{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T23:02:05Z","timestamp":1793833325737,"version":"4.6.1"},"reference-count":87,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100009367","name":"Mansoura University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009367","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Epigenetic editing has emerged as a promising approach in the treatment of neurological and neuropsychiatric disorders, enabling the precise and enduring modification of genes associated with these conditions. Interventions that focus on chromatin, such as programmable systems like CRISPR\/dCas9, zinc-finger proteins, and TALEs linked to epigenetic effector domains, enable the modification of DNA methylation, histone modifications, and noncoding RNA control at specific loci. This work integrates current progress in understanding the epigenetic landscape of neurological neuropsychiatric disorders, highlighting the functions of DNA methylation (de novo vs maintenance, active versus passive demethylation), histone remodeling, and context-dependent gene regulation. We emphasize that the dysregulation of these processes is essential to diseases such as Alzheimer\u2019s disease (AD), Parkinson\u2019s disease (PD), Huntington\u2019s disease (HD), and major psychiatric disorders. Innovative therapeutic approaches, including KRAB- and TET-based repressors, \u201chit-and-run\u201d epigenome editing, and targeted noncoding RNA regulation, are analyzed alongside translational methodologies that utilize gene therapy vectors, nanoparticle delivery systems, and inducible expression mechanisms. We also examine proof-of-concept studies that demonstrate how to prevent gene expression and alter the transcriptional networks of diseased cells in living organisms. We identify current challenges, including off-target effects, delivery issues, inadequate understanding of long-term stability, and the need for reliable diagnostics, while highlighting the translational promise of combining epigenetic clearance with biogenesis and repair. This review is aimed at providing a comprehensive and critical examination of the molecular principles, therapeutic strategies, and translational obstacles associated with epigenetic editing in neurological and neuropsychiatric disorders, thereby facilitating the development of next-generation precision therapies.<\/jats:p>","DOI":"10.1007\/s12035-025-05590-1","type":"journal-article","created":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T01:42:21Z","timestamp":1766886141000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Epigenetic Editing in Neurological and Neuropsychiatric Disorders: Pioneering Next-Gen Therapeutics for Precision Gene Control"],"prefix":"10.1007","volume":"63","author":[{"given":"Hany E.","family":"Marei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,28]]},"reference":[{"issue":"4","key":"5590_CR1","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/j.pneurobio.2008.10.001","volume":"86","author":"MF Mehler","year":"2008","unstructured":"Mehler MF (2008) Epigenetic principles and mechanisms underlying nervous system functions in health and disease. Prog Neurobiol 86(4):305\u2013341","journal-title":"Prog Neurobiol"},{"key":"5590_CR2","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.neuropharm.2012.11.015","volume":"68","author":"MJ Millan","year":"2013","unstructured":"Millan MJ (2013) An epigenetic framework for neurodevelopmental disorders: from pathogenesis to potential therapy. Neuropharmacology 68:2\u201382","journal-title":"Neuropharmacology"},{"key":"5590_CR3","doi-asserted-by":"crossref","unstructured":"Bashtrykov P, Jeltsch A (2017) Epigenome editing in the brain. Neuroepigenomics Aging Dis. 409\u201324.","DOI":"10.1007\/978-3-319-53889-1_21"},{"issue":"5","key":"5590_CR4","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24054778","volume":"24","author":"J Ueda","year":"2023","unstructured":"Ueda J, Yamazaki T, Funakoshi H (2023) Toward the development of epigenome editing-based therapeutics: potentials and challenges. Int J Mol Sci 24(5):4778","journal-title":"Int J Mol Sci"},{"issue":"5","key":"5590_CR5","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a019133","volume":"6","author":"E