Rett Syndrome: New Strategy Boosts Key Brain Protein & Offers Hope for Treatment

A promising new strategy to increase a critical brain protein offers a potential path toward treating Rett syndrome, a rare genetic neurodevelopmental disorder that primarily affects girls. Researchers at Texas Children’s Duncan Neurological Research Institute and Baylor College of Medicine have published findings in Science Translational Medicine detailing a method to boost levels of the MeCP2 protein, which is disrupted in individuals with Rett syndrome. While still early, the research provides a crucial step forward in addressing a condition for which there is currently no cure.

Understanding Rett Syndrome and the Role of MECP2

Rett syndrome is characterized by a regression in development, typically occurring after a period of 6 to 18 months of normal growth. This regression leads to significant impairments in motor skills, speech, and communication. Approximately 1 in 10,000 live births are affected, with the vast majority of cases occurring in girls. The underlying cause of Rett syndrome is often linked to mutations in the MECP2 gene.

The MECP2 gene is vital for normal brain function, acting as a regulator of numerous other genes involved in neurological processes. Mutations in this gene can result in a loss of the MeCP2 protein, or the production of a defective protein that cannot perform its normal functions. These defective proteins may be present in reduced amounts or have a diminished ability to bind to DNA – a crucial step in controlling gene activity.

Reversing Symptoms in Mouse Models

Previous research, including studies using mouse models, has demonstrated that Rett syndrome symptoms can be reversed by introducing a healthy MeCP2 protein into the brain. Importantly, increasing the levels of even a partially functional mutant MeCP2 protein has too shown improvements in survival, motor coordination, and respiratory function in mice. This finding is particularly relevant because approximately 65% of individuals with Rett syndrome possess partially functional MeCP2 proteins.

The E1 and E2 Variants of MeCP2

Researchers have long known that the brain produces two slightly different versions of the MeCP2 protein, designated E1 and E2. Both versions originate from the same gene, but are created through different processing pathways. Feel of the gene as a recipe: to develop E1, the cells combine ingredients e1, e3, and e4, while E2 includes all four ingredients (e1, e2, e3, and e4). The brain primarily produces the E1 version, and crucially, mutations causing Rett syndrome have only been observed to disrupt the E1 protein, not E2.

This observation led researchers to hypothesize that preventing the production of the E2 protein could encourage the brain to produce more of the functional E1 protein, potentially alleviating symptoms of Rett syndrome. “We hypothesized 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,” explained Harini Tirumala, a graduate student involved in the study.

Boosting MeCP2 Production in the Lab

To test this hypothesis, the research team initially removed the e2 segment from the Mecp2 gene in mice. This modification resulted in a significant increase in MeCP2 production. Further experiments were conducted using cells derived from patients with Rett syndrome carrying MECP2 mutations that reduce protein levels. Deleting the e2 component from the mutant gene in these cells also enhanced MeCP2 production, and in some cases, restored normal cellular structure, electrical activity, and gene regulation.

Exploring a Drug-Based Approach

Beyond gene modification, the researchers also investigated whether a drug could be used to block the production of the E2 protein and, boost MeCP2 levels. They tested morpholinos – synthetic molecules designed to prevent the production of MeCP2-E2 by blocking access to the e2 ingredient – in mice. The results showed that morpholinos significantly increased MeCP2 protein levels in the animals.

However, Dr. Zoghbi cautioned that morpholinos themselves are not suitable for therapeutic use due to their toxicity. She suggested that similar strategies, such as antisense oligonucleotide therapies – already used in the treatment of other conditions – could potentially be developed for Rett syndrome.

What’s Next: From Preclinical Evidence to Potential Therapies

The research team emphasizes that this work provides a foundation for future therapeutic development. While the findings are promising, significant hurdles remain before a treatment for Rett syndrome becomes available. Further research is needed to refine the approach, assess its long-term safety and efficacy, and determine the optimal method for delivering the therapy to patients. The team is currently focused on exploring alternative strategies to block the e2 segment, such as antisense oligonucleotide therapies, which have a more favorable safety profile than morpholinos.

The National Institutes of Health, the Howard Hughes Medical Institute, and several philanthropic organizations provided funding for this research. The study involved contributions from researchers at Baylor College of Medicine and the Duncan Neurological Research Institute at Texas Children’s Hospital.

Individuals seeking more information about Rett syndrome can discover resources at the Rett Syndrome Foundation and the Centers for Disease Control and Prevention (CDC).