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Fragile X and Autism: Study Identifies Mechanism and Possible Treatment

Working in cell cultures, researchers show how experimental drug blocks genetic trigger behind fragile X syndrome
February 27, 2014

Researchers report that they’ve found the gene-silencing mechanism that causes fragile X syndrome, the most common wholly genetic cause of autism. They also describe reversing the problem in cell cultures using an experimental drug. The findings offer early promise that a similar approach might prevent or treat the root cause of fragile X syndrome in people.

The study, led by researchers at New York’s Weill Cornell Medical College, appears today in the journal Science.

“This is cutting-edge science that uncovers new details about the precise cause of fragile X and is new territory in the search for treatments aimed at its genetic cause rather than the symptoms,” comments Daniel Smith, Autism Speaks senior director for discovery neuroscience. Dr. Smith was not involved in the research. “It will be essential to determine whether these findings in a cellular model reflect the actual human condition and have the potential for truly new treatments,” he says.

Scientists have long known that fragile X syndrome involves an unusual mutation that causes the excessive repetition of a particular gene segment. Less clear was how this genetic change causes the syndrome and its common symptoms – including autism.

In the new study, researchers studied stem cells from donated human embryos that have a genetic mutation resembling that in fragile X syndrome. Normally, messenger RNA helps translate DNA into proteins. In the fragile X cells, however, the messenger RNA begins sticking to the mutated DNA segments during early cell development. This sticky binding appears to block the gene’s expression. As a result, the cell doesn’t produce a protein crucial to the transmission of signals between brain cells.

The malfunction appears to occur suddenly – before the end of the first trimester in humans and after 50 days in the cultured stem cells.

"We discovered that the messenger RNA can jam up one strand of the gene's DNA, shutting down the gene, which wasn’t known before,” says senior author Samie Jaffrey. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression. But this mechanism is completely novel and very exciting."

Early hope for treatment
Working with their cell cultures, the researchers used a drug developed by co-author Matthew Disney, of California’s Scripps Research Institute. The compound binds to a sequence in the fragile X gene's RNA in a way that allows the gene to continue producing its vital brain-cell protein.

This suggests a potential strategy for preventing or treating fragile X syndrome, Dr. Jaffrey says. "If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation. This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients."

A cell culture study such as this is a long way from treatment in humans, Dr. Smith comments. However the study is important in how it advances understanding of the genetic causes of autism in ways that can guide the development of better medicines, he says.

Autism Speaks continues to fund a broad range of research on fragile X and other genetic syndromes associated with autism. This and all Autism Speaks research is made possible by the passion and generosity of the organization’s donors and volunteers. You can explore all the research Autism Speaks is funding using this website’s grant search

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