{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T19:31:16Z","timestamp":1785007876078,"version":"3.55.0"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Diagn Ther"],"published-print":{"date-parts":[[2026,7]]},"DOI":"10.1007\/s40291-026-00847-4","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T15:14:50Z","timestamp":1776093290000},"page":"575-585","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["From Gene to Hope: Rett Syndrome and the Rise of Molecular Therapies"],"prefix":"10.1007","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4995-631X","authenticated-orcid":false,"given":"Yoann","family":"Leblay","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3271-3964","authenticated-orcid":false,"given":"Marie-Solenne","family":"Felix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9721-8844","authenticated-orcid":false,"given":"Jean-Christophe","family":"Roux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6204-6771","authenticated-orcid":false,"given":"Nicolas","family":"Panayotis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"847_CR1","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/s41572-024-00568-0","volume":"10","author":"WA Gold","year":"2024","unstructured":"Gold WA, Percy AK, Neul JL, Cobb SR, Pozzo-Miller L, Issar JK, et al. Rett syndrome. Nat Rev Dis Primers. 2024;10:84. https:\/\/doi.org\/10.1038\/s41572-024-00568-0.","journal-title":"Nat Rev Dis Primers"},{"key":"847_CR2","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.1126\/science.1138389","volume":"315","author":"J Guy","year":"2007","unstructured":"Guy J, Gan J, Selfridge J, Cobb S, Bird A. Reversal of neurological defects in a mouse model of Rett syndrome. Science. 2007;315:1143\u20137. https:\/\/doi.org\/10.1126\/science.1138389.","journal-title":"Science"},{"issue":"2","key":"847_CR3","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1111\/dmcn.15383","volume":"65","author":"N Panayotis","year":"2023","unstructured":"Panayotis N, Ehinger Y, Felix MS, Roux JC. State-of-the-art therapies for Rett syndrome. Dev Med Child Neurol. 2023;65(2):162\u201370. https:\/\/doi.org\/10.1111\/dmcn.15383.","journal-title":"Dev Med Child Neurol"},{"key":"847_CR4","doi-asserted-by":"publisher","first-page":"1172805","DOI":"10.3389\/fnins.2023.1172805","volume":"17","author":"M Palmieri","year":"2023","unstructured":"Palmieri M, Pozzer D, Landsberger N. Advanced genetic therapies for the treatment of Rett syndrome: state of the art and future perspectives. Front Neurosci. 2023;17:1172805. https:\/\/doi.org\/10.3389\/fnins.2023.1172805.","journal-title":"Front Neurosci"},{"key":"847_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2025.102635","volume":"36","author":"B Kantor","year":"2025","unstructured":"Kantor B, O\u2019Donovan B, Chiba-Falek O. Trends and challenges of AAV-delivered gene editing therapeutics for CNS disorders: Implications for neurodegenerative disease. Mol Ther Nucleic Acids. 2025;36:102635. https:\/\/doi.org\/10.1016\/j.omtn.2025.102635.","journal-title":"Mol Ther Nucleic Acids."},{"key":"847_CR6","doi-asserted-by":"publisher","first-page":"2479","DOI":"10.1016\/j.ymthe.2025.04.045","volume":"33","author":"BJ Byrne","year":"2025","unstructured":"Byrne BJ, Flanigan KM, Matesanz SE, Finkel RS, Waldrop MA, D\u2019Ambrosio ES, et al. Current clinical applications of AAV-mediated gene therapy. Mol Ther. 2025;33:2479\u2013516. https:\/\/doi.org\/10.1016\/j.ymthe.2025.04.045.","journal-title":"Mol Ther"},{"key":"847_CR7","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/nature24058","volume":"550","author":"R Tillotson","year":"2017","unstructured":"Tillotson R, Selfridge J, Koerner MV, Gadalla KKE, Guy J, De Sousa D, et al. Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature. 