X chromosome activation may offer hope for girls with Rett syndrome

Scientists have developed a gene therapy that can treat Rett syndrome by activating a silent gene.

A team of researchers led by Sanchita Bhatnagar of UC Davis Health has developed a promising gene therapy that could treat Rett syndrome. The therapy aims to reactivate the healthy but silent genes responsible for the rare disorder, as well as potentially other X-linked diseases such as fragile X syndrome.

The results of the study were published in the journal Nature Communications.

What is Rett syndrome?

Rett syndrome is a genetic disorder that mostly affects girls. It is caused by a defective gene called MECP2, located on the X chromosome. This gene contains instructions for making the MeCP2 protein.

Girls with Rett syndrome either have too little of this protein or it doesn't work properly. The protein deficiency causes a variety of symptoms, including loss of speech, impaired hand movement, difficulty breathing, and seizures.

Silent genes

Women have two X chromosomes (XX). In each cell, one of them is randomly inactivated, a process called X chromosome inactivation (XCI). In girls with Rett syndrome, the X chromosome that is inactivated may be the one with a healthy copy of MECP2.

"Our study aimed to reactivate the silent X chromosome containing the healthy gene. We showed that reactivation is possible and can reverse the symptoms of the disease," explained Bhatnagar, the senior author of the paper.

Sanchita Bhatnagar is an assistant professor in the Department of Medical Microbiology and Immunology at UC Davis, director of the Bhatnagar Laboratory, and an investigator at the UC Davis Cancer Center and the MIND Institute.

Sponge molecules versus microRNA

In the new study, the team conducted a genome-wide screen to identify small RNAs (microRNAs) involved in X-chromosome inactivation and X-linked gene silencing. They found that miR-106a plays an important role in X-chromosome and MECP2 gene silencing.

The scientists tested the idea of blocking miR-106a to weaken its effect and “wake up” the silent healthy gene. To do this, they used a female mouse model with Rett syndrome and a gene therapy vector developed by Professor Katherine Mayer from the Nationwide Children’s Hospital. This vector delivered a special DNA molecule that acted as a “sponge”, attracting miR-106a. This reduced the availability of miR-106a on the X chromosome, creating a therapeutic window for gene activation and MeCP2 production.

Impressive results

The results were impressive: treated mice lived longer, moved better, and demonstrated higher cognitive abilities compared to untreated mice. There was also a significant improvement in respiratory disorders in treated mice.

“The diseased cell itself contains the cure for its condition. Our technology simply helps it ‘remember’ its ability to replace the defective gene with a working one,” Bhatnagar explained. “Even a small amount of gene expression (activation) brings a therapeutic effect.”

Importantly, the Rett syndrome mouse model tolerated the treatment well.

“Our gene therapy approach to silencing the inactivated X chromosome has shown dramatic improvements in a range of symptoms in Rett syndrome,” Bhatnagar said. “Girls with the syndrome have limited motor and communication skills. They have sleep apnea and seizures. If we can help them talk when they’re hungry or walk to get a glass of water, that could change their lives. What if we could prevent or at least reduce the seizures and breathing pauses?”

Rett syndrome remains incurable. However, for families affected by the condition, the discovery offers hope that a cure may become a reality in the future. The approach may also be effective for other diseases caused by X-linked genes.

Before moving on to clinical trials, scientists will need to conduct additional safety studies to accurately determine the effectiveness of the therapy and its dosage.