Researchers have developed a gene editing strategy that could repair the genetic problems that lead to Huntington's disease and Friedreich's ataxia. These disorders arise because of abnormal repeats of three letters, or bases, in certain parts of DNA. These repeats grow longer over time and eventually cause the death of neurons in the brain in Huntington's, and neuron degeneration in Friedreich's ataxia. But scientists have now created a method that can prevent these abnormal repeats from getting too long. The work has been reported in Nature Genetics.
Abnormal, three-base repeats can lead to disease, and people with more repeats usually have more severe disease. Sometimes, people with these disorders also carry mutations within their repeats, and these carriers tend to have milder symptoms and are less likely to pass down their mutations compared to those who do not carry those additional mutations.
So researchers decided to try introducing a small mutation into the repeats, which could potentially slow down their expansion. They used a single-base editor that can swap one letter of the genome for another, like changing a G-C base pair to an A-T. They did so within the CAG repeat of Huntington's disease, and altered A-T pairs to G-C pairs in GAA repeats of Friedreich's ataxia.
While a lot more research will be necessary before this technique can be applied to people, there have been recent applications of gene editing that have been transformative for patients of certain diseases. This study is an important first step in a technique that could eventually become a treatment for diseases that are usually fatal. The method can also help scientists learn more about disorders like this in the research lab.
"A lot more studies would be needed before we can know if disrupting these repeats with a base editor could be a viable therapeutic strategy to treat patients. But being able to illuminate the biological consequences of interrupted repeats is a really useful and important milestone," explained senior study author David Liu, the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at the Broad Institute of MIT and Harvard, and a Howard Hughes Medical Institute investigator, among other appointments.
When these modified cells were grown over time, the repeats did not expand, unlike unmodified cells that carry these repeats. In some cases, the number of repeats even decreased in the modified cells.
Next, the researchers applied this approach to mouse models of Huntington's disease and Friedreich's ataxia. Once again, the method was able to halt the expansion of repeats.
Gene editors come with the possibility of introducing unwanted edits to the genome. But this work also suggested that most undesired edits happen tended to arise in parts of the genome that do not code for protein, reducing the potential risks from unwanted edits. Introducing mutations to repeats may one day be a viable treatment strategy.
"Not only does this study show for the first time that inducing interruptions has a profound stabilizing effect on repeats, but that the base-editing approach we've used can also be applied to study any of over a dozen repeat disorders," added study co-author Mandana Arbab, who is formerly of the Liu lab and is now an assistant professor at Boston Children’s Hospital. "There's still a lot of work to be done, but we're hopeful that this approach could really accelerate therapeutic development for a lot of these diseases."
The researchers are still at work on this and other treatment approaches for neurodegenerative disorders that involve expanded repeats.
Sources: Broad Institute of MIT and Harvard, Nature Genetics