Wang W, Takashima S, Segawa Y, et al. The developmental changes of Na(v)1.1 and Na(v)1.2 expression in the human hippocampus and temporal lobe. Brain Res. 2011;1389:61–70.
  • Connolly MB. Dravet syndrome: diagnosis and long-term course. Can J Neurol Sci. 2016;43(S3):S3–8.
  • Lagae L. Dravet syndrome. Curr Opin Neurol. 2021;34(2):213–218.
  • Chiron C, Dulac O. The pharmacologic treatment of Dravet syndrome. Epilepsia. 2011;52(Suppl 2):72–75.
  • Inoue Y, Nishida T. Expert consensus on treatment of epilepsy. J Jpn Epilepsy Soc. 2004: 128–139
  • Wirrell EC, Laux L, Donner E, et al. Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American Consensus Panel. Pediatr Neurol. 2017;68:18–34.e3.
  • Cross JH, Caraballo RH, Nabbout R, et al. Dravet syndrome: treatment options and management of prolonged seizures. Epilepsia. 2019;60 Suppl 3:S39–S48.
  • Wallace A, Wirrell E, Kenney-Jung DL. Pharmacotherapy for Dravet Syndrome. Paediatr Drugs. 2016;18(3):197–208.
  • Inoue Y, Ohtsuka Y, Oguni H, et al. Stiripentol open study in Japanese patients with Dravet syndrome. Epilepsia. 2009;50(11):2362–2368.
  • Nickels KC, Wirrell EC. Stiripentol in the management of epilepsy. CNS Drugs. 2017;31(5):405–416.
  • Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet. 2000;356(9242):1638–1642.
  • Thanh TN, Chiron C, Dellatolas G, et al. Efficacité et tolérance à long terme du stiripentol dans le traitement de l’épilepsie myoclonique sévère du nourrisson (syndrome de Dravet) [Long-term efficacy and tolerance of stiripentaol in severe myoclonic epilepsy of infancy (Dravet’s syndrome)]. Arch Pediatr. 2002;9(11):1120–1127. French.
  • Nieto-Barrera M, Candau R, Nieto-Jimenez M, et al. Topiramate in the treatment of severe myoclonic epilepsy in infancy. Seizure. 2000;9(8):590–594.
  • Coppola G, Capovilla G, Montagnini A, et al. Topiramate as add-on drug in severe myoclonic epilepsy in infancy: an Italian multicenter open trial. Epilepsy Res. 2002;49(1):45–48.
  • Kröll-Seger J, Portilla P, Dulac O, et al. Topiramate in the treatment of highly refractory patients with Dravet syndrome. Neuropediatrics. 2006;37(6):325–329.
  • Korff C, Laux L, Kelley K, et al. Dravet syndrome (severe myoclonic epilepsy in infancy): a retrospective study of 16 patients. J Child Neurol. 2007;22(2):185–194.
  • Striano P, Coppola A, Pezzella M, et al. An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy. Neurology. 2007;69(3):250–254.
  • Verrotti A, Castagnino M, Maccarrone M, et al. Plant-derived and endogenous cannabinoids in epilepsy. Clin Drug Investig. 2016;36(5):331–340.
  • Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011–2020.
  • an open label extension study of cannabidiol (GWP42003-P) in children and adults with Dravet or lennox-gastaut syndromes (GWPCARE5). ClinicalTrials.gov Identifier: NCT02224573. https://clinicaltrials.gov/ct2/show/study/NCT02224573
  • Scheffer IE, Halford JJ, Miller I, et al. Add-on cannabidiol in patients with Dravet syndrome: results of a long-term open-label extension trial. Epilepsia. 2021;62(10):2505–2517.
  • Johannessen Landmark C, Potschka H, Auvin S, et al., The role of new medical treatments for the management of developmental and epileptic encephalopathies: novel concepts and results. Epilepsia. 2021;62(4):857–873.
  • Schoonjans AS, Ceulemans B. A critical evaluation of fenfluramine hydrochloride for the treatment of Dravet syndrome. Expert Rev Neurother. 2022;22(5):351–364.
