Hand movement of girl with Rett syndrome. Credit: Ingridplg
Researchers have developed a potential new approach to treat Rett syndrome, offering early promise for a rare neurodevelopmental disorder 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. The disorder primarily affects girls—about 1 in 10,000 live births. It is caused by loss-of-function mutations in the MECP2 gene, which modulates the levels of several genes regulating typical neurological functions.
Now, a new study on mouse models of Rett syndrome shows the disorder is reversible.
Disrupting proteins
Scientists knew from previous studies that the brain normally produces two slightly different versions of the MeCP2 protein, known as E1 and E2. These versions come from the same gene, which is processed one way to produce E1 and a different way to produce E2. There have been no reports of Rett syndrome patients carrying mutations on the E2 protein—only mutations that disrupt E1 protein seem to cause the condition.
“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,” said first author Harini Tirumala, graduate student of molecular and human genetics at Baylor.
But, developing therapeutics that modulate MeCP2 is a delicate balance. Too little MeCP2 causes Rett syndrome, yet too much MeCP2 causes a different neurological disorder termed MECP2 Duplication Syndrome.
For the study, published in Science Translational Medicine, the researchers genetically deleted e2 from the normal Mecp2 gene in mice. They found that this led to a 50 to 60% increase of MeCP2 protein in normal mice.
The team then applied the same approach to cells derived from patients with Rett syndrome carrying MECP2 mutations that reduce the abundance and activity of the protein. They deleted e2 from this mutant MECP2 gene, which resulted in enhanced MeCP2 production.
Importantly, depending on the severity of the mutation, the cells recovered part or all of their normal structure, their normal electrical activity and their ability to regulate the levels of other genes.
The researchers then tested the therapeutic power of morpholinos, synthetic, non-ionic nucleic acid analogs used to knock down gene expression. In this case, the morpholinos were designed to prevent the production of MeCP2-E2 protein by blocking access to the e2 ingredient—which subsequently 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,” said Huda Zoghbi, Distinguished Service Professor at Baylor. “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.”