A CRISPR/Cas9 display screen identifies miRNAs as regulators of mammalian XCI. Credit score: Nature Communications (2025). DOI: 10.1038/s41467-025-61092-7
Researchers led by UC Davis Well being scientist Sanchita Bhatnagar have developed a promising gene remedy that might deal with Rett syndrome. The remedy works on reactivating wholesome however silent genes answerable for this uncommon dysfunction and probably different X-linked situations, equivalent to fragile X syndrome.
Their findings had been printed in Nature Communications.
Rett syndrome is a genetic situation that principally impacts women. It’s attributable to a faulty MECP2 gene positioned on the X chromosome. This gene comprises directions for the synthesis of MeCP2 protein.
Women with Rett syndrome could have too little of this protein or their protein could not work correctly. This protein deficiency may cause a variety of signs, together with lack of speech, impaired hand actions, respiratory difficulties and seizures.
Silenced genes
Females have two X chromosomes (XX). In every cell, one X chromosome will randomly be silenced in a course of often called X chromosome inactivation (XCI). In women with Rett syndrome, the silenced chromosome carries a wholesome copy of MECP2.
“Our study looked at reactivating the silenced X chromosome carrying the healthy gene. It showed that reactivating the gene is possible and can reverse the symptoms,” mentioned Bhatnagar, the research’s senior writer.
Bhatnagar is an affiliate professor with the UC Davis Division of Medical Microbiology and Immunology and runs The Bhatnagar Laboratory. She is an assistant analysis program chief on the UC Davis Complete Most cancers Middle and a researcher on the MIND Institute.
Sponge-like molecules to beat microRNA’s silencing energy
The brand new research did a genome-wide screening to determine small RNA molecules (microRNA) concerned in XCI and X-linked gene silencing. It discovered that microRNA-106a (miR-106a) was lively in switching off X chromosomes and the MECP2 gene.
The staff examined whether or not blocking miR-106a may weaken the silencing impact and “wake up” the dormant wholesome gene. For that, they used a feminine mouse mannequin of Rett syndrome and a gene remedy vector developed by Professor Kathrin Meyer on the Nationwide Youngsters’s Hospital. The vector delivered a particular DNA-based molecule that acts as a “sponge” by attracting miR-106a. The molecule reduces the supply of miR-106a on the X chromosome, which supplies a therapeutic window for gene activation and MeCP2 manufacturing.
Spectacular outcomes
The outcomes had been very spectacular: The handled mice lived longer and confirmed higher motion and cognition than the untreated ones. The research additionally confirmed a major enchancment within the respiratory irregularities of the handled mice.
“The diseased cell holds its own cure. With our technology, we are just making it aware of its ability to replace the faulty gene with a functional gene,” Bhatnagar defined. “Even a small amount of this gene expression (activation) has therapeutic benefit.”
Importantly, the Rett mouse mannequin dealt with the therapy nicely.
“Our gene therapy-based approach targeting X chromosome silencing showed significant improvement in several symptoms of Rett syndrome,” Bhatnagar mentioned. “Girls with Rett exhibit a wide range of symptoms, limited mobility and communication skills. They have apnea and seizures. It would be life-changing if we could help reverse some of their symptoms, so they can speak if they’re hungry or walk to get a drink. What if we could prevent these seizures and apnea episodes, or simply reduce them?”
Rett syndrome nonetheless has no treatment. For households affected by Rett syndrome, this discovery brings some hope {that a} therapy may in the future change lives. This method may additionally work for related situations attributable to X-linked genes.
Earlier than shifting to scientific trials, the researchers have to conduct security research to additional consider the efficiency of the therapy and the appropriate dosage.
Extra info:
Music Lou et al, Focusing on microRNA-dependent management of X chromosome inactivation improves the Rett Syndrome phenotype, Nature Communications (2025). DOI: 10.1038/s41467-025-61092-7
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An X chromosome swap provides hope for ladies with Rett syndrome (2025, July 23)
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