2017;550:398\u2013401. https:\/\/doi.org\/10.1038\/nature24058.","journal-title":"Nature"},{"key":"847_CR8","doi-asserted-by":"publisher","first-page":"1943","DOI":"10.1016\/j.neuron.2024.04.007","volume":"112","author":"Y Liu","year":"2024","unstructured":"Liu Y, Flamier A, Bell GW, Diao AJ, Whitfield TW, Wang H-C, et al. MECP2 directly interacts with RNA polymerase II to modulate transcription in human neurons. Neuron. 2024;112:1943-58.e10. https:\/\/doi.org\/10.1016\/j.neuron.2024.04.007.","journal-title":"Neuron"},{"key":"847_CR9","doi-asserted-by":"publisher","first-page":"5136","DOI":"10.1038\/s41467-024-49368-w","volume":"15","author":"J Zhang","year":"2024","unstructured":"Zhang J, Li H, Niswander LA. m5C methylated lncRncr3\u2013MeCP2 interaction restricts miR124a-initiated neurogenesis. Nat Commun. 2024;15:5136. https:\/\/doi.org\/10.1038\/s41467-024-49368-w.","journal-title":"Nat Commun"},{"key":"847_CR10","doi-asserted-by":"publisher","first-page":"3005","DOI":"10.1093\/brain\/awab182","volume":"144","author":"SE Sinnett","year":"2021","unstructured":"Sinnett SE, Boyle E, Lyons C, Gray SJ. Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice. Brain. 2021;144:3005\u201319. https:\/\/doi.org\/10.1093\/brain\/awab182.","journal-title":"Brain"},{"key":"847_CR11","doi-asserted-by":"publisher","DOI":"10.3390\/genes15010031","volume":"15","author":"C Sadhu","year":"2023","unstructured":"Sadhu C, Lyons C, Oh J, Jagadeeswaran I, Gray SJ, Sinnett SE. The efficacy of a human-ready miniMECP2 gene therapy in a pre-clinical model of Rett syndrome. Genes. 2023;15:31. https:\/\/doi.org\/10.3390\/genes15010031.","journal-title":"Genes"},{"key":"847_CR12","unstructured":"Taysha Gene Therapies announces FDA breakthrough therapy designation and provides positive regulatory update on TSHA-102 in Rett syndrome. 2025. https:\/\/ir.tayshagtx.com\/news-releases\/news-release-details\/taysha-gene-therapies-announces-fda-breakthrough-therapy. Accessed 3 Apr 2026."},{"key":"847_CR13","unstructured":"Taysha Gene Therapies announces progress across TSHA-102 Pivotal Gene Therapy Program in Rett syndrome. 2026. https:\/\/ir.tayshagtx.com\/news-releases\/news-release-details\/taysha-gene-therapies-announces-progress-across-tsha-102-pivotal. Accessed 3 Apr 2026."},{"issue":"2","key":"847_CR14","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1159\/000539267","volume":"47","author":"I Jagadeeswaran","year":"2025","unstructured":"Jagadeeswaran I, Oh J, Sinnett SE. Preclinical milestones in MECP2 gene transfer for treating Rett syndrome. Dev Neurosci. 2025;47(2):147\u201356. https:\/\/doi.org\/10.1159\/000539267.","journal-title":"Dev Neurosci"},{"issue":"792","key":"847_CR15","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adq3614","volume":"17","author":"PD Ross","year":"2025","unstructured":"Ross PD, Gadalla KKE, Thomson SR, Selfridge J, Bahey NG, Benito J, et al. Self-regulating gene therapy ameliorates phenotypes and overcomes gene dosage sensitivity in a mouse model of Rett syndrome. Sci Transl Med. 2025;17(792):eadq3614.","journal-title":"Sci Transl Med"},{"key":"847_CR16","doi-asserted-by":"publisher","DOI":"10.53053\/NLVD9770","author":"C McMurray","year":"2024","unstructured":"McMurray C. What\u2019s next for brain-directed gene therapy after death in Neurogene trial. Transmitter. 2024. https:\/\/doi.org\/10.53053\/NLVD9770.","journal-title":"Transmitter"},{"key":"847_CR17","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1007\/s12264-022-00974-y","volume":"39","author":"K Yang","year":"2023","unstructured":"Yang K, Cheng C, Yuan Y, Zhang Y, Shan S, Qiu Z. Extension of the lifespan of a mouse model of Rett syndrome by intracerebroventricular delivery of MECP2. Neurosci Bull. 2023;39:297\u2013302. https:\/\/doi.org\/10.1007\/s12264-022-00974-y.","journal-title":"Neurosci Bull"},{"key":"847_CR18","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/mt.2012.200","volume":"21","author":"KK Gadalla","year":"2013","unstructured":"Gadalla KK, Bailey ME, Spike RC, Ross PD, Woodard KT, Kalburgi SN, et al. Improved survival and reduced phenotypic severity following AAV9\/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol Ther. 2013;21:18\u201330. https:\/\/doi.org\/10.1038\/mt.2012.200.","journal-title":"Mol Ther"},{"key":"847_CR19","doi-asserted-by":"publisher","first-page":"13612","DOI":"10.1523\/JNEUROSCI.1854-13.2013","volume":"33","author":"SK Garg","year":"2013","unstructured":"Garg SK, Lioy DT, Cheval H, McGann JC, Bissonnette JM, Murtha MJ, et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J Neurosci. 