  • Tupal S, Faingold CL. Fenfluramine, a serotonin-releasing drug, prevents seizure-induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP. Epilepsia. 2019;60(3):485–494.
  • Strzelczyk A, Pringsheim M, Mayer T, et al. Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: compassionate use program in Germany. Epilepsia. 2021;62(10):2518–2527.
  • Gil-Nagel A, Sullivan J, Ceulemans B, et al. Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth. Epilepsy Behav. 2021;122:108212.
  • Lagae L, Sullivan J, Knupp K, et al., Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomized, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243–2254.
  • Nabbout R, Mistry A, Zuberi S, et al. Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77(3):300–308.
  • Sullivan J, Specchio N, Devinsky O, et al. Fenfluramine significantly reduces day-to-day seizure burden by increasing number of seizure-free days and time between seizures in patients with Dravet syndrome: a time-to-event analysis. Epilepsia. 2022;63(1):130–138.
  • Lai WW, Galer BS, Wong PC, et al. Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing long-term open-label safety extension study. Epilepsia. 2020;61(11):2386–2395.
  • Sullivan J, Scheffer IE, Lagae L, et al. Fenfluramine HCl (Fintepla ®) provides long-term clinically meaningful reduction in seizure frequency: analysis of an ongoing open-label extension study. Epilepsia. 2020;61(11):2396–2404.
  • Specchio N, Pietrafusa N, Doccini V, et al. Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia. 2020;61(11):2405–2414.
  • Brigo F, Striano P, Balagura G, et al. Emerging drugs for the treatment of Dravet syndrome. Expert Opin Emerg Drugs. 2018;23(4):261–269.
  • Samanta D. Changing landscape of Dravet syndrome management: an overview. Neuropediatrics. 2020;51(2):135–145.
  • Iannetti P, Parisi P, Spalice A, et al. Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. Epilepsy Res. 2009;85(1):89–95.
  • Nicita F, Spalice A, Papetti L, et al. Efficacy of verapamil as an adjunctive treatment in children with drug-resistant epilepsy: a pilot study. Seizure. 2014;23(1):36–40.
  • Cardenal-Muñoz E, Auvin S, Villanueva V, et al. Guidance on Dravet syndrome from infant to adult care: road map for treatment planning in Europe. Epilepsia Open. 2022;7(1):11–26.
  • Wang Y-Q, Fang Z-X, Zhang Y-W, et al. Efficacy of the ketogenic diet in patients with Dravet syndrome: a meta-analysis. Seizure. 2020;81:36–42.
  • Rotondo E, Riva A, Graziosi A, et al., Non-pharmacological treatments for pediatric refractory epilepsies. Expert Rev Neurother. 2022;22(4):337–349.
  • Hawkins NA, Jurado M, Thaxton TT, et al. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice. Epilepsia. 2021;62(11):2845–2857.
  • Paul SM, Doherty JJ, Robichaud AJ, et al. The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors. J Neurosci. 2013;33(44):17290–17300.
  • Bialer M, Johannessen SI, Koepp MJ, et al. Progress report on new antiepileptic drugs: a summary of the fourteenth Eilat conference on new antiepileptic drugs and devices (EILAT XIV). I. Drugs in preclinical and early clinical development. Epilepsia. Madrid. 1811–1841 (2018).
  • Nishi T, Kondo S, Miyamoto M, et al. Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice. Sci Rep. 2020;10(1):17081.
  • Study of TAK-935 as an adjunctive therapy in participants with developmental and/or epileptic encephalopathies. ClinicalTrials.gov Identifier: NCT03166215NCT03166215. https://clinicaltrials.gov/ct2/show/NCT03166215
  • Halford JJ, Sperling MR, Arkilo D, et al. A phase 1b/2a study of soticlestat as adjunctive therapy in participants with developmental and/or epileptic encephalopathies. Epilepsy Res. 2021;174:106646.
