Login Register Cart 0
Review Article

癫痫脑的基因治疗修复：治疗潜力和未来方向

卷 19, 期 6, 2019

页: [367 - 375] 页: 9

弟呕挨: 10.2174/1566523220666200131142423

价格: $65

摘要

癫痫病是一种常见的癫痫发作综合征，是最普遍的神经系统疾病之一，三分之一的癫痫患者对现有药物有抗药性。外科手术被认为是治疗多药耐药性癫痫的主要方法，但是它是一个剧烈的过程。基因组技术的进步表明基因治疗可以使这种手术成为不必要。大量的新研究显示了雷帕霉素途径，NMDA受体，GABA受体，钾通道和G蛋白偶联受体在哺乳动物靶标中的突变的重要性。给出了针对癫痫病中的细微药物的例证，该药物靶向SCN8A，GRIN2A，GRIN2D和KCNT1中突变的新表达。利用各种方法在大脑的精确区域表达基因。以离体方法移植细胞（胎儿细胞，成纤维细胞，永生细胞），非病毒载体递送和病毒载体递送，如逆转录病毒，单纯疱疹病毒腺病毒和腺相关病毒。因此，已经探索了基因疗法来产生抗癫痫药，抗癫痫发作和改善疾病的作用。基因疗法可促进对癫痫发生区的特异性靶向，从而节省邻近的健康组织并减少与抗癫痫药物经常并存的不良反应。

