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DOI: 10.1055/s-0044-1779694
Antisense Molecules in Epilepsy—A Neuropharmacological Educational Review
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Abstract
Epilepsy is a common neurological disorder. Epilepsy has many therapeutic options, the popular one being antiseizure medications. A good proportion of patients always responds well to the existing treatment modalities. But some patients develop resistant epilepsy, and treating them can be challenging with the current treatment; such scenarios are encountered frequently in patients, especially those under treatment for long-term as well as specific syndromes and channelopathies. Resistant epilepsy warrants the need to develop newer therapeutics for better treatment outcomes, and antisense oligonucleotides (ASOs) are one among them. Our review discusses the more recent startups called ASOs in the context of epilepsy therapeutics.
Publication History
Article published online:
04 March 2024
© 2024. Indian Epilepsy Society. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)
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References
- 1 Thijs RD, Surges R, O'Brien TJ, Sander JW. Epilepsy in adults. Lancet 2019; 393 (10172): 689-701
- 2 Bialer M, White HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov 2010; 9 (01) 68-82
- 3 Pitkänen A, Henshall DC, Cross JH. et al. Advancing research toward faster diagnosis, better treatment, and end of stigma in epilepsy. Epilepsia 2019; 60 (07) 1281-1292
- 4 Klein P, Dingledine R, Aronica E. et al. Commonalities in epileptogenic processes from different acute brain insults: do they translate?. Epilepsia 2018; 59 (01) 37-66
- 5 Blümcke I, Thom M, Aronica E. et al. International Consensus Classification of Hippocampal Sclerosis in Temporal Lobe Epilepsy: a task force report from the ILAE Commission on Diagnostic Methods. Epilepsia 2013; 54 (07) 1315-1329
- 6 Löscher W. The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments. Neuropharmacology 2020; 167: 107605
- 7 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 (04) 512-521
- 8 Liao Y, Deprez L, Maljevic S. et al. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 2010; 133 (Pt 5): 1403-1414
- 9 Gazina EV, Leaw BT, Richards KL. et al. 'Neonatal' Nav1.2 reduces neuronal excitability and affects seizure susceptibility and behaviour. Hum Mol Genet 2015; 24 (05) 1457-1468
- 10 Maljevic S, Reid CA, Petrou S. Models for discovery of targeted therapy in genetic epileptic encephalopathies. J Neurochem 2017; 143 (01) 30-48
- 11 Wolff M, Johannesen KM, Hedrich UBS. et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017; 140 (05) 1316-1336
- 12 Berecki G, Howell KB, Deerasooriya YH. et al. Dynamic action potential clamp predicts functional separation in mild familial and severe de novo forms of SCN2A epilepsy. Proc Natl Acad Sci U S A 2018; 115 (24) E5516-E5525
- 13 Li M, Nikola J, Jafar-Nejad P. et al. Antisense oligonucleotide therapy for SCN2A gain-of-function epilepsy. BioRxiv January 1, 2020; 289-900
- 14 Dravet C, Bureau M, Dalla Bernardina B, Guerrini R. Severe myoclonic epilepsy in infancy (Dravet syndrome) 30 years later. Epilepsia 2011; 52 (Suppl. 02) 1-2
- 15 Dravet C, Bureau M, Oguni H, Fukuyama Y, Cokar O. Severe myoclonic epilepsy in infancy: Dravet syndrome. Adv Neurol 2005; 95: 71-102
- 16 Guerrini R, Aicardi J. Epileptic encephalopathies with myoclonic seizures in infants and children (severe myoclonic epilepsy and myoclonic-astatic epilepsy). J Clin Neurophysiol 2003; 20 (06) 449-461
- 17 Cooper MS, Mcintosh A, Crompton DE. et al. Mortality in Dravet syndrome. Epilepsy Res 2016; 128: 43-47
- 18 Brigo F, Striano P, Balagura G, Belcastro V. Emerging drugs for the treatment of Dravet syndrome. Expert Opin Emerg Drugs 2018; 23 (04) 261-269
