Genetic information in the human body is stored as code inside DNA. This code is written using four different building blocks, called bases. Different combinations of these bases encode different messages that are stored in genes. Cells read these genes to produce the proteins required for various bodily functions from walking, to thinking, to breathing.
Some human genes contain highly repetitive sequences of bases. Because these repetitive sections are difficult for cells to deal with, the number of repeats can continue to increase, growing in length uncontrollably. These repeat sequences cause cells to either produce bulky, toxic proteins or stop making essential proteins altogether. This is what occurs in certain inherited neurological disorders such as Huntington’s disease or Friedreich’s ataxia, where repeat expansion occurs in genes critical to brain function. Individuals with these disorders may have trouble with movement, planning tasks, or may develop psychiatric symptoms. While existing treatments can help manage symptoms or slow disease progression, neither disorder currently has an approved treatment to halt or reverse disease progression.
In a scientific first, researchers supported by the NIH Common Fund’s Somatic Cell Genome Editing program used a gene editing technology called ‘base editing’ to change single DNA bases and disrupt the repetitive sequence mutation. They applied this technology to laboratory models of Huntington’s disease and Friedreich’s ataxia. Researchers first tested base editors in cells donated by patients and later treated the brains of mice that modeled these diseases. For Huntington’s disease, where symptoms may not appear until the number of repeats reaches a certain threshold, the researchers were able to prevent further repeat expansion and moderately reduce the number of repeats over time. For Friedrich’s ataxia, the gene editing technology reduced the number of repeats and increased the amount of healthy protein that cells were able to produce.
Importantly, while this research focused on just two disorders, the broad flexibility of the base editing strategy suggests it could potentially be used to treat the fifty or more other repeat expansion diseases that currently have no cure. Although more work is needed to translate this approach to human treatments, this study represents an encouraging step forward in the search for therapies that target the root causes of genetic brain diseases.
References
Matuszek, Z., Arbab, M., Kesavan, M., Hsu, A., Roy, J. C. L., Zhao, J., Yu, T., Weisburd, B., Newby, G. A., Doherty, N. J., Wu, M., Shibata, S., Cristian, A., Tao, Y. A., Fearnley, L. G., Bahlo, M., Rehm, H. L., Xie, J., Gao, G., Mouro Pinto, R., … Liu, D. R. (2025). Base editing of trinucleotide repeats that cause Huntington's disease and Friedreich's ataxia reduces somatic repeat expansions in patient cells and in mice. Nature genetics, 57(6), 1437–1451. https://doi.org/10.1038/s41588-025-02172-8
