Modulating alternative splicing of MECP2 is a potential therapeutic strategy for Rett syndrome

作者：Harini P. Tirumala, Li Wang, Yan Li, Sameer S. Bajikar, Ashley G. Anderson, W. Wang, Alexander J. Trostle, Mahla Zahabiyon, Aleksandar Bajić, Jean J. Kim, Hu Chen, Feng Li, Huda Y. Zoghbi · 发表于：Science Translational Medicine · 年份：2026 · DOI：10.1126/scitranslmed.adq4529 · 被引用次数：6 · 研究领域：Genetics and Neurodevelopmental Disorders、Williams Syndrome Research、Neurogenetic and Muscular Disorders Research

Rett syndrome (RTT) is a neurological disorder caused by loss-of-function mutations in methyl-CpG–binding protein 2 ( MECP2 ), which encodes a transcriptional regulator essential for maintenance of normal neuronal function. The current US Food and Drug Administration–approved 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 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 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)–derived 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...