Li","year":"2014","unstructured":"Li E, Zhang Y (2014) DNA methylation in mammals. Cold Spring Harb Perspect Biol 6(5):a019133","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"2","key":"5590_CR6","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nrg.2017.80","volume":"19","author":"F Lyko","year":"2018","unstructured":"Lyko F (2018) The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet 19(2):81\u201392","journal-title":"Nat Rev Genet"},{"issue":"7534","key":"5590_CR7","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature14192","volume":"517","author":"D Sch\u00fcbeler","year":"2015","unstructured":"Sch\u00fcbeler D (2015) Function and information content of DNA methylation. Nature 517(7534):321\u2013326","journal-title":"Nature"},{"issue":"7","key":"5590_CR8","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1038\/nrg3230","volume":"13","author":"PA Jones","year":"2012","unstructured":"Jones PA (2012) Functions of DNA methylation: islands, start sites, gene bodies, and beyond. Nat Rev Genet 13(7):484\u2013492","journal-title":"Nat Rev Genet"},{"key":"5590_CR9","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.pneurobio.2015.05.002","volume":"131","author":"R Lardenoije","year":"2015","unstructured":"Lardenoije R, Iatrou A, Kenis G, Kompotis K, Steinbusch HW, Mastroeni D et al (2015) The epigenetics of aging and neurodegeneration. Prog Neurobiol 131:21\u201364","journal-title":"Prog Neurobiol"},{"issue":"3","key":"5590_CR10","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/cr.2011.22","volume":"21","author":"AJ Bannister","year":"2011","unstructured":"Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21(3):381\u2013395","journal-title":"Cell Res"},{"key":"5590_CR11","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.biocel.2015.05.002","volume":"67","author":"J Tu","year":"2015","unstructured":"Tu J, Liao J, Luk ACS, Tang NLS, Chan WY, Lee TL (2015) Micrornas mediated targeting on the Yin-yang dynamics of DNA methylation in disease and development. Int J Biochem Cell Biol 67:115\u2013120","journal-title":"Int J Biochem Cell Biol"},{"issue":"6","key":"5590_CR12","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1038\/s41588-024-01706-w","volume":"56","author":"C Policarpi","year":"2024","unstructured":"Policarpi C, Munaf\u00f2 M, Tsagkris S, Carlini V, Hackett JA (2024) Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications. Nat Genet 56(6):1168\u20131180","journal-title":"Nat Genet"},{"issue":"5","key":"5590_CR13","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1038\/nrg.2016.20","volume":"17","author":"DW Thomson","year":"2016","unstructured":"Thomson DW, Dinger ME (2016) Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet 17(5):272\u2013283","journal-title":"Nat Rev Genet"},{"issue":"9","key":"5590_CR14","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/nrg.2017.33","volume":"18","author":"X Wu","year":"2017","unstructured":"Wu X, Zhang Y (2017) TET-mediated active DNA demethylation: mechanism, function and beyond. Nat Rev Genet 18(9):517\u2013534","journal-title":"Nat Rev Genet"},{"issue":"8","key":"5590_CR15","volume":"14","author":"J Qian","year":"2024","unstructured":"Qian J, Liu SX (2024) CRISPR\/dCas9-tet1-mediated DNA methylation editing. Bio-Protoc 14(8):e4976","journal-title":"Bio-Protoc"},{"issue":"5","key":"5590_CR16","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.3390\/biomedicines11051334","volume":"11","author":"N Yano","year":"2023","unstructured":"Yano N, Fedulov AV (2023) Targeted DNA demethylation: vectors, effectors and perspectives. Biomedicines 11(5):1334","journal-title":"Biomedicines"},{"issue":"10","key":"5590_CR17","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.3390\/cancers11101515","volume":"11","author":"A Urbano","year":"2019","unstructured":"Urbano A, Smith J, Weeks RJ, Chatterjee A (2019) Gene-specific targeting of DNA methylation in the mammalian genome. Cancers 11(10):1515","journal-title":"Cancers"},{"issue":"20","key":"5590_CR18","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.2217\/epi-2020-0110","volume":"12","author":"F Maroufi","year":"2020","unstructured":"Maroufi F, Maali A, Abdollahpour-Alitappeh