A new gene-targeting strategy that boosts a crucial brain protein could pave the way for the first effective treatment for Rett syndrome.
Researchers at Texas Children’s Duncan Neurological Research Institute (NRI) and Baylor College of Medicine have identified a possible new strategy for treating Rett syndrome. Their findings, published today (March 4) in Science Translational Medicine, suggest a novel way to increase levels of a crucial brain protein that is disrupted in the disorder. The approach shows early promise for addressing a rare neurodevelopmental condition that currently has no cure.
“Rett syndrome is a rare genetic neurodevelopmental condition that causes a regression in development, typically after 6 to 18 months of normal growth, leading to severe impairments in motor skills, speech, and communication,” said corresponding author Dr. Huda Zoghbi, director of the Duncan NRI, Distinguished Service Professor at Baylor, and a Howard Hughes Medical Institute investigator. “The disorder primarily affects girls; about 1 in 10,000 live births.”
The condition arises from loss-of-function mutations in the MECP2 gene. This gene plays an essential role in brain development by regulating the activity of many other genes involved in neurological processes. When mutations occur, the resulting MeCP2 protein may be missing entirely or may not function properly. In some cases, mutant forms of the protein are present but at lower levels or with reduced ability to bind DNA, which is critical for its role in regulating gene activity.
Evidence From Mouse Models
Studies using mouse models of Rett syndrome have shown that symptoms can be reversed under certain conditions. When healthy MeCP2 protein is introduced into the brains of affected mice, many symptoms improve. Researchers have also found that increasing levels of a partially functional mutant version of MeCP2 can help alleviate symptoms. Improvements observed in mice include longer survival, better motor coordination, and reduced breathing abnormalities.
“This is important because about 65% of patients with Rett syndrome have partially functional MeCP2 that either has decreased DNA binding or is less abundant than normal,” said first author Harini Tirumala, graduate student of molecular and human genetics in the Zoghbi lab. “Working with mouse models and cells derived from patients with Rett syndrome, our study provides proof of concept that increasing the levels of mutant MeCP2 in patients with the condition could provide therapeutic benefit.”
Understanding the MECP2 Gene Leads to a New Strategy
Designing treatments that adjust MeCP2 levels is difficult because the brain requires a precise balance. Too little MeCP2 leads to Rett syndrome, while too much causes another neurological disorder called MECP2 Duplication Syndrome. Maintaining this balance has made it challenging to develop safe therapies.
“We knew from previous studies that the brain normally produces two slightly different versions of the MeCP2 protein, known as E1 and E2,” Zoghbi said. “These versions come from the same gene, which is processed one way to produce E1 and a different way for E2.”
One way to picture this is to think of a gene as a recipe for making a protein. The instructions for MeCP2 contain four components: e1, e2, e3 and e4. When cells produce the MeCP2 E1 protein, they combine e1, e3, and e4. When they produce MeCP2 E2, all four components are included. This means the e2 ingredient is unique to the E2 version. The brain produces both proteins, but E1 is far more common.
“We also knew that there have been no reports of Rett syndrome patients carrying mutations on E2 protein. Only mutations that disrupt E1 protein cause the condition,” Tirumala said. “Studies in mice support this observation.”
“Altogether, we knew that MeCP2 E2 differs from MeCP2 E1 by a single ingredient in the gene, is less abundant than E1, is not associated with Rett syndrome and is not needed for MeCP2 function in the brain,” Tirumala said. “This led us to hypothesize that guiding brain cells to skip the e2 ingredient would promote the production of more MeCP2-E1 protein in patients with Rett syndrome and improve disease outcomes. We tested our hypothesis in mice and in cells derived from patients with Rett syndrome.”
Boosting MeCP2 Protein Levels
To test the idea, researchers first removed the e2 component from the normal Mecp2 gene in mice and studied the effects on protein production and neurological function. The change increased overall MeCP2 protein levels by about 50% to 60% in healthy mice.
“We were pleased to find that this approach led to 50% to 60% increase of MeCP2 protein in normal mice,” Tirumala said.
Next, the scientists applied the same strategy to cells taken from Rett syndrome patients carrying MECP2 mutations that reduce the amount and activity of the protein. By deleting the e2 component from the mutant gene, they examined how the change affected the cells.
“We were excited to see that deleting ingredient e2 enhanced MeCP2 production,” Tirumala said. “Importantly, depending on the severity of the mutation, these cells recovered part or all of their normal structure, their normal electrical activity, and their ability to regulate the levels of other genes.”
Exploring Potential Therapies
The team also investigated whether a drug could be used to block the e2 component and raise MeCP2 levels.
“We tested the value of morpholinos to enhance the production of MeCP2 protein in mice,” Tirumala said. “Morpholinos are synthetic molecules designed, in this case, to prevent the production of MeCP2-E2 protein by blocking the access to the e2 ingredient,” Tirumala said. “It was exciting to see that our morpholinos significantly increased MeCP2 protein in mice.”
“Our work lays the foundation and provides preclinical evidence for a therapeutic approach for Rett syndrome that increases MeCP2 and confers functional improvement,” Zoghbi said. “Although morpholinos themselves are not an option because of their toxicity, similar strategies, like antisense oligonucleotide therapies already used in other conditions, could potentially be developed for Rett syndrome.”
Reference: “Modulating alternative splicing of MECP2 is a potential therapeutic strategy for Rett syndrome” by Harini P. Tirumala, Li Wang, Yan Li, Sameer S. Bajikar, Ashley G. Anderson, Wei Wang, Alexander J. Trostle, Mahla Zahabiyon, Aleksandar Bajic, Jean J. Kim, Hu Chen, Zhandong Liu and Huda Y. Zoghbi, 4 March 2026, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adq4529
Other contributors to this research include Li Wang, Yan Li, Sameer S. Bajikar, Ashley G. Anderson, Wei Wang, Alexander J. Trostle, Mahla Zahabiyon, Aleksandar Bajic, Jean J. Kim, Hu Chen and Zhandong Liu. All authors were affiliated with Baylor College of Medicine and Duncan NRI during the study, though some have since moved to institutions including Stanford University, University of Virginia and UT Southwestern Medical Center – Dallas.
Funding for the project came from the National Institutes of Health (grants 5R01NS057819, P30 CA125123 and S10OD028591), the Howard Hughes Medical Institute, National Institute of Neurological Disorders and Stroke (F32NS122920), the Henry Engel Fund and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555).
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