关键词: 通道病，癫痫，基因治疗，神经保护，癫痫持续状态，颞叶癫痫，非病毒载体的递送，病毒载体的递送。

« Previous Next »
图形摘要

[1]
Nagabhushan KS, Khan NN, Gray SJ. Recent gene therapy advancements for neurological diseases. Discov Med 2013; 15(81): 111-9.
[PMID: 23449113]
[2]
Pottoo FH, Tabassum N, Javed MN, et al. The synergistic effect of raloxifene, fluoxetine, and bromocriptine protects against pilocarpine-induced status epilepticus and temporal lobe epilepsy. Mol Neurobiol 2019; 56(2): 1233-47.
[http://dx.doi.org/10.1007/s12035-018-1121-x]
[3]
Nigar S, Pottoo FH, Tabassum N, Verma SK, Javed MN. Molecular insights into the role of inflammation and oxidative stress in epilepsy. J Adv Med PharmSci 2016; 10: 1-9.
[http://dx.doi.org/10.9734/JAMPS/2016/24441]
[4]
Acharya MM, Hattiangady B, Shetty AK. Progress in neuroprotective strategies for preventing epilepsy. Prog Neurobiol 2008; 84(4): 363-404.
[http://dx.doi.org/10.1016/j.pneurobio.2007.10.010] [PMID: 18207302]
[5]
Chepurnov SA, Suleĭmanova EM, Guliaev MV, Abbasova KR, Pirogov IuA, Chepurnova NE. [Neuroprotection in epilepsy]. Usp Fiziol Nauk 2012; 43(2): 55-71.
[PMID: 22690591]
[6]
Pottoo FH, Bhowmik M, Vohora D. Raloxifene protects against seizures and neurodegeneration in a mouse model mimicking epilepsy in postmenopausal woman. Eur J Pharm Sci 2014; 65: 167-73.
[http://dx.doi.org/10.1016/j.ejps.2014.09.002] [PMID: 25218046]
[7]
Galanopoulou AS, Buckmaster PS, Staley KJ, et al. Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 2012; 53(3): 571-82.
[http://dx.doi.org/10.1111/j.1528-1167.2011.03391.x] [PMID: 22292566]
[8]
Simonato M, Bennett J, Boulis NM, et al. Progress in gene therapy for neurological disorders. Nat Rev Neurol 2013; 9(5): 277-91.
[http://dx.doi.org/10.1038/nrneurol.2013.56] [PMID: 23609618]
[9]
Simonato M, Tongiorgi E, Kokaia M. Angels and demons: neurotrophic factors and epilepsy. Trends Pharmacol Sci 2006; 27(12): 631-8.
[http://dx.doi.org/10.1016/j.tips.2006.10.002] [PMID: 17055067]
[10]
Haberman R, Criswell H, Snowdy S, et al. Therapeutic liabilities of in vivo viral vector tropism: adeno-associated virus vectors, NMDAR1 antisense, and focal seizure sensitivity. Mol Ther 2002; 6(4): 495-500.
[http://dx.doi.org/10.1006/mthe.2002.0701] [PMID: 12377191]
[11]
Woldbye DP, Angehagen M, Gøtzsche CR, et al. Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures. Brain 2010; 133(9): 2778-88.
[http://dx.doi.org/10.1093/brain/awq219] [PMID: 20688813]
[12]
Berkovic SF, Mulley JC, Scheffer IE, Petrou S. Human epilepsies: interaction of genetic and acquired factors. Trends Neurosci 2006; 29(7): 391-7.
[http://dx.doi.org/10.1016/j.tins.2006.05.009] [PMID: 16769131]
[13]
Riban V, Fitzsimons HL, During MJ. Gene therapy in epilepsy. Epilepsia 2009; 50(1): 24-32.
[http://dx.doi.org/10.1111/j.1528-1167.2008.01743.x] [PMID: 18717707]
[14]
Vezzani A. Gene therapy in epilepsy. Epilepsy Curr 2004; 4(3): 87-90.
[http://dx.doi.org/10.1111/j.1535-7597.2004.43001.x] [PMID: 16059458]
[15]
Vadlamudi L, Milne RL, Lawrence K, et al. Genetics of epilepsy: The testimony of twins in the molecular era. Neurology 2014; 83(12): 1042-8.
[http://dx.doi.org/10.1212/WNL.0000000000000790] [PMID: 25107880]
[16]
Symonds JD, Zuberi SM, Johnson MR. Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment. Curr Opin Neurol 2017; 30(2): 193-9.
[http://dx.doi.org/10.1097/WCO.0000000000000433] [PMID: 28212175]
[17]
Laing JM, Gober MD, Golembewski EK, et al. Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice. Mol Ther 2006; 13(5): 870-81.
[http://dx.doi.org/10.1016/j.ymthe.2005.12.013] [PMID: 16500153]
[18]
