Reawakening the X chromosome: New possible therapeutic targets for rare neurological disorder

Study points to potential reversal of rare childhood neurological disorder by reactivating silenced copy of the disease-linked gene
Dr. Antonio Bedalov
"It's devastating for the families," said Fred Hutch's Dr. Antonio Bedalov of Rett syndrome, for which there is currently no specific treatment or cure. Photo by Robert Hood / Fred Hutch News Service

Scientists have uncovered 30 genes that could, one day, serve as therapeutic targets to reverse Rett syndrome, a rare neurological disorder that affects primarily girls and women. The new findings are described in a study published this week in the journal Proceedings of the National Academy of Sciences.

Rett syndrome, which is linked to a genetic mutation, causes neurological problems that manifest early in life, affecting everything from sleep and mood to speech and gastrointestinal function. It can be misdiagnosed as autism or cerebral palsy.

There is currently no specific treatment or cure for Rett syndrome, which affects approximately 15,000 girls and women in the U.S. and 350,000 around the world. It’s much rarer in boys, although it can occur.

Girls born with Rett syndrome have one normal and one mutant copy of a gene known as MECP2. At first, they appear normal, growing and learning like any other baby up to 1 or 2 years of age. But then they start missing milestones and backslide in development. If they were walking, for example, they may stop — perhaps permanently. Some girls with the disorder will never learn to talk and may have difficulties swallowing and even breathing.

“They have this period of normal development, and then it’s taken away from them,” said Fred Hutchinson Cancer Research Center physician-scientist Dr. Antonio Bedalov, who led the research team. “It’s devastating for the families.”

Bedalov’s team’s approach aims to take advantage of a unique aspect of female biology, known as “X inactivation.” Women — and all female mammals — have two copies of the X chromosome, but one of these chromosomes is tightly bundled and almost completely shut off in every cell, effectively muting nearly all of its approximately 2,000 genes.

X inactivation is somewhat mysterious, but researchers know that the choice to silence a given X chromosome happens early in embryonic development, and that choice appears to be random. About half of a female embryo’s cells silence their maternal X chromosome; the other half switch off dad’s X. Once that X is silenced, it stays off — as cells continue to grow and divide as the embryo grows, each new cell keeps the same chromosome silenced as its ancestor did.

This phenomenon is responsible for a variety of natural occurrences, from calico coloration in cats (the genes coding for black or orange fur reside on the X chromosome) to the fact that identical female twins are often less identical than their male counterparts. (Even though identical female twins carry identical DNA instructions in all their cells, X inactivation means female twins sometimes use their genetic code differently from their sisters.)

And X inactivation also underlies certain sex-linked disorders like Rett syndrome — the disease-causing gene, MECP2, is carried on the X chromosome.

Even though, on average, half of a girl’s neurons will produce the healthy version of the MeCP2 protein, the loss of the protein due to the mutation in the other half of neurons is enough to trigger the syndrome.

The research team is working toward a therapy that would reawaken the “inactive X,” the silenced X chromosome in every cell, thus potentially reversing the syndrome by spurring the activity of the normal version of the gene in formerly diseased cells. The 30 genes that Bedalov and his team found do just that in adult mouse cells.

It’s not implausible to believe that the developmental syndrome could be reversed, said Bedalov, who is also an oncologist and transplant physician at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner. Ten years ago, a mouse study from researchers at the University of Edinburgh made waves in the Rett syndrome community because it suggested that the disease’s symptoms could be overcome by restoring normal levels of the healthy version of the MECP2 gene. Girls with Rett syndrome don’t produce enough of the MeCP2 protein in many of their neurons, which leads to developmental delays ranging from mild to severe.

The landmark 2007 study showed that restoring levels of MeCP2 in a mouse model of Rett syndrome could reverse these symptoms — even in adult animals, showing that the mutation’s effects may not do permanent damage to the brain. Although a promising first step, the approach that team used to target MeCP2 in mice is not possible to do in humans.

‘We just have to find a way to wake it up’

Now, Bedalov and his colleagues at Fred Hutch, Harvard Medical School and the University of Pennsylvania have identified a class of genes that could be new therapeutic targets for the disease in humans. The researchers found that when these genes’ activity is blocked, the normal copy of MECP2 is partially reactivated — along with other genes on the inactive X — in adult mouse cells in the lab.

Although there are U.S. Food and Drug Administration-approved drugs that target some of the 30 genes uncovered in their study, Bedalov cautioned that even an early-stage clinical trial for their approach is a long way off. First, the researchers want to confirm that reactivating the X chromosome works in a female mouse model of Rett syndrome. They’re currently in the process of developing this animal model. Because the genes they’ve found don’t fully reactivate the silent X chromosome, it’s not clear whether blocking their activity will be enough to reverse the syndrome. Next, they will test some of those drugs, which include a class of targeted cancer drugs known as PI3K inhibitors, in the mouse model.

Because the research team’s approach leads to the reactivation of the entire chromosome, it could also apply to other, similar disorders, as several other genes on the X chromosome have been linked to developmental disorders in girls.

Researchers used to think that reawakening the entire silent X chromosome could be disastrous, Bedalov said. Studies in animal models showed that embryos unable to silence one of their X chromosomes die well before birth. But his lab has seen early hints that partially lifting X-chromosome silencing in adult mouse brains appears to not harm the animals.

The research project was initiated and funded by the Rett Syndrome Research Trust, or RSRT, an organization launched by Monica Coenraads, whose daughter, Chelsea, has Rett syndrome. When Chelsea was first diagnosed in 1998, a genetic test for the disease hadn’t yet been developed.

Chelsea, who is now 20, has a long list of symptoms she lives with, Coenraads said, but “she’s so much more than the laundry list of symptoms.” Even though Chelsea is wheelchair-bound, doesn’t speak or use her hands, she loves being around people and has an amazing smile, her mother said.

“She deals with so much and yet she does it with grace and courage,” said Coenraads, the executive director of RSRT. “We can’t wait for the day to have something that improves her life.”

Coenraads led a different foundation that helped fund the 2007 study showing that the disease could be reversed in animals. Scientists working on Rett syndrome — many of them partnering with RSRT — are pursuing multiple different avenues to overcoming the deficit of MECP2, Coenraads said. Reactivating the naturally occurring, inactive form of the gene has a certain logical appeal, she said.

“The concept that there is a healthy copy of this gene in every cell, we don’t have to deliver it, it’s already there, we just have to find a way to wake it up … it’s a very attractive approach,” Coenraads said.

Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

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