A research team from Baylor College of Medicine and the Duncan Neurological Research Institute at Texas Children’s Hospital has reported a potential new therapeutic approach for Rett syndrome. Their findings were published in Science Translational Medicine.
“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 Dr. Huda Zoghbi, Distinguished Service Professor at Baylor, director of the Duncan NRI and a Howard Hughes Medical Institute investigator. “The disorder primarily affects girls; about 1 in 10,000 live births.”
The disorder results from loss-of-function mutations in the MECP2 gene, which plays an important role in regulating neurological functions. Some mutations cause the protein to be less abundant or reduce its ability to bind DNA.
Mouse models have shown that symptoms can be reversed by introducing normal MeCP2 protein into the brain. Researchers also found that increasing levels of partially functional mutant MeCP2 proteins improved symptoms such as survival and motor coordination in mice.
“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 Harini Tirumala, graduate student in molecular and human genetics at Baylor. “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.”
Developing treatments that adjust MeCP2 abundance is complex because both insufficient and excessive amounts can cause neurological disorders.
“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.”
Tirumala explained: “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.” She added: “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. 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.”
By deleting ingredient e2 from normal Mecp2 genes in mice, researchers observed an increase of 50% to 60% in MeCP2 protein levels without adverse effects.
When applying this strategy to patient-derived cells with MECP2 mutations affecting abundance or activity, they found increased production of MeCP2 led these cells to recover part or all their typical structure and electrical activity.
The team then tested whether drugs blocking access to ingredient e2 could 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,” she added. The use of morpholinos significantly increased MeCP2 protein levels.
“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.”
Other contributors included 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 affiliated with Baylor College of Medicine or Duncan NRI during their involvement but now at institutions including Stanford University and UT Southwestern Medical Center – Dallas.
This research received funding from organizations such as National Institutes of Health (NIH), Howard Hughes Medical Institute (HHMI), Henry Engel Fund and others.
Baylor College of Medicine operates as an independent health sciences university focused on research advancement across fields such as biomedical science while engaging extensively through community service initiatives (official website). The institution maintains partnerships for education delivery across its schools as well as patient care programs (official website). Paul Klotman serves as president and chief executive officer (official website).