- 19 O'Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav 2017; 70 (Pt B): 341-348
- 20 Buck ML, Goodkin HP. Stiripentol: a novel antiseizure medication for the management of Dravet syndrome. Ann Pharmacother 2019; 53 (11) 1136-1144
- 21 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
- 22 Hsiao J, Yuan TY, Tsai MS. et al. Upregulation of Haploinsufficient Gene expression in the brain by targeting a long non-coding RNA improves seizure phenotype in a model of Dravet syndrome. EBioMedicine 2016; 9: 257-277
- 23 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 (03) 339-346
- 24 Wagnon JL. TANGO with SCN1A: can this molecular dance defeat Dravet syndrome?. Epilepsy Curr 2020; 21 (01) 60-61
- 25 Sullivan J, Wirrell EC. Dravet syndrome as an example of precision medicine in epilepsy. Epilepsy Curr 2022; 23 (01) 4-7
- 26 Isom LL, Knupp KG. Dravet syndrome: novel approaches for the most common genetic epilepsy. Neurotherapeutics 2021; 18 (03) 1524-1534
- 27 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 (01) 235-253
- 28 Chilcott E, Díaz JA, Bertram C, Berti M, Karda R. Genetic therapeutic advancements for Dravet syndrome. Epilepsy Behav 2022; 132: 108741
- 29 Glasscock E, Yoo JW, Chen TT, Klassen TL, Noebels JL. Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci 2010; 30 (15) 5167-5175
- 30 Kalachikov S, Evgrafov O, Ross B. et al. Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 2002; 30 (03) 335-341
- 31 Morante-Redolat JM, Gorostidi-Pagola A, Piquer-Sirerol S. et al. Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy. Hum Mol Genet 2002; 11 (09) 1119-1128
- 32 Nobile C, Michelucci R, Andreazza S, Pasini E, Tosatto SC, Striano P. LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum Mutat 2009; 30 (04) 530-536
- 33 Ottman R, Winawer MR, Kalachikov S. et al. LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 2004; 62 (07) 1120-1126
- 34 Rajakulendran S, Hanna MG. The role of calcium channels in epilepsy. Cold Spring Harb Perspect Med 2016; 6 (01) a022723
- 35 Coenen AM, Van Luijtelaar EL. Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet 2003; 33 (06) 635-655
- 36 Turnbull J, Tiberia E, Striano P. et al. Lafora disease. Epileptic Disord 2016; 18 (S2): 38-62
- 37 Nitschke F, Ahonen SJ, Nitschke S, Mitra S, Minassian BA. Lafora disease - from pathogenesis to treatment strategies. Nat Rev Neurol 2018; 14 (10) 606-617
- 38 Ahonen S, Nitschke S, Grossman TR. et al. Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease. Brain 2021; 144 (10) 2985-2993
- 39 Patel DC, Tewari BP, Chaunsali L, Sontheimer H. Neuron-glia interactions in the pathophysiology of epilepsy. Nat Rev Neurosci 2019; 20 (05) 282-297
- 40 Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions. Int J Mol Sci 2016; 17 (10) 1712
- 41 Li MM, Li XM, Zheng XP, Yu JT, Tan L. MicroRNAs dysregulation in epilepsy. Brain Res 2014; 1584: 94-104
- 42 Bencurova P, Baloun J, Musilova K. et al. MicroRNA and mesial temporal lobe epilepsy with hippocampal sclerosis: whole miRNome profiling of human hippocampus. Epilepsia 2017; 58 (10) 1782-1793
- 43 Jimenez-Mateos EM, Engel T, Merino-Serrais P. et al. Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus. Brain Struct Funct 2015; 220 (04) 2387-2399
- 44 Wang W, Guo Y, He L. et al. Overexpression of miRNA-137 in the brain suppresses seizure activity and neuronal excitability: a new potential therapeutic strategy for epilepsy. Neuropharmacology 2018; 138: 170-181
- 45 Gao X, Guo M, Meng D. et al. Silencing MicroRNA-134 alleviates hippocampal damage and occurrence of spontaneous seizures after intraventricular kainic acid-induced status epilepticus in rats. Front Cell Neurosci 2019; 13: 145
- 46 Wang J, Zhao J. MicroRNA dysregulation in epilepsy: from pathogenetic involvement to diagnostic biomarker and therapeutic agent development. Front Mol Neurosci 2021; 14: 650372