  • Hahn CD, Jiang Y, Villanueva V, et al. Efficacy, safety and tolerability of soticlestat (TAK-935/OV935) as adjunctive therapy in pediatric patients with Dravet syndrome and lennox-gastaut syndrome (ELEKTRA) (4234). Neurology. 2021;4234(15 Supplement).
  • A phase 2, prospective, interventional, open-label, multi-site, extension study to assess the long-term safety and tolerability of TAK-935 (OV935) as adjunctive therapy in patients with rare epilepsy (Endymion). ClinicalTrials.gov Identifier: NCT03635073. https://clinicaltrials.gov/ct2/show/NCT03635073
  • A study of soticlestat as an add-on therapy in children and young adults with Dravet syndrome. ClinicalTrials.gov Identifier: NCT04940624. https://clinicaltrials.gov/ct2/show/NCT04940624
  • Baraban SC, Dinday MT, Hortopan GA. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun. 2013;4(1):2410.
  • Griffin A, Hamling KR, Knupp K, et al. Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017;140(3):669–683.
  • Thomsen WJ, Grottick AJ, Menzaghi F, et al. Lorcaserin, a novel selective human 5-hydroxytryptamine 2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther. 2008;325(2):577–587.
  • Tolete P, Knupp K, Karlovich M, et al. Lorcaserin therapy for severe epilepsy of childhood onset: a case series. Neurology. 2018;91(18):837–839.
  • Bialer M, Perucca E. Lorcaserin for Dravet syndrome: a potential advance over fenfluramine? CNS Drugs. 2022;36(2):113–122.
  • A study of lorcaserin as adjunctive treatment in participants with Dravet syndrome (MOMENTUM 1). ClinicalTrials.gov Identifier: NCT04572243. https://clinicaltrials.gov/ct2/show/NCT04572243
  • EPX-100 (Clemizole Hydrochloride) as add-on therapy to control convulsive seizures in patients with Dravet syndrome (ARGUS). ClinicalTrials.gov Identifier: NCT04462770. https://clinicaltrials.gov/ct2/show/NCT04462770
  • Wong JC, Dutton SB, Collins SD, et al. Huperzine A provides robust and sustained protection against induced seizures in scn1a mutant mice. Front Pharmacol. 2016;7:357.
  • Bioavailability, safety, and tolerability of BIS-001 ER. ClinicalTrials.gov Identifier: NCT03156439. https://clinicaltrials.gov/ct2/show/NCT03156439
  • BIS-001-ER for the treatment of adult focal impaired awareness Seizures (FIAS). ClinicalTrials.gov Identifier: NCT03474770. https://clinicaltrials.gov/ct2/show/NCT03474770
  • Wong JC, Thelin JT, Escayg A. Donepezil increases resistance to induced seizures in a mouse model of Dravet syndrome. Ann Clin Transl Neurol. 2019;6(8):1566–1571.
  • Campbell C, Barohn RJ, Bertini E, et al. Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy. J Comp Eff Res. 2020;9(14):973–984.
  • Devinsky O, King L, Bluvstein J, et al. Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder. Ann Clin Transl Neurol. 2021;8(3):639–644.
  • Ataluren for nonsense mutation in CDKL5 and Dravet syndrome. ClinicalTrials.gov Identifier: NCT02758626. https://clinicaltrials.gov/ct2/show/NCT02758626
  • Anderson LL, Hawkins NA, Thompson CH, et al. Unexpected efficacy of a novel sodium channel modulator in Dravet syndrome. Sci Rep. 2017;7(1):1682.
  • Jensen HS, Grunnet M, Bastlund JF. Therapeutic potential of Na(V)1.1 activators. Trends Pharmacol Sci. 2014;35(3):113–118.
  • Weuring WJ, Singh S, Volkers L, et al. NaV1.1 and NaV1.6 selective compounds reduce the behavior phenotype and epileptiform activity in a novel zebrafish model for Dravet syndrome. PLoS One. 2020;15(3):e0219106.
  • Richards KL, Milligan CJ, Richardson RJ, et al. Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death. Proc Natl Acad Sci U S A. 2018;115(34):E8077–E8085.
