Researchers at Texas Children’s Hospital’s Duncan Neurological Research Institute and Baylor College of Medicine report an experimental gene-targeting approach designed to increase levels of the MeCP2 protein disrupted in Rett syndrome. In mouse experiments and neurons derived from patient cells, the strategy boosted MeCP2 and partially restored cellular structure, electrical activity and gene-expression patterns, according to findings published in Science Translational Medicine.
Rett syndrome is a rare genetic neurodevelopmental disorder that predominantly affects girls and typically involves a period of apparently normal early development followed by regression. Symptoms often emerge after roughly 6 to 18 months of typical growth and can include major impairments in motor skills, speech and communication, researchers at Texas Children’s Hospital said.
The condition is caused by loss-of-function mutations in MECP2, a gene that encodes the MeCP2 protein, a transcriptional regulator required to maintain normal neuronal function. When MECP2 is altered, MeCP2 can be absent, dysfunctional, or produced at lower levels. Dr. Huda Zoghbi, director of the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s and a Baylor College of Medicine professor, said the disorder affects about 1 in 10,000 live births.
The new work focuses on how brain cells make two closely related MeCP2 isoforms, commonly called E1 and E2, through alternative splicing and translation. E1 is the more abundant form in the brain. The researchers reported that Rett syndrome has been linked to mutations that disrupt the E1 protein, while mutations affecting the E2-specific segment have not been reported, and mouse work supports the idea that E2 is not required for MeCP2’s essential brain functions.
Building on that biology, the team tested whether forcing cells to skip the exon 2 segment—unique to the E2 isoform—could shift production toward E1 and thereby modestly increase overall MeCP2 protein.
In experiments that deleted exon 2 from the normal Mecp2 gene in mice, the researchers found MeCP2 protein levels rose by about 50% to 60%, Harini Tirumala, the study’s first author and a graduate student in Zoghbi’s lab, said.
The team also examined human neurons generated from induced pluripotent stem cells derived from Rett syndrome patients. In those models, exon 2 deletion increased MeCP2 and, depending on the mutation and its severity, improved aspects of neuronal morphology and electrophysiology and corrected some gene-expression abnormalities, the researchers reported.
As a step toward a drug-like approach, the study tested an exon 2-skipping morpholino—a synthetic molecule designed to block production of the E2 isoform—showing it could increase MeCP2-E1 in mice. But the researchers cautioned that morpholinos are not considered a viable therapeutic option in this context because of toxicity, and they pointed instead to the possibility of developing antisense oligonucleotide strategies to achieve a similar isoform switch.
The paper also notes earlier mouse studies suggesting that reintroducing MeCP2 or increasing its levels can improve neurological features and survival in Rett syndrome models, a line of evidence that has helped motivate efforts aimed at carefully raising MeCP2 without exceeding safe limits.
The study, published March 4, 2026 in Science Translational Medicine, lists contributors from Baylor College of Medicine and the Duncan NRI and reports support from the National Institutes of Health, the Howard Hughes Medical Institute and other funders.
