Fragile X syndrome is not well known to the public, but it is, in fact, the most common cause of inherited mental retardation, affecting hundreds of thousands of patients worldwide. Now, thanks to Hebrew University of Jerusalem researchers, there is a better understanding of it. They produced a generation of neuronal cells from stem cells in Fragile X patients, paving the way for research that will examine restoration of normal gene expression in such patients.

The syndrome is caused by lack of normal expression (functioning) of the FMR1 gene, which is critical for normal cognitive function in brain neuronal cells. Absence of the gene’s expression is caused by a mutation in the regulatory elements that govern it. The abnormal addition of chemical methyl groups to the regulatory elements causes “gene silencing” in patients, culminating in severe mental retardation. A possible way to help patients is to find compounds that will clear the abnormal methyl groups from the regulatory elements and reactivate normal gene expression. In their work, the HU researchers have identified a chemical compound that restored normal gene expression specifically in neuronal cells, the cell type most affected in patients.

The research was conducted in the laboratory of cancer researcher Prof. Nissim Benvenisty by doctoral student Ori Bar-Nur and undergraduate student Inbal Caspi. They managed for the first time to generate brain neuronal cells from patients with the syndrome in a dish culture and found a substance that restored normal gene expression in patients’ cells.

In a previous study conducted in the Benvenisty laboratory, a novel technology was used to induce pluripotent stem cells from skin cells of Fragile X patients – pluripotent stem cells have the amazing ability to differentiate into any human cell type in a dish culture.

In their latest study, published recently in the Journal of Molecular Cell Biology, the researchers harnessed this ability to turn the stem cells into neuronal brain cells. After generating the cells, they screened several chemical substances with the aim of finding one that would restore FMR1 normal gene expression. They showed that the substance 5-azaC was able to clear the methyl groups from the regulatory elements of the gene, allowing for the efficient restoration of FMR1 expression in both stem and neuronal brain cells.

The substance has been known for many years to clear methyl groups from regulatory elements of genes, and it is also an already established drug for other diseases. However, this is the first time that it has been shown to successfully clear the methylation in neurons or stem cells of Fragile X patients. In addition, the researchers were able to show that gene expression is maintained even after 5-azaC withdrawal, so there is no need to administer it continuously. This raises hopes for the use of the compound as a potential drug for the benefit of such patients.

According to Bar-Nur, “There is still a substantial gap between the restoration of gene expression in cultured patients’ cells and restoring it in patients; however, the finding that it is possible to restore gene expression in neuronal cells paves the way for further study of its restoration in patients. New technologies developed in recent years in the stem cell field allow us to conduct research that was not possible until recently.”

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