  • Frederiksen K, Lu D, Yang J, et al. A small molecule activator of Nav 1.1 channels increases fast-spiking interneuron excitability and GABAergic transmission in vitro and has anti-convulsive effects in vivo. Eur J Neurosci. 2017;46(3):1887–1896.
  • Chow CY, Chin YK, Walker AA, et al. Venom peptides with dual modulatory activity on the voltage-gated sodium channel NaV1.1 provide novel leads for development of antiepileptic drugs. ACS Pharmacol Transl Sci. 2019;3(1):119–134.
  • Chow CY, Chin YKY, Ma L, et al. A selective NaV1.1 activator with potential for treatment of Dravet syndrome epilepsy. Biochem Pharmacol. 2020;181:113991. DOI:10.1016/j.bcp.2020.113991.
  • Miyazaki T, Kawasaki M, Suzuki A, et al. Discovery of novel 4-phenyl-2-(pyrrolidinyl)nicotinamide derivatives as potent Nav1.1 activators. Bioorg Med Chem Lett. 2019;29(6):815–820.
  • Arribas-Blázquez M, Piniella D, Olivos-Oré LA, et al. Regulation of the voltage-dependent sodium channel NaV1.1 by AKT1. Neuropharmacology. 2021;197:108745.
  • Riva A, Guglielmo A, Balagura G, et al. Emerging treatments for progressive myoclonus epilepsies. Expert Rev Neurother. 2020;20(4):341–350.
  • Higurashi N, Broccoli V, Hirose S. Genetics and gene therapy in Dravet syndrome. Epilepsy Behav. 2021;131(Pt B):108043.
  • Wang D, Tai PWL, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18(5):358–378.
  • Sha S, Maloney AJ, Katsikis G, et al. Cellular pathways of recombinant adeno-associated virus production for gene therpay. Biotechnol Adv. 2021;49:107764.
  • Wagnon JL. TANGO With SCN1A: can this molecular dance defeat Dravet syndrome? Epilepsy Curr. 2021;21(1):60–61.
  • Han Z, Chen C, Christiansen A, et al. Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome. Sci Transl Med. 2020;12(558):eaaz6100.
  • Voskobiynyk Y, Battu G, Felker SA, et al. Aberrant regulation of a poison exon caused by a non-coding variant in a mouse model of Scn1a-associated epileptic encephalopathy. PLoS Genet. 2021;17(1):e1009195.
  • Lenk GM, Jafar-Nejad P, Hill SF, et al. Scn8a antisense oligonucleotide is protective in mouse models of SCN8A encephalopathy and Dravet syndrome. Ann Neurol. 2020;87(3):339–346.
  • Guan L, Han Y, Yang C, et al. CRISPR-Cas9-mediated gene therapy in neurological disorders. Mol Neurobiol. 2022;59(2):968–982.
  • Adli M. The CRISPR tool kit for genome editing and beyond. Nat Commun. 2018;9(1):1911.
  • Colasante G, Lignani G, Brusco S, et al., dCas9-based scn1a gene activation restores inhibitory interneuron excitability and attenuates seizures in Dravet syndrome mice. Mol Ther. 2020;28(1):235–253.
  • Yamagata T, Raveau M, Kobayashi K, et al. CRISPR/dCas9-based Scn1a gene activation in inhibitory neurons ameliorates epileptic and behavioral phenotypes of Dravet syndrome model mice. Neurobiol Dis. 2020;141:104954.
  • Ricci R, Colasante G. CRISPR/dCas9 as a therapeutic approach for neurodevelopmental disorders: innovations and limitations compared to traditional strategies. Dev Neurosci. 2021;43(3–4):253–261.
  • A study to assess the safety and tolerability of zx008 in children and young adults with Dravet syndrome or lennox gastaut syndrome currently taking cannabidiol. Clinical Trials Identifier: NCT03467113. https://clinicaltrials.gov/ct2/show/NCT03467113

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.