Muzyczka N, Warrington KH Jr. Custom adeno-associated virus capsids: the next generation of recombinant vectors with novel tropism. Hum Gene Ther 2005; 16(4): 408-16.
[http://dx.doi.org/10.1089/hum.2005.16.408] [PMID: 15871672]
[19]
Ruitenberg MJ, Eggers R, Boer GJ, Verhaagen J. Adeno-associated viral vectors as agents for gene delivery: application in disorders and trauma of the central nervous system. Methods 2002; 28(2): 182-94.
[http://dx.doi.org/10.1016/S1046-2023(02)00222-0] [PMID: 12413416]
[20]
Hickey WF. Basic principles of immunological surveillance of the normal central nervous system. Glia 2001; 36(2): 118-24.
[http://dx.doi.org/10.1002/glia.1101] [PMID: 11596120]
[21]
Barker RA, Widner H. Immune problems in central nervous system cell therapy. NeuroRx 2004; 1(4): 472-81.
[http://dx.doi.org/10.1602/neurorx.1.4.472] [PMID: 15717048]
[22]
Ewert K, Slack NL, Ahmad A, et al. Cationic lipid-DNA complexes for gene therapy: understanding the relationship between complex structure and gene delivery pathways at the molecular level. Curr Med Chem 2004; 11(2): 133-49.
[http://dx.doi.org/10.2174/0929867043456160] [PMID: 14754413]
[23]
Pezzoli D, Kajaste-Rudnitski A, Chiesa R, Candiani G. Lipid-based nanoparticles as nonviral gene delivery vectors. Methods Mol Biol 2013; 1025: 269-79.
[http://dx.doi.org/10.1007/978-1-62703-462-3_21] [PMID: 23918345]
[24]
Rathjen J, Rathjen PD. Mouse ES cells: experimental exploitation of pluripotent differentiation potential. Curr Opin Genet Dev 2001; 11(5): 587-94.
[http://dx.doi.org/10.1016/S0959-437X(00)00237-9] [PMID: 11532403]
[25]
Riess P, Molcanyi M, Bentz K, et al. Embryonic stem cell transplantation after experimental traumatic brain injury dramatically improves neurological outcome, but may cause tumors. J Neurotrauma 2007; 24(1): 216-25.
[http://dx.doi.org/10.1089/neu.2006.0141] [PMID: 17263685]
[26]
Deacon T, Schumacher J, Dinsmore J, et al. Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson’s disease. Nat Med 1997; 3(3): 350-3.
[http://dx.doi.org/10.1038/nm0397-350] [PMID: 9055867]
[27]
Fink JS, Schumacher JM, Ellias SL, et al. Porcine xenografts in Parkinson’s disease and Huntington’s disease patients: preliminary results. Cell Transplant 2000; 9(2): 273-8.
[http://dx.doi.org/10.1177/096368970000900212] [PMID: 10811399]
[28]
Isacson O, Breakefield XO. Benefits and risks of hosting animal cells in the human brain. Nat Med 1997; 3(9): 964-9.
[http://dx.doi.org/10.1038/nm0997-964] [PMID: 9288721]
[29]
Berges BK, Wolfe JH, Fraser NW. Transduction of brain by herpes simplex virus vectors. Mol Ther 2007; 15(1): 20-9.
[http://dx.doi.org/10.1038/sj.mt.6300018] [PMID: 17164771]
[30]
McMenamin MM, Byrnes AP, Charlton HM, Coffin RS, Latchman DS, Wood MJA. A gamma34.5 mutant of herpes simplex 1 causes severe inflammation in the brain. Neuroscience 1998; 83(4): 1225-37.
[http://dx.doi.org/10.1016/S0306-4522(97)00513-7] [PMID: 9502260]
[31]
Cao H, Zhang GR, Wang X, Kong L, Geller AI. Enhanced nigrostriatal neuron-specific, long-term expression by using neural-specific promoters in combination with targeted gene transfer by modified helper virus-free HSV-1 vector particles. BMC Neurosci 2008; 9: 37.
[http://dx.doi.org/10.1186/1471-2202-9-37] [PMID: 18402684]
[32]
Jakobsson J, Lundberg C. Lentiviral vectors for use in the central nervous system. Mol Ther 2006; 13(3): 484-93.
[http://dx.doi.org/10.1016/j.ymthe.2005.11.012] [PMID: 16403676]
[33]
Zhao J, Lever AM. Lentivirus-mediated gene expression. Methods Mol Biol 2007; 366: 343-55.
[http://dx.doi.org/10.1007/978-1-59745-030-0_20] [PMID: 17568135]
[34]
Löscher W, Ebert U, Lehmann H, Rosenthal C, Nikkhah G. Seizure suppression in kindling epilepsy by grafts of fetal GABAergic neurons in rat substantia nigra. J Neurosci Res 1998; 51(2): 196-209.