M, Ahmadi MH, Azad M (2020) CRISPR-mediated modification of DNA methylation pattern in the new era of cancer therapy. Epigenomics 12(20):1845\u20131859","journal-title":"Epigenomics"},{"issue":"9","key":"5590_CR19","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/s41582-020-0373-z","volume":"16","author":"M Kampmann","year":"2020","unstructured":"Kampmann M (2020) CRISPR-based functional genomics for neurological disease. Nat Rev Neurol 16(9):465\u2013480","journal-title":"Nat Rev Neurol"},{"key":"5590_CR20","doi-asserted-by":"crossref","unstructured":"Hilton IB, D\u2019ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015;33(5):510\u20137.","DOI":"10.1038\/nbt.3199"},{"key":"5590_CR21","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2023.147480","volume":"874","author":"L Ma","year":"2023","unstructured":"Ma L, Yang S, Peng Q, Zhang J, Zhang J (2023) CRISPR\/Cas9-based gene-editing technology for sickle cell disease. Gene 874:147480","journal-title":"Gene"},{"issue":"12","key":"5590_CR22","doi-asserted-by":"publisher","first-page":"1677","DOI":"10.1007\/s00439-023-02610-9","volume":"142","author":"S Zeng","year":"2023","unstructured":"Zeng S, Lei S, Qu C, Wang Y, Teng S, Huang P (2023) CRISPR\/Cas-based gene editing in therapeutic strategies for beta-thalassemia. Hum Genet 142(12):1677\u20131703","journal-title":"Hum Genet"},{"issue":"10","key":"5590_CR23","doi-asserted-by":"publisher","first-page":"4509","DOI":"10.1073\/pnas.91.10.4509","volume":"91","author":"JF Margolin","year":"1994","unstructured":"Margolin JF, Friedman JR, Meyer W, Vissing H, Thiesen HJ, Rauscher F 3rd (1994) Kr\u00fcppel-associated boxes are potent transcriptional repression domains. Proc Natl Acad Sci U S A 91(10):4509\u20134513","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7290","key":"5590_CR24","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1038\/nature08858","volume":"464","author":"T Matsui","year":"2010","unstructured":"Matsui T, Leung D, Miyashita H, Maksakova IA, Miyachi H, Kimura H et al (2010) Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET. Nature 464(7290):927\u2013931","journal-title":"Nature"},{"issue":"2","key":"5590_CR25","doi-asserted-by":"publisher","first-page":"442","DOI":"10.1016\/j.cell.2013.06.044","volume":"154","author":"LA Gilbert","year":"2013","unstructured":"Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE et al (2013) CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell 154(2):442\u2013451","journal-title":"Cell"},{"issue":"3","key":"5590_CR26","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/j.cell.2014.09.029","volume":"159","author":"LA Gilbert","year":"2014","unstructured":"Gilbert LA, Horlbeck MA, Adamson B, Villalta JE, Chen Y, Whitehead EH et al (2014) Genome-scale CRISPR-mediated control of gene repression and activation. Cell 159(3):647\u2013661","journal-title":"Cell"},{"issue":"5","key":"5590_CR27","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1016\/j.cell.2013.02.022","volume":"152","author":"LS Qi","year":"2013","unstructured":"Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP et al (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152(5):1173\u20131183","journal-title":"Cell"},{"key":"5590_CR28","doi-asserted-by":"crossref","unstructured":"UE29.Yano N, Fedulov AV (2023) Targeted DNA demethylation: vectors, effectors and perspectives. Biomedicines. 11(5):1334.","DOI":"10.3390\/biomedicines11051334"},{"issue":"12","key":"5590_CR29","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.tins.2019.10.003","volume":"42","author":"XS Liu","year":"2019","unstructured":"Liu XS, Jaenisch R (2019) Editing the epigenome to tackle brain disorders. Trends Neurosci 42(12):861\u2013870","journal-title":"Trends Neurosci"},{"issue":"8","key":"5590_CR30","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1038\/s41592-018-0048-5","volume":"15","author":"NC Yeo","year":"2018","unstructured":"Yeo NC, Chavez A, Lance-Byrne A, Chan Y, Menn D, Milanova D et al (2018) An enhanced CRISPR repressor for targeted mammalian gene regulation. Nat Methods 15(8):611\u2013616","journal-title":"Nat Methods"},{"issue":"9","key":"5590_CR31","doi-asserted-by":"publisher","first-page":"2503","DOI":"10.1016\/j.cell.2021.03.025","volume":"184","author":"JK