Researchers Win $1.1M to Switch On Backup Copy of MECP2

The Rett Syndrome Research Trust (RSRT) has given two researchers $1.1 million to collaborate on the development of a therapy capable of switching on a healthy, backup copy of MECP2 — the gene mutated in most cases of Rett syndrome.

The collaboration involves Antonio Bedalov, MD, PhD, a professor at the Fred Hutchinson Cancer Research Center, in Washington, and Kyle Fink, PhD, a professor at the University of California, in Davis. Together, they plan to unite their efforts and expertise to find a way to revert the symptoms of the rare neurodevelopmental disorder.

“The key was our first meeting through RSRT,” Bedalov said in a trust press release.

“It became clear that we could complement each other’s strengths in a synergistic way, and that led to developing this project together,” Bedalov said.

Rett syndrome, a disorder that almost exclusively affects girls, is most commonly caused by mutations in a single gene, MECP2, that’s located on the X chromosome. The MECP2 gene contains instructions for making a protein called MeCP2, which is needed for proper brain development.

In cells from females, one X chromosome is active and another is inactive, or silent. In cases where MECP2 is mutated, girls with Rett have a healthy copy of this gene on one X chromosome and a Rett-causing copy on the other X chromosome, but only one is used to make protein. The choice occurs randomly — sometimes it is the healthy copy; other times it is the Rett-causing copy.

“Mutations in MECP2 in females result in mosaicism: there are healthy cells that have the healthy copy of MECP2 on and the mutant copy off, but in other cells, the opposite is happening, the mutant copy is on with the healthy copy off,” Fink said.

The researchers think that turning on the silent, healthy copy of MECP2 could rescue cells that are using the Rett-causing copy and provide a therapeutic strategy. This strategy is known as MECP2 reactivation.

The approach makes use of two ways to modify the epigenome — a record of all chemical changes, or marks, capable of turning genes on and off. One is to reduce the amount of Xist, a special type of RNA molecule that surrounds the inactive X chromosome, keeping its genes turned off. The other is to use a modified version of CRISPR technology — a gene-editing tool — to remove a different kind of epigenetic mark from the MECP2 gene, thereby turning it back on.

This gene-editing tool has been used by the Fink lab to reactivate the silent copy of a different gene, CDKL5 — whose mutations cause a form of infantile epilepsy previously classified as an atypical form of Rett. Now, the team will work toward reactivating the silent copy of MECP2 in cells derived from individuals with Rett.

Using a mouse model of Rett created specifically to look at MECP2 reactivation, the Bedalov lab will test the same tools, translating results from isolated cells into whole animals.

The quest for a strategy to switch on the healthy copy of MECP2 started more than a decade ago. With funding from the RSRT, researchers have screened for compounds that might reactivate the healthy copy of MECP2. However, the treatment candidates were not safe or effective enough.

Now, modern tools are paving the way for new strategies.

In addition to the new tools, researchers “have a better understanding of the biology of X-chromosome inactivation,” Bedalov said. “And we have built excellent experimental tools, including cell lines and mouse models that let us really test our success at MECP2 reactivation.”

“It’s exciting to see therapeutic approaches based on reactivating healthy copies of genes that were turned off becoming a reality, as we see in the successful clinical trials for sickle cell disease,” Bedalov added.

If the strategy works, it may have benefits over gene replacement therapy, which provides a healthy copy of the mutated gene.

“Rett is a disease where it is very important to get the gene dosage right,” Bedalov said. “In gene therapy, you add a new copy of a gene and hope that it makes a lot of protein. But for MeCP2, having too much is nearly as harmful as having too little. Getting the right dose is tricky. This approach helps get the dosage right.”

“It’s a high risk project, but if it works it will have a high reward,” added Fink.

Bedalov and Fink will provide an update about the progress being made on their research via a webinar hosted by RSRT on June 18.