2013;33:13612\u201320. https:\/\/doi.org\/10.1523\/JNEUROSCI.1854-13.2013.","journal-title":"J Neurosci"},{"key":"847_CR20","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.omtm.2017.04.006","volume":"5","author":"SE Sinnett","year":"2017","unstructured":"Sinnett SE, Hector RD, Gadalla KKE, Heindel C, Chen D, Zaric V, et al. Improved MECP2 gene therapy extends the survival of MeCP2-Null mice without apparent toxicity after intracisternal delivery. Mol Ther Methods Clin Dev. 2017;5:106\u201315. https:\/\/doi.org\/10.1016\/j.omtm.2017.04.006.","journal-title":"Mol Ther Methods Clin Dev"},{"key":"847_CR21","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.omtm.2017.04.007","volume":"5","author":"KKE Gadalla","year":"2017","unstructured":"Gadalla KKE, Vudhironarit T, Hector RD, Sinnett S, Bahey NG, Bailey MES, et al. Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome. Mol Ther Methods Clin Dev. 2017;5:180\u201390. https:\/\/doi.org\/10.1016\/j.omtm.2017.04.007.","journal-title":"Mol Ther Methods Clin Dev"},{"key":"847_CR22","doi-asserted-by":"publisher","DOI":"10.1101\/2024.03.13.584179","author":"MJ Flynn","year":"2024","unstructured":"Flynn MJ, Mayfield AMH, Du R, Gradinaru V, Elowitz MB. Synthetic dosage-compensating miRNA circuits allow precision gene therapy for Rett syndrome. BiorXiv. 2024. https:\/\/doi.org\/10.1101\/2024.03.13.584179.","journal-title":"BiorXiv"},{"key":"847_CR23","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.52629","volume":"9","author":"M Luoni","year":"2020","unstructured":"Luoni M, Giannelli S, Indrigo MT, Niro A, Massimino L, Iannielli A, et al. Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome. Elife. 2020;9:e52629. https:\/\/doi.org\/10.7554\/eLife.52629.","journal-title":"Elife"},{"key":"847_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.nbd.2016.12.009","volume":"99","author":"V Matagne","year":"2017","unstructured":"Matagne V, Ehinger Y, Saidi L, Borges-Correia A, Barkats M, Bartoli M, et al. A codon-optimized Mecp2 transgene corrects breathing deficits and improves survival in a mouse model of Rett syndrome. Neurobiol Dis. 2017;99:1\u201311. https:\/\/doi.org\/10.1016\/j.nbd.2016.12.009.","journal-title":"Neurobiol Dis"},{"key":"847_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105235","volume":"149","author":"V Matagne","year":"2021","unstructured":"Matagne V, Borloz E, Ehinger Y, Saidi L, Villard L, Roux JC. Severe offtarget effects following intravenous delivery of AAV9-MECP2 in a female mouse model of Rett syndrome. Neurobiol Dis. 2021;149:105235. https:\/\/doi.org\/10.1016\/j.nbd.2020.105235.","journal-title":"Neurobiol Dis"},{"key":"847_CR26","doi-asserted-by":"publisher","first-page":"2767","DOI":"10.1016\/j.ymthe.2023.07.013","volume":"31","author":"S Powers","year":"2023","unstructured":"Powers S, Likhite S, Gadalla KK, Miranda CJ, Huffenberger AJ, Dennys C, et al. Novel MECP2 gene therapy is effective in a multicenter study using two mouse models of Rett syndrome and is safe in non-human primates. Mol Ther. 2023;31:2767\u201382. https:\/\/doi.org\/10.1016\/j.ymthe.2023.07.013.","journal-title":"Mol Ther"},{"key":"847_CR27","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nature13324","volume":"509","author":"A Ben-Zvi","year":"2014","unstructured":"Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, et al. Mfsd2a is critical for the formation and function of the blood\u2013brain barrier. Nature. 