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Neurotherapeutics

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01.07.2021 | Review

Dravet Syndrome: Novel Approaches for the Most Common Genetic Epilepsy

verfasst von: Lori L. Isom, Kelly G. Knupp

Erschienen in: Neurotherapeutics | Ausgabe 3/2021

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Abstract

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy that is mainly associated with variants in SCN1A. While drug-resistant epilepsy is the most notable feature of this syndrome, numerous symptoms are present that have significant impact on patients’ quality of life. In spite of novel, third-generation anti-seizure treatment options becoming available over the last several years, seizure freedom is often not attained and non-seizure symptoms remain. Precision medicine now offers realistic hope for seizure freedom in DS patients, with several approaches demonstrating preclinical success. Therapeutic approaches such as antisense oligonucleotides (ASO) and adeno-associated virus (AAV)-delivered gene modulation have expanded the potential treatment options for DS, with some of these approaches now transitioning to clinical trials. Several of these treatments may risk the exacerbation of gain-of-function variants and may not be reversible, therefore emphasizing the need for functional testing of new pathogenic variants. The current absence of treatments that address the overall disease, in addition to seizures, exposes the urgent need for reliable, valid measures of the entire complement of symptoms as outcome measures to truly know the impact of treatments on DS. Additionally, with so many treatment options on the horizon, there will be a need to understand how to select appropriate patients for each treatment, whether treatments are complementary or adverse to each other, and long-term risks of the treatment. Nevertheless, precision therapeutics hold tremendous potential to provide long-lasting seizure freedom and even complete cures for this devastating disease.

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Wu, Y.W., et al., Incidence of Dravet Syndrome in a US Population. Pediatrics, 2015. 136(5): p. e1310-5.PubMedPubMedCentralCrossRef

Depienne, C., et al., Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet, 2009. 46(3): p. 183-91.PubMedCrossRef

Zuberi, S.M., et al., Genotype-phenotype associations in SCN1A-related epilepsies. Neurology, 2011. 76(7): p. 594-600.PubMedCrossRef

Genton, P., R. Velizarova, and C. Dravet, Dravet syndrome: the long-term outcome. Epilepsia, 2011. 52 Suppl 2: p. 44-9.PubMedCrossRef

Wolff, M., C. Casse-Perrot, and C. Dravet, Severe myoclonic epilepsy of infants (Dravet syndrome): natural history and neuropsychological findings. Epilepsia, 2006. 47 Suppl 2: p. 45-8.PubMedCrossRef

Wirrell, E.C., et al., Optimizing the Diagnosis and Management of Dravet Syndrome: Recommendations From a North American Consensus Panel. Pediatr Neurol, 2017. 68: p. 18–34 e3.

Akiyama, M., et al., A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia, 2010. 51(6): p. 1043-52.PubMedCrossRef

Takayama, R., et al., Long-term course of Dravet syndrome: a study from an epilepsy center in Japan. Epilepsia, 2014. 55(4): p. 528-38.PubMedCrossRef

Wirrell, E.C. and R. Nabbout, Recent Advances in the Drug Treatment of Dravet Syndrome. CNS Drugs, 2019. 33(9): p. 867-881.PubMedCrossRef

10.

Cross, J.H., et al., Dravet syndrome: Treatment options and management of prolonged seizures. Epilepsia, 2019. 60 Suppl 3: p. S39-S48.PubMed

11.

de Lange, I.M., et al., Outcomes and comorbidities of SCN1A-related seizure disorders. Epilepsy Behav, 2019. 90: p. 252-259.PubMedCrossRef

12.

Licheni, S.H., et al., Sleep problems in Dravet syndrome: a modifiable comorbidity. Dev Med Child Neurol, 2018. 60(2): p. 192-198.PubMedCrossRef

13.

Lagae, L., et al., Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey. Dev Med Child Neurol, 2018. 60(1): p. 63-72.PubMedCrossRef

14.

Villas, N., M.A. Meskis, and S. Goodliffe, Dravet syndrome: Characteristics, comorbidities, and caregiver concerns. Epilepsy Behav, 2017. 74: p. 81-86.PubMedCrossRef

15.

