Modulating alternative splicing of MECP2 is a potential therapeutic strategy for Rett syndrome - PubMed
4 hours ago
- #MECP2
- #alternative splicing
- #Rett syndrome
- Modulating alternative splicing of MECP2 is a potential therapeutic strategy for Rett syndrome (RTT).
- RTT is caused by loss-of-function mutations in MECP2, a gene essential for neuronal function.
- Current FDA-approved treatment (trofinetide) only mildly alleviates symptoms, while increasing MeCP2 improves neurological phenotypes in mice.
- The study focused on switching the less efficiently translated e2 isoform to the more efficient e1 isoform of MECP2.
- Deleting Mecp2 exon 2 (unique to e2) increased MeCP2 protein by 50-60% in mice.
- Isoform switching in RTT patient-derived neurons improved morphology, electrophysiology, and transcriptome dysregulation.
- An exon 2-skipping morpholino successfully up-regulated MeCP2-E1 in mice, suggesting a potential antisense oligonucleotide therapy for RTT.