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Transl. Med."],"published-print":{"date-parts":[[2026,3,4]]},"abstract":"<jats:p>\n                    Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl-CpG\u2013binding protein 2 (\n                    <jats:italic toggle=\"yes\">MECP2<\/jats:italic>\n                    ), which encodes a transcriptional regulator essential for maintenance of normal neuronal function. The current US Food and Drug Administration\u2013approved treatment for RTT, trofinetide, mildly alleviates some symptoms. In contrast, reintroducing MeCP2 or increasing its amount through transgenesis in mouse RTT models improves most neurological phenotypes and enhances survival. Here, we devised a therapeutic strategy to moderately increase MeCP2 protein by modulating the alternative splicing of\n                    <jats:italic toggle=\"yes\">MECP2<\/jats:italic>\n                    to switch the less efficiently translated\n                    <jats:italic toggle=\"yes\">e2<\/jats:italic>\n                    to the more efficiently translated\n                    <jats:italic toggle=\"yes\">e1<\/jats:italic>\n                    isoform. We deleted\n                    <jats:italic toggle=\"yes\">Mecp2<\/jats:italic>\n                    exon 2 (unique to\n                    <jats:italic toggle=\"yes\">e2<\/jats:italic>\n                    ), leading to production of only\n                    <jats:italic toggle=\"yes\">e1<\/jats:italic>\n                    mRNA, and showed that this up-regulated MeCP2 by 50 to 60% in mice. Next, we investigated the consequences of isoform switching in two independent RTT induced pluripotent stem cell (iPSC)\u2013derived neuron models harboring mutations that reduce both MeCP2 expression and function. Exon 2 deletion in neurons derived from patients with MeCP2-G118E up-regulated MeCP2, ameliorated morphological and electrophysiological changes, and corrected the dysregulated transcriptome in these neurons. Isoform switching in neurons derived from patients with MeCP2-G118E, modeling a severe RTT mutation, only modestly affected MeCP2 protein abundance and, despite this, led to a partial transcriptomic rescue. Last, an exon 2\u2013skipping morpholino up-regulated MeCP2-E1 in vivo in mice. These data set the stage for a potential therapeutic strategy using antisense oligonucleotides to promote isoform switching in patients with RTT who carry partially functioning alleles of\n                    <jats:italic toggle=\"yes\">MECP2<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adq4529","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T18:58:28Z","timestamp":1772650708000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["Modulating alternative splicing of\n                    <i>MECP2<\/i>\n                    is a potential therapeutic strategy for Rett syndrome"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1318-2072","authenticated-orcid":true,"given":"Harini P.","family":"Tirumala","sequence":"first","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9510-6294","authenticated-orcid":true,"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1656-3452","authenticated-orcid":true,"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8868-881X","authenticated-orcid":true,"given":"Sameer S.","family":"Bajikar","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9650-1130","authenticated-orcid":true,"given":"Ashley G.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5500-6712","authenticated-orcid":true,"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander J.","family":"Trostle","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahla","family":"Zahabiyon","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1255-9835","authenticated-orcid":true,"given":"Aleksandar","family":"Bajic","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, TX 77030, USA."},{"name":"Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4709-262X","authenticated-orcid":true,"given":"Jean J.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, 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