Olivieri, G., et al., Cognitive-behavioral profiles in teenagers with Dravet syndrome. Brain Dev, 2016. 38(6): p. 554-62.PubMedCrossRef

16.

Connolly, M.B., Dravet Syndrome: Diagnosis and Long-Term Course. Can J Neurol Sci, 2016. 43 Suppl 3: p. S3-8.PubMedCrossRef

17.

Knupp, K.G., et al., Parental Perception of Comorbidities in Children With Dravet Syndrome. Pediatr Neurol, 2017. 76: p. 60-65.PubMedCrossRef

18.

Eschbach, K., et al., Growth and endocrine function in children with Dravet syndrome. Seizure, 2017. 52: p. 117-122.PubMedCrossRef

19.

Berg, A.T., et al., Nonseizure consequences of Dravet syndrome, KCNQ2-DEE, KCNB1-DEE, Lennox-Gastaut syndrome, ESES: A functional framework. Epilepsy Behav, 2020. 111: p. 107287.

20.

Nabbout, R., et al., Perception of impact of Dravet syndrome on children and caregivers in multiple countries: looking beyond seizures. Dev Med Child Neurol, 2019. 61(10): p. 1229-1236.PubMedCrossRef

21.

Cooper, M.S., et al., Mortality in Dravet syndrome. Epilepsy Res, 2016. 128: p. 43-47.PubMedCrossRef

22.

Shmuely, S., et al., Mortality in Dravet syndrome: A review. Epilepsy Behav, 2016. 64(Pt A): p. 69-74.PubMedCrossRef

23.

Jansson, J.S., T. Hallböök, and C. Reilly, Intellectual functioning and behavior in Dravet syndrome: A systematic review. Epilepsy Behav, 2020. 108: p. 107079.

24.

Brown, A., et al., Cognitive, behavioral, and social functioning in children and adults with Dravet syndrome. Epilepsy Behav, 2020. 112: p. 107319.

25.

Verheyen, K., et al., Independent walking and cognitive development in preschool children with Dravet syndrome. Dev Med Child Neurol, 2020.

26.

Ceulemans, B., Overall management of patients with Dravet syndrome. Dev Med Child Neurol, 2011. 53 Suppl 2: p. 19-23.PubMedCrossRef

27.

Ishii, A., et al., Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome. Epilepsia, 2017. 58(2): p. 282-290.PubMedCrossRef

28.

Riva, D., et al., Progressive neurocognitive decline in two children with Dravet syndrome, de novo SCN1A truncations and different epileptic phenotypes. Am J Med Genet A, 2009. 149a(10): p. 2339–45.

29.

Rilstone, J.J., et al., Dravet syndrome: seizure control and gait in adults with different SCN1A mutations. Epilepsia, 2012. 53(8): p. 1421-8.PubMedCrossRef

30.

Rodda, J.M., et al., Progressive gait deterioration in adolescents with Dravet syndrome. Arch Neurol, 2012. 69(7): p. 873-8.PubMedCrossRef

31.

Black, L. and D. Gaebler-Spira, Crouch Gait in Dravet Syndrome. Pediatr Neurol Briefs, 2016. 30(11): p. 42.PubMedPubMedCentralCrossRef

32.

Claes, L., et al., De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet, 2001. 68(6): p. 1327-32.PubMedPubMedCentralCrossRef

33.

Scheffer, I.E. and R. Nabbout, SCN1A-related phenotypes: Epilepsy and beyond. Epilepsia, 2019. 60 Suppl 3: p. S17-S24.PubMed

34.

Catterall, W.A., Dravet Syndrome: A Sodium Channel Interneuronopathy. Curr Opin Physiol, 2018. 2: p. 42-50.PubMedCrossRef

35.

Berecki, G., et al., SCN1A gain of function in early infantile encephalopathy. Ann Neurol, 2019. 85(4): p. 514-525.PubMedCrossRef

36.

Loscher, W., et al., Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options. Pharmacol Rev, 2020. 72(3): p. 606-638.PubMedPubMedCentralCrossRef

37.

Han, Z., 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).

38.

Lim, K.H., et al., Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression. Nat Commun, 2020. 11(1): p. 3501.PubMedPubMedCentralCrossRef

39.

