Innovative Gene Editing Technique Stabilizes and Disrupts Huntington's Disease Mutations in Mice

Researchers at the Broad Institute have advanced the field of genetic therapy by developing a novel gene editing approach targeting the root cause of Huntington's disease and Friedreich's ataxia. These neurodegenerative disorders are caused by abnormal expansions of three-letter DNA sequences, such as CAG repeats, which grow uncontrollably beyond a certain threshold, leading to progressive neuronal damage. Currently, there are no treatments capable of halting disease progression.

The team employed base editing—a precise gene editing technique—to introduce single-letter modifications within the problematic repetitive DNA segments. In patient-derived cells and mouse models, these edits effectively prevented the repeats from expanding further, with some cases showing the repeats becoming shorter over time. This approach was achieved by inserting specific interruptions into the repeats, mimicking naturally occurring variations associated with milder symptoms and reduced inheritance risk.

The researchers utilized adeno-associated virus vectors to deliver the base editors specifically to nerve cells in mice. This targeted delivery stabilized or shortened the trinucleotide repeats in models of Huntington's and Friedreich's ataxia, demonstrating a promising path toward therapeutic interventions.

While promising, the team notes the potential for off-target effects where the base editors might make unintended modifications elsewhere in the genome. However, preliminary data suggests that most off-target activity occurs in non-coding regions, which might reduce risks. Further studies are needed to assess side effects and safety.

The significance of this research lies in its demonstration that inducing interruptions in repeat sequences can stabilize the genome, offering a potential strategy not only for treatment but also for understanding disease mechanisms. The approach paves the way for future therapies that could prevent the progression of repeat expansion disorders, including Huntington's disease and Friedreich's ataxia.

As Dr. Liu and colleagues continue refining the technology, they are also exploring prime editing methods to replace long, unstable repeat tracts with shorter, stable versions. This comprehensive work holds new hope for managing, or potentially stopping, these devastating neurological diseases.

Source: https://medicalxpress.com/news/2025-05-gene-disrupts-huntington-mutation-mice.html