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.”