2014;509:507\u201311. https:\/\/doi.org\/10.1038\/nature13324.","journal-title":"Nature"},{"key":"847_CR28","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1007\/978-1-4939-9139-6_8","volume-title":"Adeno-associated virus vectors: design and delivery","author":"DJ Gessler","year":"2019","unstructured":"Gessler DJ, Tai PWL, Li J, Gao G. Intravenous infusion of AAV for widespread gene delivery to the nervous system. In: Castle MJ, editor. Adeno-associated virus vectors: design and delivery. New York: Springer; 2019. p. 143\u201363. https:\/\/doi.org\/10.1007\/978-1-4939-9139-6_8."},{"key":"847_CR29","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/s41583-025-00976-5","volume":"26","author":"A Friedman","year":"2025","unstructured":"Friedman A, Prager O, Serlin Y, Kaufer D. Dynamic modulation of the blood\u2013brain barrier in the healthy brain. Nat Rev Neurosci. 2025;26:749\u201364. https:\/\/doi.org\/10.1038\/s41583-025-00976-5.","journal-title":"Nat Rev Neurosci"},{"key":"847_CR30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25021050","volume":"25","author":"R Daci","year":"2024","unstructured":"Daci R, Flotte TR. Delivery of adeno-associated virus vectors to the central nervous system for correction of single gene disorders. Int J Mol Sci. 2024;25:1050. https:\/\/doi.org\/10.3390\/ijms25021050.","journal-title":"Int J Mol Sci"},{"key":"847_CR31","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurot.2024.e00434","volume":"21","author":"RV Patel","year":"2024","unstructured":"Patel RV, Nanda P, Richardson RM. Neurosurgical gene therapy for central nervous system diseases. Neurotherapeutics. 2024;21:e00434. https:\/\/doi.org\/10.1016\/j.neurot.2024.e00434.","journal-title":"Neurotherapeutics"},{"key":"847_CR32","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00086","volume":"10","author":"KT Chen","year":"2019","unstructured":"Chen KT, Wei KC, Liu HL. Theranostic strategy of focused ultrasound induced blood-brain barrier opening for CNS disease treatment. Front Pharmacol. 2019;10:86. https:\/\/doi.org\/10.3389\/fphar.2019.00086.","journal-title":"Front Pharmacol"},{"key":"847_CR33","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics13081245","volume":"13","author":"MS Felix","year":"2021","unstructured":"Felix MS, Borloz E, Metwally K, Dauba A, Larrat B, Matagne V, et al. Ultrasound-mediated blood-brain barrier opening improves whole brain gene delivery in mice. Pharmaceutics. 2021;13:1245. https:\/\/doi.org\/10.3390\/pharmaceutics13081245.","journal-title":"Pharmaceutics"},{"key":"847_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48974-y","volume":"15","author":"HR Li","year":"2024","unstructured":"Li HR, Harb M, Heath JE, Trippett JS, Shapiro MG, Szablowski JO. Engineering viral vectors for acoustically targeted gene delivery. Nat Commun. 2024;15:4924. https:\/\/doi.org\/10.1038\/s41467-024-48974-y.","journal-title":"Nat Commun"},{"key":"847_CR35","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. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat Biotechnol. 2016;34:204\u20139. https:\/\/doi.org\/10.1038\/nbt.3440.","journal-title":"Nat Biotechnol"},{"key":"847_CR36","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1038\/nn.4593","volume":"20","author":"KY Chan","year":"2017","unstructured":"Chan KY, Jang MJ, Yoo BB, Greenbaum A, Ravi N, Wu W-L, et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat Neurosci. 2017;20:1172\u20139. https:\/\/doi.org\/10.1038\/nn.4593.","journal-title":"Nat Neurosci"},{"key":"847_CR37","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/s41593-021-00969-4","volume":"25","author":"D Goertsen","year":"2022","unstructured":"Goertsen D, Flytzanis NC, Goeden N, Chuapoco MR, Cummins A, Chen Y, et al. AAV capsid variants with brain-wide transgene expression and decreased liver targeting after intravenous delivery in mouse and marmoset. Nat Neurosci. 