Λεπτομέρειες βιβλιογραφικής εγγραφής
| Τίτλος: |
Modulating alternative splicing of MECP2 is a potential therapeutic strategy for Rett syndrome. |
| Συγγραφείς: |
Tirumala, Harini P., Wang, Li, Li, Yan, Bajikar, Sameer S., Anderson, Ashley G., Wang, Wei, Trostle, Alexander J., Zahabiyon, Mahla, Bajic, Aleksandar, Kim, Jean J., Chen, Hu, Liu, Zhandong, Zoghbi, Huda Y. |
| Πηγή: |
Science Translational Medicine; 3/4/2026, Vol. 18 Issue 839, p1-13, 13p |
| Θεματικοί όροι: |
Alternative RNA splicing, Antisense RNA, Genes, Genetic engineering, Rett syndrome, Neurophysiology, Neural development |
| Περίληψη: |
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 2–skipping 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 MECP2. Editor's summary: Overexpression of methyl-CpG–binding protein 2 (MeCP2) shows therapeutic promise in preclinical models of Rett syndrome, a severe neurodevelopmental disorder caused by loss-of-function (LOF) mutations in MECP2. Because too much of the protein causes adverse effects, boosting endogenous MeCP2 expression might be a safer therapeutic approach. Of the two alternatively spliced MECP2 mRNA isoforms (e1 and e2), e2 is less efficiently translated and dispensable for MeCP2 function in the postnatal brain. Here, Tirumala et al. show that deletion of exon 2 of MECP2 results in a switch from e2 to e1 mRNA and increased MeCP2 protein in mice. Isoform switching by gene editing also augmented MeCP2 expression and ameliorated certain electrophysiological properties in patient-derived neurons harboring the G118E mutation and, more moderately so, in neurons harboring the T158M mutation. These results suggest that isoform switching could be a viable strategy to boost endogenous MeCP2, although therapeutic efficacy might depend on the type of MECP2 LOF mutations. —Daniela Neuhofer [ABSTRACT FROM AUTHOR] |
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| Βάση Δεδομένων: |
Complementary Index |