[http://dx.doi.org/10.1002/(SICI)1097-4547(19980115)51:2<196:: AID-JNR8>3.0.CO;2-8] [PMID: 9469573]
[35]
Thompson K, Anantharam V, Behrstock S, Bongarzone E, Campagnoni A, Tobin AJ. Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures. Exp Neurol 2000; 161(2): 481-9.
[http://dx.doi.org/10.1006/exnr.1999.7305] [PMID: 10686070]
[36]
Liu W, He X, Cao Z, et al. Efficient therapeutic gene expression in cultured rat hippocampal neurons mediated by human foamy virus vectors: a potential for the treatment of neurological diseases. Intervirology 2005; 48(5): 329-35.
[http://dx.doi.org/10.1159/000085102] [PMID: 15956801]
[37]
Johannesen K, Marini C, Pfeffer S, et al. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. Neurology 2016; 87(11): 1140-51.
[http://dx.doi.org/10.1212/WNL.0000000000003087] [PMID: 27521439]
[38]
Consortium E. De Novo Mutations in SLC1A2 and CACNA1A are important causes of epileptic encephalopathies. Am J Hum Genet 2016; 99(2): 287-98.
[http://dx.doi.org/10.1016/j.ajhg.2016.06.003] [PMID: 27476654]
[39]
Janve VS, Hernandez CC, Verdier KM, Hu N, Macdonald RL. Epileptic encephalopathy de novo GABRB mutations impair GABAA receptor function. Ann Neurol 2016; 79: 806-25.
[http://dx.doi.org/10.1002/ana.24631] [PMID: 26950270]
[40]
Endele S, Rosenberger G, Geider K, et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 2010; 42(11): 1021-6.
[http://dx.doi.org/10.1038/ng.677] [PMID: 20890276]
[41]
Carvill GL, Regan BM, Yendle SC, et al. GRIN2A mutations cause epilepsy-aphasia spectrum disorders. Nat Genet 2013; 45(9): 1073-6.
[http://dx.doi.org/10.1038/ng.2727] [PMID: 23933818]
[42]
Lesca G, Rudolf G, Bruneau N, et al. GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nat Genet 2013; 45(9): 1061-6.
[http://dx.doi.org/10.1038/ng.2726] [PMID: 23933820]
[43]
Li D, Yuan H, Ortiz-Gonzalez XR, et al. GRIN2D recurrent de novo dominant mutation causes a severe epileptic encephalopathy treatable with NMDA receptor channel blockers. Am J Hum Genet 2016; 99(4): 802-16.
[http://dx.doi.org/10.1016/j.ajhg.2016.07.013] [PMID: 27616483]
[44]
Syrbe S, Hedrich UBS, Riesch E, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet 2015; 47(4): 393-9.
[http://dx.doi.org/10.1038/ng.3239] [PMID: 25751627]
[45]
Corbett MA, Bellows ST, Li M, et al. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology 2016; 87(19): 1975-84.
[http://dx.doi.org/10.1212/WNL.0000000000003309]
[46]
Allou L, Julia S, Amsallem D, et al. Rett-like phenotypes: expanding the genetic heterogeneity to the KCNA2 gene and first familial case of CDKL5-related disease. Clin Genet 2017; 91(3): 431-40.
[http://dx.doi.org/10.1111/cge.12784] [PMID: 27062609]
[47]
Petrovski S, Küry S, Myers CT, et al. Germline De Novo mutations in gnb1 cause severe neurodevelopmental disability, hypotonia, and seizures. Am J Hum Genet 2016; 98(5): 1001-10.
[http://dx.doi.org/10.1016/j.ajhg.2016.03.011] [PMID: 27108799]
[48]
Sim JC, Scerri T, Fanjul-Fernández M, et al. Familial cortical dysplasia caused by mutation in the mTOR regulator NPRL3. Ann Neurol 2016; 79(1): 132-7.
[http://dx.doi.org/10.1002/ana.24502] [PMID: 26285051]
[49]
Broix L, Jagline H, Ivanova E, et al. Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Nat Genet 2016; 48(11): 1349-58.
[http://dx.doi.org/10.1038/ng.3676] [PMID: 27694961]
[50]
Lim JS, Kim WI, Kang H-C, et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015; 21(4): 395-400.
[http://dx.doi.org/10.1038/nm.3824] [PMID: 25799227]
[51]
Thomas RH, Zhang LM, Carvill GL, et al. CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology 2015; 84(9): 951-8.