2022;25:106\u201315. https:\/\/doi.org\/10.1038\/s41593-021-00969-4.","journal-title":"Nat Neurosci"},{"key":"847_CR38","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1126\/science.adm8386","volume":"384","author":"Q Huang","year":"2024","unstructured":"Huang Q, Chan KY, Wu J, Botticello-Romero NR, Zheng Q, Lou S, et al. An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery. Science. 2024;384:1220\u20137. https:\/\/doi.org\/10.1126\/science.adm8386.","journal-title":"Science"},{"key":"847_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-60000-3","volume":"16","author":"DE Leib","year":"2025","unstructured":"Leib DE, Chen YH, Tecedor L, Ranum PT, Keiser MS, Lewandowski BC, et al. Optimized AAV capsids for basal ganglia diseases show robust potency and distribution. Nat Commun. 2025;16:4653. https:\/\/doi.org\/10.1038\/s41467-025-60000-3.","journal-title":"Nat Commun"},{"key":"847_CR40","doi-asserted-by":"publisher","first-page":"912","DOI":"10.1016\/j.ymthe.2019.02.013","volume":"27","author":"J Hordeaux","year":"2019","unstructured":"Hordeaux J, Yuan Y, Clark PM, Wang Q, Martino RA, Sims JJ, et al. The GPI-linked protein LY6A drives AAV-PHP.B transport across the blood-brain barrier. Mol Ther. 2019;27:912\u201321. https:\/\/doi.org\/10.1016\/j.ymthe.2019.02.013.","journal-title":"Mol Ther"},{"key":"847_CR41","doi-asserted-by":"publisher","first-page":"R3","DOI":"10.1093\/hmg\/ddz148","volume":"28","author":"C Domenger","year":"2019","unstructured":"Domenger C, Grimm D. Next-generation AAV vectors: do not judge a virus (only) by its cover. Hum Mol Genet. 2019;28:R3-14. https:\/\/doi.org\/10.1093\/hmg\/ddz148.","journal-title":"Hum Mol Genet"},{"key":"847_CR42","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.omtm.2018.07.006","volume":"10","author":"E Hudry","year":"2018","unstructured":"Hudry E, Andres-Mateos E, Lerner EP, Volak A, Cohen O, Hyman BT, et al. Efficient gene transfer to the central nervous system by single-stranded Anc80L65. Mol Ther. 2018;10:197\u2013209. https:\/\/doi.org\/10.1016\/j.omtm.2018.07.006.","journal-title":"Mol Ther"},{"key":"847_CR43","doi-asserted-by":"publisher","first-page":"920","DOI":"10.1016\/j.tig.2022.01.007","volume":"38","author":"N-B Grimm","year":"2022","unstructured":"Grimm N-B, Lee JT. Selective Xi reactivation and alternative methods to restore MECP2 function in Rett syndrome. Trends Genet. 2022;38:920\u201343. https:\/\/doi.org\/10.1016\/j.tig.2022.01.007.","journal-title":"Trends Genet"},{"key":"847_CR44","doi-asserted-by":"publisher","first-page":"7991","DOI":"10.1073\/pnas.1803792115","volume":"115","author":"P Przanowski","year":"2018","unstructured":"Przanowski P, Wasko U, Zheng Z, Yu J, Sherman R, Zhu LJ, et al. Pharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice. Proc Natl Acad Sci USA. 2018;115:7991\u20136. https:\/\/doi.org\/10.1073\/pnas.1803792115.","journal-title":"Proc Natl Acad Sci USA"},{"key":"847_CR45","doi-asserted-by":"publisher","DOI":"10.1186\/s11689-020-09332-3","volume":"12","author":"HM Lee","year":"2020","unstructured":"Lee HM, Kuijer MB, Ruiz Blanes N, Clark EP, Aita M, Galiano Arjona L, et al. A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance. J Neurodev Disord. 2020;12:29. https:\/\/doi.org\/10.1186\/s11689-020-09332-3.","journal-title":"J Neurodev Disord"},{"key":"847_CR46","doi-asserted-by":"publisher","first-page":"E668","DOI":"10.1073\/pnas.1715124115","volume":"115","author":"LLG Carrette","year":"2018","unstructured":"Carrette LLG, Wang CY, Wei C, Press W, Ma W, Kelleher RJ 3rd, et al. A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders. Proc Natl Acad Sci USA. 2018;115:E668\u201375. https:\/\/doi.org\/10.1073\/pnas.1715124115.","journal-title":"Proc Natl Acad Sci USA"},{"key":"847_CR47","doi-asserted-by":"publisher","first-page":"8185","DOI":"10.1073\/pnas.1800931115","volume":"115","author":"LLG Carrette","year":"2018","unstructured":"Carrette LLG, Blum R, Ma W, Kelleher