Rett syndrome is a rare neurodevelopmental disorder that is caused by mutations in the MECP2 gene situated on the X-chromosome. This gene provides instructions to make MeCP2, a transcription factor or protein that regulates the activity of other genes. Because MeCP2 plays a crucial role in brain development and function, a mutation in the MECP2 gene leads to Rett syndrome symptoms, such as motor, cognitive, and emotional problems.

There is currently no cure for Rett syndrome, but research is investigating ways to interfere with the course of the disease. One approach is the reactivation of the second healthy copy of the MECP2 gene.

How MECP2 reactivation works

Women have two X-chromosomes, but only one of them is active in each cell while the other is inactive, which means its genes do not initiate the production of proteins. Each X-chromosome contains one copy of the MECP2 gene.

In women with Rett syndrome, one of the two MECP2 gene copies is mutated and the other copy is normal. The inactivation of one X-chromosome occurs randomly in each cell. This means that in some cells the X-chromosome with the normal MECP2 gene copy is active. In these cells, the amount of MeCP2 produced is the same as in healthy individuals without Rett syndrome. In other cells, however, the X-chromosome with the mutated MECP2 gene copy is active. These cells lack functional MeCP2 protein.  There is a 50/50 chance that the X-chromosome with the mutated MECP2 gene is active in each cell. Consequently, in about half of the neuronal cells, the mutant MECP2 gene is active, while in the other half the normal MECP2 gene is active.

The aim of the reactivation approach is to activate the normal MECP2 gene copy so that all neurons can produce functional MeCP2 protein. There are different strategies that are being tested to achieve this. These strategies are still in early stages of development and are currently being tested in in-vitro assays and cells grown in the laboratory before being validated in animal models.

Zinc finger proteins and artificial transcription factors

The regulation of gene activity takes place in so-called promoter regions. Specific proteins known as transcription factors bind to the promoter region of a gene and activates it. The transcription factors, in turn, are regulated by another class of proteins, known as zinc finger proteins. Researchers working on this approach are testing different combinations of zinc finger proteins and artificial transcription factors to activate the MECP2 promoter.

Deactivation of Xist

The inactivation of one female X-chromosome is initiated by a molecule called Xist. Researchers try to reactivate the inactive X-chromosome by inhibiting the Xist molecule. They test different compounds for their ability to inhibit Xist. The tested compounds are small and can cross the blood-brain barrier, which makes their use as a medication for Rett syndrome feasible.

Epigenetic activation

The activity of genes is regulated by the addition or removal of biochemical tags, either to the DNA itself or to proteins that package the DNA, known as histones. This mechanism of gene regulation is called epigenetics. Researchers try to deliver epigenetic molecules to neurons that can remove gene silencing tags and add gene-activating tags to reactivate the normal MECP2 gene copy.

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