A Promising New Path Forward in Huntington's Disease Research and Treatment

Huntington's disease (HD) is a fatal genetic condition that causes progressive loss of brain cells, leading to involuntary movements, changes in thinking and mood, and difficulties with voluntary movements and gait. An estimated 7 per 100,000 people in the United States have HD.

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For years, the search for effective HD treatments focused on HTT, the gene that produces a mutant protein called huntingtin. The early 2020s, however, saw the failures of gene-targeting therapies in several prominent clinical trials.

Ricardo Mouro Pinto, PhD, MSc, of the Center for Genomic Medicine at Massachusetts General Hospital, is among the investigators exploring a different approach to treat HD. He is corresponding author of a 2025 paper published in Nature Genetics that outlines efforts to use CRISPR gene editing to screen for and then modify individual genes responsible for somatic CAG repeat expansion.

The National Institute of Neurological Disorders and Stroke named the study—along with two complementary studies—one of its Top 10 Research Advances of 2025.

An inherited repeat expansion disorder

HD is one of the more than 50 inherited repeat expansion disorders, which are caused by the abnormal expansion of repeat DNA sequences. In HD, a repeating stretch of the letters C-A-G in HTT constitutes the etiology. As noted in the paper, "Inherited CAG repeat length is the primary determinant of age of onset, with human genetic studies underscoring that the disease is driven by the CAG length-dependent propensity of the repeat to further expand in the brain."

As a postdoctoral research fellow at the Center for Genomic Medicine in the early to mid-2010s, Dr. Mouro Pinto studied mechanisms of somatic instability in repeat expansion diseases such as HD and Friedreich's ataxia with his mentor, Vanessa C. Wheeler, PhD. Observing that the CAG repeats were extremely unstable, particularly in brain regions affected in HD, Drs. Mouro Pinto and Wheeler hypothesized that they might contribute to disease onset.

Concurrently, the Center for Genomic Medicine's James F. Gusella, PhD, and Marcy E. MacDonald, PhD, were leading an international consortium study that showed that the genes involved in DNA repair were associated with age of onset in HD. At the time, Dr. Mouro Pinto was studying those same genes in mice.

"We knew some of those DNA repair genes were modifiers of somatic expansion in the brains of HD mice," he says. "Dr. Gusella and Dr. MacDonald's study revealed those genes as well as a number of other genes whose role in HD we didn't know then. But the strategies we were using until this point involved creating new mouse models for each of the new genes, and were therefore too slow and expensive. That was the moment the idea for this study came together."

The DNA mismatch repair pathway's crucial role

For the study, Dr. Mouro Pinto and his fellow investigators used CRISPR-Cas9 editing in mice with an HD-like mutation to enable in vivo screening of expansion-modifier candidates at scale. They leveraged this same technology to turn off genes, one by one, to evaluate their effect on somatic instability. Their work also included testing HD onset modifier genes emerging from human genome-wide association studies.

"We found there's one group of DNA repair genes that protect against repeat expansion and another group that promotes it. So, we came away with an understanding of the different effects that targeting different genes can have," Dr. Mouro Pinto says. "In addition, we identified some novel genes that were not previously known to affect somatic expansion."

As Dr. Mouro Pinto explains, the study sheds new light on the role of the DNA mismatch repair pathway in HD pathogenesis. The study authors' hypothesis is that the CAG repeats form abnormal structures within the cell that appear to be mismatches. DNA repair genes attempt to repair those structures but, in doing so, introduce more repeats.

"So that's the mechanism," Dr. Mouro Pinto says. "We have components of that repair machinery that get recruited and repair the abnormal structures with fidelity, and others that introduce these mistakes. Somatic expansions, then, are a consequence of erroneous DNA repair."

Identifying potential therapeutic targets

This study provides evidence that as drivers of somatic CAG expansion, certain DNA mismatch repair members represent potential therapeutic targets. Modifying these pathways could make it possible to slow repeat expansion, delaying HD onset and progression. The findings have already sparked efforts within academia and industry to explore various therapeutic modalities, including small molecules and antisense oligonucleotides.

Dr. Mouro Pinto is now leading a team of investigators from Mass General, Brigham and Women's Hospital, and the Broad Institute of MIT and Harvard who are also pursuing new therapies. They aim to develop a "one-and-done" CRISPR base-editing therapeutic that specifically targets somatic repeat instability. If successful, this research could transform the treatment of HD, Friedreich's ataxia, spinocerebellar ataxias, and a host of other repeat expansion disorders.

In 2025, the group received a five-year, $3 million Rappaport MGH Grand Challenge Award to advance their work.

"We've been applying our CRISPR screening methodology in different mouse models, comparing the direction of effects in HD and other repeat expansion diseases," Dr. Mouro Pinto says. "The interesting thing we're finding is that these diseases have many similarities. And that means you might be able to develop a drug that would work equally well across multiple repeat expansion diseases."

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