Scharner, J. and I. Aznarez, Clinical Applications of Single-Stranded Oligonucleotides: Current Landscape of Approved and In-Development Therapeutics. Mol Ther, 2021. 29(2): p. 540-554.PubMedCrossRef

40.

Carvill, G.L., et al., Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies. Am J Hum Genet, 2018. 103(6): p. 1022-1029.PubMedPubMedCentralCrossRef

41.

Mistry, A.M., et al., Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice. Neurobiol Dis, 2014. 65: p. 1-11.PubMedPubMedCentralCrossRef

42.

Liau, G., et al., TANGO OLIGONUCLEOTIDES FOR THE TREATMENT OF DRAVET SYNDROME: SAFETY, BIODISTRIBUTION, AND PHARMACOLOGY IN THE NON-HUMAN PRIMATE. AES 2019 Annual Meeting Abstract Database. AESnet.org., 2019. Abstr. 2.195.

43.

Laux, L., et al., SAFETY AND PHARMACOKINETICS OF ANTISENSE OLIGONUCLEOTIDE STK-001 IN CHILDREN AND ADOLESCENTS WITH DRAVET SYNDROME: SINGLE ASCENDING DOSE DESIGN FOR THE OPEN-LABEL PHASE 1/2A MONARCH STUDY. AES 2020 Annual Meeting Abstract Database. AESnet.org., 2020. Abstr. 344.

44.

Marini, C., et al., The genetics of Dravet syndrome. Epilepsia, 2011. 52 Suppl 2: p. 24-9.PubMedCrossRef

45.

Sadleir, L.G., et al., Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype. Neurology, 2017. 89(10): p. 1035-1042.PubMedPubMedCentralCrossRef

46.

Meisler, M.H., SCN8A encephalopathy: Mechanisms and models. Epilepsia, 2019. 60 Suppl 3: p. S86-S91.PubMedPubMedCentral

47.

Martin, M.S., et al., The voltage-gated sodium channel Scn8a is a genetic modifier of severe myoclonic epilepsy of infancy. Hum Mol Genet, 2007. 16(23): p. 2892-9.PubMedCrossRef

48.

Lenk, G.M., et al., Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome. Ann Neurol, 2020. 87(3): p. 339-346.PubMedPubMedCentralCrossRef

49.

Wu, Z., H. Yang, and P. Colosi, Effect of genome size on AAV vector packaging. Mol Ther, 2010. 18(1): p. 80-6.PubMedCrossRef

50.

Ricobaraza, A., et al., High-Capacity Adenoviral Vectors: Expanding the Scope of Gene Therapy. Int J Mol Sci, 2020. 21(10).

51.

Yu, F.H., et al., Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nat Neurosci, 2006. 9(9): p. 1142-9.PubMedCrossRef

52.

Liu, Y., et al., Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol, 2013. 74(1): p. 128-39.PubMedPubMedCentralCrossRef

53.

AN, Y., et al., A GABA-Selective AAV Vector-Based Approach to Up-Regulate Endogenous Scn1a Expression Reverses Key Phenotypes in a Mouse Model of Dravet Syndrome. Molecular Therapy, 2019. 27(4S1): p. Abstract 915.

54.

Belle, A., et al., ETX101, A GABAERGIC INTERNEURON SELECTIVE AAV-MEDIATED GENE THERAPY FOR THE TREATMENT OF SCN1A+ DRAVET SYNDROME: BIODISTRIBUTION AND SAFETY IN NON-HUMAN PRIMATES. AES 2020 Annual Meeting Abstract Database. AESnet.org., 2020. Abst. 391.

55.

O'Malley, H.A. and L.L. Isom, Sodium Channel beta Subunits: Emerging Targets in Channelopathies. Annu Rev Physiol, 2015. 77: p. 481-504.PubMedPubMedCentralCrossRef

56.

Bouza, A.A., et al., Sodium channel beta1 subunits participate in regulated intramembrane proteolysis-excitation coupling. JCI Insight, 2021 Feb 8;6(3):e141776. https://doi.org/10.1172/jci.insight.141776.

57.

Niibori, Y., et al., Sexually Divergent Mortality and Partial Phenotypic Rescue After Gene Therapy in a Mouse Model of Dravet Syndrome. Hum Gene Ther, 2020. 31(5-6): p. 339-351.PubMedPubMedCentralCrossRef

58.