Nu\u00f1ez","year":"2021","unstructured":"Nu\u00f1ez JK, Chen J, Pommier GC, Cogan JZ, Replogle JM, Adriaens C et al (2021) Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing. Cell 184(9):2503\u20132519","journal-title":"Cell"},{"key":"5590_CR32","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1007\/s11596-020-2249-2","volume":"40","author":"M Chen","year":"2020","unstructured":"Chen M, Zhu H, juanMao Y, Cao N, liYu Y, yunLi L et al (2020) Regulation of IL12B expression in human macrophages by TALEN-mediated epigenome editing. Curr Med Sci 40:900\u2013909","journal-title":"Curr Med Sci"},{"issue":"12","key":"5590_CR33","doi-asserted-by":"publisher","first-page":"5615","DOI":"10.1093\/nar\/gkw159","volume":"44","author":"A Vojta","year":"2016","unstructured":"Vojta A, Dobrini\u0107 P, Tadi\u0107 V, Bo\u010dkor L, Kora\u0107 P, Julg B et al (2016) Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res 44(12):5615\u20135628","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"5590_CR34","doi-asserted-by":"publisher","first-page":"4951","DOI":"10.1038\/s41467-019-12861-8","volume":"10","author":"S Manickavinayaham","year":"2019","unstructured":"Manickavinayaham S, V\u00e9lez-Cruz R, Biswas AK, Bedford E, Klein BJ, Kutateladze TG et al (2019) E2f1 acetylation directs p300\/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair. Nat Commun 10(1):4951","journal-title":"Nat Commun"},{"key":"5590_CR35","unstructured":"Nunna S (2015) Development of zinc finger methyltransferase fusion proteins for targeted DNA methylation and gene silencing in human cells"},{"issue":"31","key":"5590_CR36","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abn3986","volume":"8","author":"V Benedetti","year":"2022","unstructured":"Benedetti V, Banfi F, Zaghi M, Moll-Diaz R, Massimino L, Argelich L et al (2022) A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development. Sci Adv 8(31):eabn3986","journal-title":"Sci Adv"},{"issue":"7","key":"5590_CR37","doi-asserted-by":"publisher","first-page":"1311","DOI":"10.1016\/j.cell.2007.05.022","volume":"129","author":"JL Rinn","year":"2007","unstructured":"Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA et al (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129(7):1311\u20131323","journal-title":"Cell"},{"issue":"7291","key":"5590_CR38","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1038\/nature08975","volume":"464","author":"RA Gupta","year":"2010","unstructured":"Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ et al (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464(7291):1071\u20131076","journal-title":"Nature"},{"issue":"2","key":"5590_CR39","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nrg3863","volume":"16","author":"D Holoch","year":"2015","unstructured":"Holoch D, Moazed D (2015) RNA-mediated epigenetic regulation of gene expression. Nat Rev Genet 16(2):71\u201384","journal-title":"Nat Rev Genet"},{"key":"5590_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2019.101386","volume":"35","author":"M Riera","year":"2019","unstructured":"Riera M, Patel A, Corcostegui B, Chang S, Corneo B, Sparrow JR et al (2019) Generation of an induced pluripotent stem cell line (FRIMOi002-A) from a retinitis pigmentosa patient carrying compound heterozygous mutations in the USH2A gene. Stem Cell Res 35:101386","journal-title":"Stem Cell Res"},{"issue":"25","key":"5590_CR41","doi-asserted-by":"publisher","first-page":"6411","DOI":"10.1182\/blood-2008-07-170589","volume":"113","author":"R Garzon","year":"2009","unstructured":"Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CE, Callegari E et al (2009) Microrna-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113(25):6411\u20136418","journal-title":"Blood"},{"issue":"10","key":"5590_CR42","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1111\/j.1742-4658.2011.08089.x","volume":"278","author":"F Sato","year":"2011","unstructured":"Sato F, Tsuchiya S, Meltzer SJ, Shimizu K (2011) Micrornas and epigenetics. FEBS J 278(10):1598\u20131609","journal-title":"FEBS J"},{"issue":"1","key":"5590_CR43","doi-asserted-by":"publisher","first-page":"11960","DOI":"10.1038\/s41598-019-48130-3","volume":"9","author":"JG