RJ, Lee JT. Tsix\u2013Mecp2 female mouse model for Rett syndrome reveals that low-level MECP2 expression extends life and improves neuromotor function. Proc Natl Acad Sci USA. 2018;115:8185\u201390. https:\/\/doi.org\/10.1073\/pnas.1800931115.","journal-title":"Proc Natl Acad Sci USA"},{"issue":"679","key":"847_CR48","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. Multiplex epigenome editing of MECP2 to rescue Rett syndrome neurons. Sci Transl Med. 2023;15(679):eadd4666. https:\/\/doi.org\/10.1126\/scitranslmed.add4666.","journal-title":"Sci Transl Med"},{"key":"847_CR49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61092-7","volume":"16","author":"S Lou","year":"2025","unstructured":"Lou S, DJiake Tihagam R, Wasko UN, Equbal Z, Venkatesan S, Braczyk K, et al. Targeting microRNA-dependent control of X chromosome inactivation improves the Rett syndrome phenotype. Nat Commun. 2025;16:6169. https:\/\/doi.org\/10.1038\/s41467-025-61092-7.","journal-title":"Nat Commun"},{"key":"847_CR50","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1038\/s41586-019-1711-4","volume":"576","author":"AV Anzalone","year":"2019","unstructured":"Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019;576:149\u201357. https:\/\/doi.org\/10.1038\/s41586-019-1711-4.","journal-title":"Nature"},{"key":"847_CR51","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/nature17946","volume":"533","author":"AC Komor","year":"2016","unstructured":"Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533:420\u20134. https:\/\/doi.org\/10.1038\/nature17946.","journal-title":"Nature"},{"key":"847_CR52","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/nature24644","volume":"551","author":"NM Gaudelli","year":"2017","unstructured":"Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, et al. Programmable base editing of A\u2022T to G\u2022C in genomic DNA without DNA cleavage. Nature. 2017;551:464\u201371. https:\/\/doi.org\/10.1038\/nature24644.","journal-title":"Nature"},{"key":"847_CR53","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1038\/s41431-020-0624-x","volume":"28","author":"S Croci","year":"2020","unstructured":"Croci S, Carriero ML, Capitani K, Daga S, Donati F, Frullanti E, et al. High rate of HDR in gene editing of p.(Thr158Met) MECP2 mutational hotspot. Eur J Hum Genet. 2020;28:1231\u201342. https:\/\/doi.org\/10.1038\/s41431-020-0624-x.","journal-title":"Eur J Hum Genet"},{"key":"847_CR54","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/s41573-020-0084-6","volume":"19","author":"EM Porto","year":"2020","unstructured":"Porto EM, Komor AC, Slaymaker IM, Yeo GW. Base editing: advances and therapeutic opportunities. Nat Rev Drug Discov. 2020;19:839\u201359. https:\/\/doi.org\/10.1038\/s41573-020-0084-6.","journal-title":"Nat Rev Drug Discov"},{"key":"847_CR55","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1038\/s41586-019-1161-z","volume":"569","author":"J Gr\u00fcnewald","year":"2019","unstructured":"Gr\u00fcnewald J, Zhou R, Garcia SP, Iyer S, Lareau CA, Aryee MJ, et al. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors. Nature. 2019;569:433\u20137. https:\/\/doi.org\/10.1038\/s41586-019-1161-z.","journal-title":"Nature"},{"key":"847_CR56","doi-asserted-by":"publisher","first-page":"2557","DOI":"10.1002\/1873-3468.14970","volume":"598","author":"M Lian","year":"2024","unstructured":"Lian M, Chen T, Chen M, Peng X, Yang Y, Luo X, et al. A modified glycosylase base editor without predictable DNA off-target effects. FEBS Lett. 2024;598:2557\u201365. https:\/\/doi.org\/10.1002\/1873-3468.14970.","journal-title":"FEBS Lett"},{"key":"847_CR57","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-025-02937-w","author":"RM Perrotta","year":"2025","unstructured":"Perrotta RM, Vinke S, Ferreira R, Moret M, Mahas A, Chiappino-Pepe A, et al. Engineered base editors with reduced bystander editing through directed evolution. Nat Biotechnol. 