Doudna, J.A. and E. Charpentier, Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science, 2014. 346(6213): p. 1258096.

59.

Jinek, M., et al., A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science, 2012. 337(6096): p. 816-21.PubMedPubMedCentralCrossRef

60.

Gasiunas, G., et al., Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria. Proc Natl Acad Sci U S A, 2012. 109(39): p. E2579-86.PubMedPubMedCentralCrossRef

61.

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

62.

Colasante, G., et al., dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice. Mol Ther, 2020. 28(1): p. 235-253.PubMedCrossRef

63.

Ogiwara, I., et al., Na(v)1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci, 2007. 27(22): p. 5903–14.

64.

Wilson, J.M., Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab, 2009. 96(4): p. 151-7.PubMedCrossRef

65.

Grimm, D., et al., Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature, 2006. 441(7092): p. 537-41.PubMedCrossRef

66.

Bevan, A.K., et al., Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol Ther, 2011. 19(11): p. 1971-80.PubMedPubMedCentralCrossRef

67.

Chand, D., et al., Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J Hepatol, 2021. 74(3): p. 560-566.PubMedCrossRef

68.

Feldman, A.G., et al., Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1. J Pediatr, 2020. 225: p. 252–258 e1.

69.

Hinderer, C., et al., Severe Toxicity in Nonhuman Primates and Piglets Following High-Dose Intravenous Administration of an Adeno-Associated Virus Vector Expressing Human SMN. Hum Gene Ther, 2018. 29(3): p. 285-298.PubMedPubMedCentralCrossRef

70.

Stevens, D., et al., Onasemnogene Abeparvovec-xioi: Gene Therapy for Spinal Muscular Atrophy. Ann Pharmacother, 2020. 54(10): p. 1001-1009.PubMedCrossRef

71.

Waldrop, M.A., et al., Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes. Pediatrics, 2020. 146(3).

72.

Darras, B.T., et al., An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs, 2019. 33(9): p. 919-932.PubMedPubMedCentralCrossRef

73.

Jason, T.L., J. Koropatnick, and R.W. Berg, Toxicology of antisense therapeutics. Toxicol Appl Pharmacol, 2004. 201(1): p. 66-83.PubMedCrossRef

74.

Chan, J.H., S. Lim, and W.S. Wong, Antisense oligonucleotides: from design to therapeutic application. Clin Exp Pharmacol Physiol, 2006. 33(5-6): p. 533-40.PubMedCrossRef

75.

Connock, M., et al., Will the US$5 million onasemnogene abeparvosec treatment for spinal muscular atrophy represent 'value for money' for the NHS? A rapid inquiry into suggestions that it may be cost-effective. Expert Opin Biol Ther, 2020. 20(7): p. 823-827.PubMedCrossRef

76.

Dangouloff, T., et al., Systematic literature review of the economic burden of spinal muscular atrophy and economic evaluations of treatments. Orphanet J Rare Dis, 2021. 16(1): p. 47.PubMedPubMedCentralCrossRef

77.

Campbell, J.D., et al., Assessing the impact of caring for a child with Dravet syndrome: Results of a caregiver survey. Epilepsy Behav, 2018. 80: p. 152-156.PubMedCrossRef

78.

Jensen, M.P., et al., The humanistic and economic burden of Dravet syndrome on caregivers and families: Implications for future research. Epilepsy Behav, 2017. 70(Pt A): p. 104-109.PubMedCrossRef

79.

Whittington, M.D., et al., The direct and indirect costs of Dravet Syndrome. Epilepsy Behav, 2018. 80: p. 109-113.PubMedCrossRef

Titel: Dravet Syndrome: Novel Approaches for the Most Common Genetic Epilepsy
verfasst von: Lori L. Isom
Kelly G. Knupp
Publikationsdatum: 01.07.2021
Verlag: Springer International Publishing
Erschienen in: Neurotherapeutics / Ausgabe 3/2021
Print ISSN: 1933-7213
Elektronische ISSN: 1878-7479
DOI: https://doi.org/10.1007/s13311-021-01095-6

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