Kang","year":"2019","unstructured":"Kang JG, Park JS, Ko JH, Kim YS (2019) Regulation of gene expression by altered promoter methylation using a CRISPR\/Cas9-mediated epigenetic editing system. Sci Rep 9(1):11960","journal-title":"Sci Rep"},{"key":"5590_CR44","doi-asserted-by":"publisher","DOI":"10.1016\/j.micres.2020.126694","volume":"245","author":"X Li","year":"2021","unstructured":"Li X, Huang L, Pan L, Wang B, Pan L (2021) CRISPR\/dCas9-mediated epigenetic modification reveals differential regulation of histone acetylation on Aspergillus niger secondary metabolite. Microbiol Res 245:126694","journal-title":"Microbiol Res"},{"key":"5590_CR45","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1007\/s12035-012-8359-5","volume":"47","author":"L Tan","year":"2013","unstructured":"Tan L, Yu JT, Hu N, Tan L (2013) Non-coding RNAs in Alzheimer\u2019s disease. Mol Neurobiol 47:382\u2013393","journal-title":"Mol Neurobiol"},{"issue":"1","key":"5590_CR46","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.cell.2016.09.006","volume":"167","author":"A Amabile","year":"2016","unstructured":"Amabile A, Migliara A, Capasso P, Biffi M, Cittaro D, Naldini L et al (2016) Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell 167(1):219\u2013232","journal-title":"Cell"},{"key":"5590_CR47","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s12017-014-8295-9","volume":"16","author":"VR Liyanage","year":"2014","unstructured":"Liyanage VR, Rastegar M (2014) Rett syndrome and MeCP2. Neuromolecular Med 16:231\u2013264","journal-title":"Neuromolecular Med"},{"key":"5590_CR48","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.14198","volume":"5","author":"K Ure","year":"2016","unstructured":"Ure K, Lu H, Wang W, Ito-Ishida A, Wu Z, He L et al (2016) Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. Elife 5:e14198","journal-title":"Elife"},{"issue":"4","key":"5590_CR49","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1089\/crispr.2022.0020","volume":"5","author":"B Coorey","year":"2022","unstructured":"Coorey B, Haase F, Ellaway C, Clarke A, Lisowski L, Gold WA (2022) Gene editing and Rett syndrome: does it cut? CRISPR J 5(4):490\u2013499","journal-title":"CRISPR J"},{"issue":"792","key":"5590_CR50","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adq3614","volume":"17","author":"PD Ross","year":"2025","unstructured":"Ross PD, Gadalla KK, Thomson SR, Selfridge J, Bahey NG, Benito J et al (2025) Self-regulating gene therapy ameliorates phenotypes and overcomes gene dosage sensitivity in a mouse model of Rett syndrome. Sci Transl Med 17(792):eadq3614","journal-title":"Sci Transl Med"},{"issue":"1","key":"5590_CR51","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1093\/hmg\/7.1.109","volume":"7","author":"P Chiurazzi","year":"1998","unstructured":"Chiurazzi P, Pomponi MG, Willemsen R, Oostra BA, Neri G (1998) In vitro reactivation of the FMR1 gene involved in fragile X syndrome. Hum Mol Genet 7(1):109\u2013113","journal-title":"Hum Mol Genet"},{"issue":"5","key":"5590_CR52","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1016\/j.cell.2018.01.012","volume":"172","author":"XS Liu","year":"2018","unstructured":"Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J et al (2018) Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172(5):979\u2013992","journal-title":"Cell"},{"issue":"3","key":"5590_CR53","doi-asserted-by":"publisher","first-page":"278","DOI":"10.3390\/genes16030278","volume":"16","author":"CW Kam","year":"2025","unstructured":"Kam CW, Dumelie JG, Ciceri G, Yang WY, Disney MD, Studer L et al (2025) Sustained epigenetic reactivation in fragile X neurons with an RNA-binding small molecule. Genes 16(3):278","journal-title":"Genes"},{"key":"5590_CR54","doi-asserted-by":"crossref","unstructured":"Hilton IB, D\u2019ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al (2015) Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 33(5):510\u20137.","DOI":"10.1038\/nbt.3199"},{"issue":"679","key":"5590_CR55","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.add4666","volume":"15","author":"J Qian","year":"2023","unstructured":"Qian J, Guan X, Xie B, Xu C, Niu J, Tang X et al (2023) Multiplex epigenome editing of MECP2 to rescue Rett syndrome neurons. Sci Transl Med 15(679):eadd4666","journal-title":"Sci Transl Med"},{"key":"5590_CR56","doi-asserted-by":"crossref","unstructured":"Jagasia R, Bon C, Rasmussen SV, Badillo S, Tehler D, Buchy D, et al (2022) Angelman syndrome patient neuron screen identifies a potent and selective clinical ASO targeting UBE3A-ATS with long-lasting effect in cynomolgus monkey. bioRxiv. 