2025. https:\/\/doi.org\/10.1038\/s41587-025-02937-w. (Online ahead of print).","journal-title":"Nat Biotechnol"},{"key":"847_CR58","doi-asserted-by":"publisher","first-page":"1458","DOI":"10.1038\/s41467-024-45763-5","volume":"15","author":"N Bamidele","year":"2024","unstructured":"Bamidele N, Zhang H, Dong X, Cheng H, Gaston N, Feinzig H, et al. Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope. Nat Commun. 2024;15:1458. https:\/\/doi.org\/10.1038\/s41467-024-45763-5.","journal-title":"Nat Commun"},{"key":"847_CR59","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-025-02948-7","author":"CR Lazzarotto","year":"2026","unstructured":"Lazzarotto CR, Katta V, Li Y, Manquen G, Wood RK, Chyr J, et al. Sensitive and unbiased genome-wide profiling of base-editor-induced off-target activity using CHANGE-seq-BE. Nat Biotechnol. 2026. https:\/\/doi.org\/10.1038\/s41587-025-02948-7. (Online ahead of print).","journal-title":"Nat Biotechnol"},{"key":"847_CR60","doi-asserted-by":"publisher","first-page":"625","DOI":"10.3389\/fgene.2019.00625","volume":"10","author":"TTH Le","year":"2019","unstructured":"Le TTH, Tran NT, Dao TML, Nguyen DD, Do HD, Ha TL, et al. Efficient and precise CRISPR\/Cas9-mediated MECP2 modifications in human-induced pluripotent stem cells. Front Genet. 2019;10:625. https:\/\/doi.org\/10.3389\/fgene.2019.00625.","journal-title":"Front Genet"},{"key":"847_CR61","doi-asserted-by":"publisher","DOI":"10.1101\/2025.08.31.673354v2.full.pdf","author":"J Guy","year":"2025","unstructured":"Guy J, Hein E, Alexander-Howden B, Kleinstiver BP, Zoghbi H, Bird A. Translational reading frame determines the pathogenicity of C-terminal frameshift deletions in MeCP2: an alternative therapeutic approach. BioRxiv. 2025. https:\/\/doi.org\/10.1101\/2025.08.31.673354v2.full.pdf.","journal-title":"BioRxiv"},{"key":"847_CR62","doi-asserted-by":"publisher","first-page":"3369","DOI":"10.1038\/s41467-023-39137-6","volume":"14","author":"C Zheng","year":"2023","unstructured":"Zheng C, Liu B, Dong X, Gaston N, Sontheimer EJ, Xue W. Template-jumping prime editing enables large insertion and exon rewriting in vivo. Nat Commun. 2023;14:3369. https:\/\/doi.org\/10.1038\/s41467-023-39137-6.","journal-title":"Nat Commun"},{"key":"847_CR63","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13578-024-01216-6","volume":"14","author":"D Zhang","year":"2024","unstructured":"Zhang D, Zhu L, Gao Y, Wang Y, Li P. RNA editing enzymes: structure, biological functions and applications. Cell Biosci. 2024;14:34. https:\/\/doi.org\/10.1186\/s13578-024-01216-6.","journal-title":"Cell Biosci"},{"key":"847_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16173-0","volume":"11","author":"W Zhang","year":"2020","unstructured":"Zhang W, Aida T, Del Rosario RCH, Wilde JJ, Ding C, Zhang X, et al. Multiplex precise base editing in cynomolgus monkeys. Nat Commun. 2020;11:2325. https:\/\/doi.org\/10.1038\/s41467-020-16173-0.","journal-title":"Nat Commun"},{"key":"847_CR65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206053119","author":"J Sinnamon","year":"2022","unstructured":"Sinnamon J, Jacobson M, Yung J, Fisk J, Jeng S, McWeeney S, et al. Targeted RNA editing in brainstem alleviates respiratory dysfunction in a mouse model of Rett syndrome. Proc Natl Acad Sci USA. 2022. https:\/\/doi.org\/10.1073\/pnas.2206053119.","journal-title":"Proc Natl Acad Sci USA"},{"key":"847_CR66","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/s41587-024-02313-0","volume":"43","author":"P Reautschnig","year":"2024","unstructured":"Reautschnig P, Fruhner C, Wahn N, Wiegand C, Kragness S, Yung J, et al. Precise in vivo RNA base editing with a wobble-enhanced circular CLUSTER guide RNA. Nat Biotechnol. 