- 47 Tao H, Zhao J, Liu T. et al. Intranasal delivery of miR-146a mimics delayed seizure onset in the lithium-pilocarpine mouse model. Mediators Inflamm 2017; 2017: 6512620
- 48 Lee DY, Moon J, Lee ST. et al. Dysregulation of long non-coding RNAs in mouse models of localization-related epilepsy. Biochem Biophys Res Commun 2015; 462 (04) 433-440
- 49 Cui Z, Zhang X, Song H. et al. Differential long non-coding RNA (lncRNA) profiles associated with hippocampal sclerosis in human mesial temporal lobe epilepsy. Int J Clin Exp Pathol 2019; 12 (01) 259-266
- 50 Wan Y, Yang ZQ. LncRNA NEAT1 affects inflammatory response by targeting miR-129-5p and regulating Notch signaling pathway in epilepsy. Cell Cycle 2020; 19 (04) 419-431
- 51 Maag JL, Panja D, Sporild I. et al. Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity. Front Neurosci 2015; 9: 351
- 52 Zhang H, Tao J, Zhang S, Lv X. LncRNA MEG3 reduces hippocampal neuron apoptosis via the PI3K/AKT/mTOR pathway in a rat model of temporal lobe epilepsy. Neuropsychiatr Dis Treat 2020; 16: 2519-2528
- 53 Han CL, Liu YP, Zhao XM. et al. Whole-transcriptome screening reveals the regulatory targets and functions of long non-coding RNA H19 in epileptic rats. Biochem Biophys Res Commun 2017; 489 (02) 262-269
- 54 Wu Q, Yi X. Down-regulation of long noncoding RNA MALAT1 protects hippocampal neurons against excessive autophagy and apoptosis via the PI3K/Akt signaling pathway in rats with epilepsy. J Mol Neurosci 2018; 65 (02) 234-245
- 55 Lipovich L, Dachet F, Cai J. et al. Activity-dependent human brain coding/noncoding gene regulatory networks. Genetics 2012; 192 (03) 1133-1148
- 56 Zhang X, Hamblin MH, Yin KJ. The long noncoding RNA Malat1: its physiological and pathophysiological functions. RNA Biol 2017; 14 (12) 1705-1714
- 57 Hansen TB, Jensen TI, Clausen BH. et al. Natural RNA circles function as efficient microRNA sponges. Nature 2013; 495 (7441): 384-388
- 58 Thomas LF, Sætrom P. Circular RNAs are depleted of polymorphisms at microRNA binding sites. Bioinformatics 2014; 30 (16) 2243-2246
- 59 You X, Vlatkovic I, Babic A. et al. Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci 2015; 18 (04) 603-610
- 60 Gong GH, An FM, Wang Y, Bian M, Wang D, Wei CX. Comprehensive circular RNA profiling reveals the regulatory role of the CircRNA-0067835/miR-155 pathway in temporal lobe epilepsy. Cell Physiol Biochem 2018; 51 (03) 1399-1409
- 61 Lee WJ, Moon J, Jeon D. et al. Possible epigenetic regulatory effect of dysregulated circular RNAs in epilepsy. PLoS One 2018; 13 (12) e0209829
- 62 Chen F, Zheng H, Zhang W. et al. circ_0003170 aggravates human hippocampal neuron injuries by regulating the miR-421/CCL2 axis in cells models of epilepsy. Gen Physiol Biophys 2021; 40 (02) 115-126
- 63 Zheng D, Li M, Li G. et al. Circular RNA circ_DROSHA alleviates the neural damage in a cell model of temporal lobe epilepsy through regulating miR-106b-5p/MEF2C axis. Cell Signal 2021; 80: 109901
- 64 Lemcke H, Steinhoff G, David R. Gap junctional shuttling of miRNA–a novel pathway of intercellular gene regulation and its prospects in clinical application. Cell Signal 2015; 27 (12) 2506-2514
- 65 Betjemann JP, Josephson SA, Lowenstein DH, Burke JF. Trends in status epilepticus-related hospitalizations and mortality: redefined in US practice over time. JAMA Neurol 2015; 72 (06) 650-655
- 66 Welch EM, Barton ER, Zhuo J. et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007; 447 (7140): 87-91
- 67 Hirawat S, Welch EM, Elfring GL. et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007; 47 (04) 430-444
- 68 Devinsky O, King L, Bluvstein J, Friedman D. Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder. Ann Clin Transl Neurol 2021; 8 (03) 639-644