06.","DOI":"10.1101\/2022.06.09.495066"},{"issue":"688","key":"5590_CR57","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abf4077","volume":"15","author":"SV Dindot","year":"2023","unstructured":"Dindot SV, Christian S, Murphy WJ, Berent A, Panagoulias J, Schlafer A et al (2023) An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the UBE3A-AS transcript. Sci Transl Med 15(688):eabf4077","journal-title":"Sci Transl Med"},{"issue":"2","key":"5590_CR58","first-page":"147","volume":"47","author":"I Jagadeeswaran","year":"2025","unstructured":"Jagadeeswaran I, Oh J, Sinnett SE (2025) Preclinical milestones in MECP2 gene transfer for treating Rett syndrome. Dev Neurosci 47(2):147\u2013156","journal-title":"Dev Neurosci"},{"issue":"6","key":"5590_CR59","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1056\/NEJMoa2107454","volume":"385","author":"JD Gillmore","year":"2021","unstructured":"Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML et al (2021) CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med 385(6):493\u2013502","journal-title":"N Engl J Med"},{"issue":"3","key":"5590_CR60","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1056\/NEJMoa2031054","volume":"384","author":"H Frangoul","year":"2021","unstructured":"Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK et al (2021) CRISPR-Cas9 gene editing for sickle cell disease and \u03b2-thalassemia. N Engl J Med 384(3):252\u2013260","journal-title":"N Engl J Med"},{"issue":"11","key":"5590_CR61","doi-asserted-by":"publisher","first-page":"2638","DOI":"10.1016\/j.ymthe.2018.08.019","volume":"26","author":"B Kantor","year":"2018","unstructured":"Kantor B, Tagliafierro L, Gu J, Zamora ME, Ilich E, Grenier C et al (2018) Downregulation of SNCA expression by targeted editing of DNA methylation: a potential strategy for precision therapy in PD. Mol Ther 26(11):2638\u20132649","journal-title":"Mol Ther"},{"issue":"1","key":"5590_CR62","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1089\/crispr.2021.0025","volume":"5","author":"HH Yoon","year":"2022","unstructured":"Yoon HH, Ye S, Lim S, Jo A, Lee H, Hong F et al (2022) CRISPR-Cas9 gene editing protects from the A53T-SNCA overexpression-induced pathology of Parkinson\u2019s disease in vivo. CRISPR J 5(1):95\u2013108","journal-title":"CRISPR J"},{"issue":"8003","key":"5590_CR63","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1038\/s41586-024-07087-8","volume":"627","author":"MA Cappelluti","year":"2024","unstructured":"Cappelluti MA, Mollica Poeta V, Valsoni S, Quarato P, Merlin S, Merelli I et al (2024) Durable and efficient gene silencing in vivo by hit-and-run epigenome editing. Nature 627(8003):416\u2013423","journal-title":"Nature"},{"issue":"9","key":"5590_CR64","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1038\/s41583-020-0334-y","volume":"21","author":"YY Yim","year":"2020","unstructured":"Yim YY, Teague CD, Nestler EJ (2020) In vivo locus-specific editing of the neuroepigenome. Nat Rev Neurosci 21(9):471\u2013484","journal-title":"Nat Rev Neurosci"},{"key":"5590_CR65","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.brainres.2010.03.035","volume":"1338","author":"BH Miller","year":"2010","unstructured":"Miller BH, Wahlestedt C (2010) Microrna dysregulation in psychiatric disease. Brain Res 1338:89\u201399","journal-title":"Brain Res"},{"issue":"50","key":"5590_CR66","doi-asserted-by":"publisher","first-page":"19664","DOI":"10.1523\/JNEUROSCI.0589-13.2013","volume":"33","author":"MJ Finelli","year":"2013","unstructured":"Finelli MJ, Wong JK, Zou H (2013) Epigenetic regulation of sensory axon regeneration after spinal cord injury. J Neurosci 33(50):19664\u201319676","journal-title":"J Neurosci"},{"issue":"27","key":"5590_CR67","doi-asserted-by":"publisher","first-page":"6090","DOI":"10.1523\/JNEUROSCI.2616-17.2018","volume":"38","author":"J