[http://dx.doi.org/10.1212/WNL.0000000000001305] [PMID: 25672921]
[52]
Goldstein JHR, Tim-Aroon T, Shieh J, et al. Novel SMC1A frameshift mutations in children with developmental delay and epilepsy. Eur J Med Genet 2015; 58(10): 562-8.
[http://dx.doi.org/10.1016/j.ejmg.2015.09.007] [PMID: 26386245]
[53]
Liu JC, Ferreira CG, Yusufzai T. Human CHD2 is a chromatin assembly ATPase regulated by its chromo- and DNA-binding domains. J Biol Chem 2015; 290(1): 25-34.
[http://dx.doi.org/10.1074/jbc.M114.609156] [PMID: 25384982]
[54]
Fjaer R, Brodtkorb E, Øye AM, et al. Generalized epilepsy in a family with basal ganglia calcifications and mutations in SLC20A2 and CHRNB2. Eur J Med Genet 2015; 58(11): 624-8.
[http://dx.doi.org/10.1016/j.ejmg.2015.10.005] [PMID: 26475232]
[55]
Rocha H, Sampaio M, Rocha R, Fernandes S, Leão M. MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and review. Eur J Med Genet 2016; 59(9): 478-82.
[http://dx.doi.org/10.1016/j.ejmg.2016.05.017] [PMID: 27255693]
[56]
Larsen J, Carvill GL, Gardella E, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology 2015; 84(5): 480-9.
[http://dx.doi.org/10.1212/WNL.0000000000001211] [PMID: 25568300]
[57]
Consortium E. A roadmap for precision medicine in the epilepsies. Lancet Neurol 2015; 14(12): 1219-28.
[http://dx.doi.org/10.1016/S1474-4422(15)00199-4] [PMID: 26416172]
[58]
Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol 2014; 76(3): 457-61.
[http://dx.doi.org/10.1002/ana.24229]
[59]
Boerma RS, Braun KP, van den Broek MP, et al. Remarkable phenytoin sensitivity in 4 children with SCN8A-related epilepsy: A molecular neuropharmacological approach. Neurotherapeutics 2016; 13(1): 192-7.
[http://dx.doi.org/10.1007/s13311-015-0372-8] [PMID: 26252990]
[60]
Millichap JJ, Park KL, Tsuchida T, et al. KCNQ2 encephalopathy: Features, mutational hot spots, and ezogabine treatment of 11 patients. Neurol Genet 2016; 2(5): e96
[http://dx.doi.org/10.1212/NXG.0000000000000096] [PMID: 27602407]
[61]
Johnson MR, Shkura K, Langley SR, et al. Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Nat Neurosci 2016; 19(2): 223-32.
[http://dx.doi.org/10.1038/nn.4205] [PMID: 26691832]
[62]
Johnson MR, Behmoaras J, Bottolo L, et al. Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus. Nat Commun 2015; 6: 6031.
[http://dx.doi.org/10.1038/ncomms7031] [PMID: 25615886]
[63]
Myers KA, Johnstone DL, Dyment DA. Epilepsy genetics: Current knowledge, applications, and future directions. Clin Genet 2019; 95(1): 95-111.
[http://dx.doi.org/10.1111/cge.13414] [PMID: 29992546]
[64]
Hortopan GA, Dinday MT, Baraban SC. Zebrafish as a model for studying genetic aspects of epilepsy. Dis Model Mech 2010; 3(3-4): 144-8.
[http://dx.doi.org/10.1242/dmm.002139] [PMID: 20212082]
[65]
Baraban SC, Dinday MT, Hortopan GA. Drug screening in SCN1A zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nat Commun 2013; 4: 2410.
[http://dx.doi.org/10.1038/ncomms3410] [PMID: 24002024]
[66]
Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC. Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain 2017; 140(3): 669-83.
[http://dx.doi.org/10.1093/brain/aww342] [PMID: 28073790]
[67]
Ingusci S, Cattaneo S, Verlengia G, Zucchini S, Simonato M. A matter of genes: The hurdles of gene therapy for epilepsy. Epilepsy Curr 2019; 19(1): 38-43.
[http://dx.doi.org/10.1177/1535759718822846] [PMID: 30838918]
[68]
Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med 2015; 7: 91-9.
[http://dx.doi.org/10.1186/s13073-015-0214-7] [PMID: 26302787]

Rights & Permissions Print Cite
Article Metrics
25
© 2025 Bentham Science Publishers | Privacy Policy