2024;43:545\u201357. https:\/\/doi.org\/10.1038\/s41587-024-02313-0.","journal-title":"Nat Biotechnol"},{"key":"847_CR67","doi-asserted-by":"publisher","DOI":"10.1038\/s41525-024-00397-w","volume":"9","author":"A Dadush","year":"2024","unstructured":"Dadush A, Merdler-Rabinowicz R, Gorelik D, Feiglin A, Buchumenski I, Pal LR, et al. DNA and RNA base editors can correct the majority of pathogenic single nucleotide variants. NPJ Genom Med. 2024;9:16. https:\/\/doi.org\/10.1038\/s41525-024-00397-w.","journal-title":"NPJ Genom Med"},{"key":"847_CR68","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.02676","volume":"3","author":"LD Heckman","year":"2014","unstructured":"Heckman LD, Chahrour MH, Zoghbi HY. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. Elife. 2014;3:e02676. https:\/\/doi.org\/10.7554\/eLife.02676.","journal-title":"Elife"},{"key":"847_CR69","doi-asserted-by":"publisher","first-page":"1889","DOI":"10.1172\/JCI90967","volume":"127","author":"JM Lamonica","year":"2017","unstructured":"Lamonica JM, Kwon DY, Goffin D, Fenik P, Johnson BS, Cui Y, et al. Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome-like phenotypes. J Clin Invest. 2017;127:1889\u2013904. https:\/\/doi.org\/10.1172\/JCI90967.","journal-title":"J Clin Invest"},{"key":"847_CR70","doi-asserted-by":"publisher","first-page":"2662","DOI":"10.1093\/hmg\/ddv030","volume":"24","author":"MR Pitcher","year":"2015","unstructured":"Pitcher MR, Herrera JA, Buffington SA, Kochukov MY, Merritt JK, Fisher AR, et al. Rett syndrome like phenotypes in the R255X Mecp2 mutant mouse are rescued by MECP2 transgene. Hum Mol Genet. 2015;24:2662\u201372. https:\/\/doi.org\/10.1093\/hmg\/ddv030.","journal-title":"Hum Mol Genet"},{"key":"847_CR71","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12739","volume":"21","author":"BE Collins","year":"2022","unstructured":"Collins BE, Merritt JK, Erickson KR, Neul JL. Safety and efficacy of genetic MECP2 supplementation in the R294X mouse model of Rett syndrome. Genes Brain Behav. 2022;21:e12739. https:\/\/doi.org\/10.1111\/gbb.12739.","journal-title":"Genes Brain Behav"},{"key":"847_CR72","doi-asserted-by":"publisher","DOI":"10.1111\/gbb.12752","volume":"21","author":"SAD Vermudez","year":"2022","unstructured":"Vermudez SAD, Gogliotti RG, Arthur B, Buch A, Morales C, Moxley Y, et al. Profiling beneficial and potential adverse effects of MeCP2 overexpression in a hypomorphic Rett syndrome mouse model. Genes Brain Behav. 2022;21:e12752. https:\/\/doi.org\/10.1111\/gbb.12752.","journal-title":"Genes Brain Behav"}],"container-title":["Molecular Diagnosis & Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40291-026-00847-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40291-026-00847-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40291-026-00847-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T20:55:41Z","timestamp":1782852941000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40291-026-00847-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,13]]},"references-count":72,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["847"],"URL":"https:\/\/doi.org\/10.1007\/s40291-026-00847-4","relation":{},"ISSN":["1177-1062","1179-2000"],"issn-type":[{"value":"1177-1062","type":"print"},{"value":"1179-2000","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,13]]},"assertion":[{"value":"9 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 April 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Yoann Leblay, Marie-Solenne Felix, Jean-Christophe Roux, and Nicolas Panayotis have no conflicts of interest that are directly relevant to the content of this article.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"Not applicable.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Availability of Data and Material"}},{"value":"Not applicable.","order":7,"name":"Ethics","group":{"name":"EthicsHeading","label":"Code Availability"}},{"value":"YL, M-SF, J-CR, and NP drafted and finalized the manuscript together. All authors have read and approved the final version.","order":8,"name":"Ethics","group":{"name":"EthicsHeading","label":"Author Contributions"}}]}}