Garriga","year":"2018","unstructured":"Garriga J, Laumet G, Chen SR, Zhang Y, Madzo J, Issa JPJ et al (2018) Nerve injury-induced chronic pain is associated with persistent DNA methylation reprogramming in the dorsal root ganglion. J Neurosci 38(27):6090\u20136101","journal-title":"J Neurosci"},{"issue":"5","key":"5590_CR68","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.neuron.2019.02.017","volume":"101","author":"E Hudry","year":"2019","unstructured":"Hudry E, Vandenberghe LH (2019) Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron 101(5):839\u2013862","journal-title":"Neuron"},{"key":"5590_CR69","doi-asserted-by":"crossref","unstructured":"Ben M\u2019Barek K, Habeler W, Regent F, Monville C (2019) Developing cell-based therapies for RPE-associated degenerative eye diseases. Pluripotent Stem Cells Eye Dis Ther. 2019;55\u201397.","DOI":"10.1007\/978-3-030-28471-8_3"},{"issue":"3","key":"5590_CR70","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1016\/j.stemcr.2017.07.022","volume":"9","author":"A Gonzalez-Cordero","year":"2017","unstructured":"Gonzalez-Cordero A, Kruczek K, Naeem A, Fernando M, Kloc M, Ribeiro J et al (2017) Recapitulation of human retinal development from human pluripotent stem cells generates transplantable populations of cone photoreceptors. Stem Cell Rep 9(3):820\u2013837","journal-title":"Stem Cell Rep"},{"issue":"1","key":"5590_CR71","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1146\/annurev-genom-083118-015043","volume":"20","author":"A Maeda","year":"2019","unstructured":"Maeda A, Mandai M, Takahashi M (2019) Gene and induced pluripotent stem cell therapy for retinal diseases. Annu Rev Genomics Hum Genet 20(1):201\u2013216","journal-title":"Annu Rev Genomics Hum Genet"},{"issue":"7","key":"5590_CR72","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1038\/s41375-018-0106-0","volume":"32","author":"MC Milone","year":"2018","unstructured":"Milone MC, O\u2019Doherty U (2018) Clinical use of lentiviral vectors. Leukemia 32(7):1529\u20131541","journal-title":"Leukemia"},{"issue":"1","key":"5590_CR73","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41392-024-01780-w","volume":"9","author":"JH Wang","year":"2024","unstructured":"Wang JH, Gessler DJ, Zhan W, Gallagher TL, Gao G (2024) Adeno-associated virus as a delivery vector for gene therapy of human diseases. Signal Transduct Target Ther 9(1):78","journal-title":"Signal Transduct Target Ther"},{"issue":"12","key":"5590_CR74","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1038\/s41578-021-00358-0","volume":"6","author":"X Hou","year":"2021","unstructured":"Hou X, Zaks T, Langer R, Dong Y (2021) Lipid nanoparticles for mRNA delivery. Nat Rev Mater 6(12):1078\u20131094","journal-title":"Nat Rev Mater"},{"key":"5590_CR75","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.addr.2020.04.004","volume":"159","author":"OM Elsharkasy","year":"2020","unstructured":"Elsharkasy OM, Nordin JZ, Hagey DW, de Jong OG, Schiffelers RM, Andaloussi SE et al (2020) Extracellular vesicles as drug delivery systems: Why and how? Adv Drug Deliv Rev 159:332\u2013343","journal-title":"Adv Drug Deliv Rev"},{"issue":"2","key":"5590_CR76","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nbt.3440","volume":"34","author":"BE Deverman","year":"2016","unstructured":"Deverman BE, Pravdo PL, Simpson BP, Kumar SR, Chan KY, Banerjee A et al (2016) Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol 34(2):204\u2013209","journal-title":"Nat Biotechnol"},{"issue":"5","key":"5590_CR77","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1586\/14737175.2015.1028369","volume":"15","author":"A Burgess","year":"2015","unstructured":"Burgess A, Shah K, Hough O, Hynynen K (2015) Focused ultrasound-mediated drug delivery through the blood\u2013brain barrier. Expert Rev Neurother 15(5):477\u2013491","journal-title":"Expert Rev Neurother"},{"issue":"3","key":"5590_CR78","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurot.2024.e00352","volume":"21","author":"PG Durham","year":"2024","unstructured":"Durham PG, Butnariu A, Alghorazi R, Pinton G, Krishna V, Dayton PA (2024) Current clinical investigations of focused ultrasound blood-brain barrier