Language
English
Publication Date
3-4-2026
Journal
Science Translational Medicine
DOI
10.1126/scitranslmed.adq4529
PMID
41779872
PMCID
PMC13061089
PubMedCentral® Posted Date
4-9-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl CpG binding protein 2 (MECP2), a transcriptional regulator essential for maintenance of normal neuronal function. The current FDA-approved treatment for RTT, Trofinetide, mildly alleviates some symptoms. In contrast, re-introducing 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 MECP2 to switch the less efficiently translated e2 to the more efficiently translated e1 isoform. We deleted Mecp2 exon 2 (unique to e2), leading to production of only e1 mRNA, and show this upregulates MeCP2 by 50-60% in mice. Next, we investigated the consequences of isoform switching in two independent RTT induced pluripotent stem cell (iPSC)-derived neuron models harboring mutations that reduce both MeCP2 expression and function. Exon 2 deletion in MeCP2-G118E patient-derived neurons upregulated MeCP2, ameliorated morphological and electrophysiological changes and corrected the dysregulated transcriptome in these neurons. Isoform switching in MeCP2-T158M patient-derived neurons, modelling a severe RTT mutation, only modestly affected MeCP2 protein abundance and despite this, led to a partial transcriptomic rescue. Lastly, an exon 2-skipping Morpholino upregulated 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 MECP2.
Keywords
Methyl-CpG-Binding Protein 2, Animals, Rett Syndrome, Alternative Splicing, Humans, Neurons, Exons, Protein Isoforms, Mice, Induced Pluripotent Stem Cells, Mutation, RNA, Messenger
Published Open-Access
yes
Recommended Citation
Tirumala, Harini P; Wang, Li; Li, Yan; et al., "Modulating Alternative Splicing of MECP2 Is a Potential Therapeutic Strategy for Rett Syndrome" (2026). Faculty, Staff and Students Publications. 6872.
https://digitalcommons.library.tmc.edu/baylor_docs/6872