disruption: a review. Neurotherapeutics 21(3):e00352","journal-title":"Neurotherapeutics"},{"issue":"1","key":"5590_CR79","doi-asserted-by":"publisher","first-page":"4112","DOI":"10.1038\/s41467-019-12013-y","volume":"10","author":"CJ Peter","year":"2019","unstructured":"Peter CJ, Saito A, Hasegawa Y, Tanaka Y, Nagpal M, Perez G et al (2019) In vivo epigenetic editing of the Sema6a promoter reverses transcallosal dysconnectivity caused by the C11orf46\/Arl14ep risk gene. Nat Commun 10(1):4112","journal-title":"Nat Commun"},{"issue":"3","key":"5590_CR80","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.molcel.2016.07.004","volume":"63","author":"J Tycko","year":"2016","unstructured":"Tycko J, Myer VE, Hsu PD (2016) Methods for optimizing CRISPR-Cas9 genome editing specificity. Mol Cell 63(3):355\u2013370","journal-title":"Mol Cell"},{"issue":"2","key":"5590_CR81","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/s41591-018-0204-6","volume":"25","author":"DL Wagner","year":"2019","unstructured":"Wagner DL, Amini L, Wendering DJ, Burkhardt LM, Aky\u00fcz L, Reinke P et al (2019) High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population. Nat Med 25(2):242\u2013248","journal-title":"Nat Med"},{"issue":"2","key":"5590_CR82","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/s41591-018-0326-x","volume":"25","author":"CT Charlesworth","year":"2019","unstructured":"Charlesworth CT, Deshpande PS, Dever DP, Camarena J, Lemgart VT, Cromer MK et al (2019) Identification of preexisting adaptive immunity to Cas9 proteins in humans. Nat Med 25(2):249\u2013254","journal-title":"Nat Med"},{"issue":"4","key":"5590_CR83","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.cell.2007.02.006","volume":"128","author":"AD Goldberg","year":"2007","unstructured":"Goldberg AD, Allis CD, Bernstein E (2007) Epigenetics: a landscape takes shape. Cell 128(4):635\u2013638","journal-title":"Cell"},{"issue":"4","key":"5590_CR84","doi-asserted-by":"publisher","first-page":"1329","DOI":"10.1038\/s41591-025-03508-x","volume":"31","author":"F Tremblay","year":"2025","unstructured":"Tremblay F, Xiong Q, Shah SS, Ko CW, Kelly K, Morrison MS et al (2025) A potent epigenetic editor targeting human PCSK9 for durable reduction of low-density lipoprotein cholesterol levels. Nat Med 31(4):1329\u20131338","journal-title":"Nat Med"},{"issue":"21\u201322","key":"5590_CR85","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1089\/hum.2024.057","volume":"35","author":"R Daci","year":"2024","unstructured":"Daci R, Gray-Edwards H, Shazeeb MS, Vardar Z, Vachha B, Cataltepe OI et al (2024) Neuroimaging applications for the delivery and monitoring of gene therapy for central nervous system diseases. Hum Gene Ther 35(21\u201322):886\u2013895","journal-title":"Hum Gene Ther"},{"issue":"8","key":"5590_CR86","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1016\/j.chembiol.2024.07.007","volume":"31","author":"GV Roth","year":"2024","unstructured":"Roth GV, Gengaro IR, Qi LS (2024) Precision epigenetic editing: technological advances, enduring challenges, and therapeutic applications. Cell Chem Biol 31(8):1422\u20131446","journal-title":"Cell Chem Biol"},{"issue":"6","key":"5590_CR87","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/nbt.2908","volume":"32","author":"SQ Tsai","year":"2014","unstructured":"Tsai SQ, Wyvekens N, Khayter C, Foden JA, Thapar V, Reyon D et al (2014) Dimeric CRISPR RNA-guided FokI nucleases for precise genome editing. Nat Biotechnol 32(6):569\u2013576","journal-title":"Nat Biotechnol"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-025-05590-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-025-05590-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-025-05590-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T03:01:32Z","timestamp":1766890892000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-025-05590-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,28]]},"references-count":87,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["5590"],"URL":"https:\/\/doi.org\/10.1007\/s12035-025-05590-1","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,28]]},"assertion":[{"value":"5 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"330"}}