Genes offer new clues to stopping Huntington’s disease in its tracks

Jeff Carroll was in his mid-twenties, fresh out of the U.S. Army, when a genetic test confirmed his worst fear: He was going to develop Huntington’s disease.

He had watched his mother’s illness for years; the tremors first, small enough to explain away, then the involuntary movements that looked almost like dancing. The test revealed that the same mutation that caused her disease lived in him: a stretch of three DNA letters in a gene called HTT, repeated over and over again dozens of times.

Carroll himself was not sick yet. He would not get sick for many years. But the countdown had begun. In fact, it had likely been running all his life, deep inside vulnerable neurons in his brain. There, the mutant HTT gene was slowly growing longer, its internal repeats piling up toward a threshold that, once crossed, would tip the cell into disarray.

The first outward signs of Huntington’s often begin with mood changes and subtle cognitive effects. The hallmark jerky movements come later. Eventually, and relentlessly, patients lose the ability to speak, swallow or move. Most people die within a decade or two of symptom onset.

Huntington’s disease is rare, affecting roughly 1 in 20,000 people worldwide. Yet because each child of an affected parent has a 50 percent chance of inheriting the mutation, the disease can haunt families for generations. It had already claimed Carroll’s grandmother and would take his mother at age 54. Without a therapy capable of altering its course, Carroll — along with three of his five siblings who also inherited the mutation — seemed fated to follow his ancestors into an early grave.

Carroll decided the only rational response was to become one of the scientists seeking ways to beat the disease. He was midway through his undergraduate studies when he learned, in 2003, that he carried the mutation. He pressed on, earning a Ph.D. and completing postdoctoral training before establishing his own research group devoted to understanding and slowing the disease stalking him from within.

Now a neurobiologist at the Allen Institute in Seattle, Carroll is part of a new initiative launched in June dedicated to tackling fatal neurodegenerative diseases. He is leading the Huntington’s strand of that work, with a major focus on somatic expansion, the lifelong growth of specific repeating DNA sequences. In Huntington’s, this takes the form of CAG (encoding the nucleotides cytosine, adenine and guanine) in the HTT gene.

Once dismissed as a biological curiosity, somatic expansion is now viewed as a key force shaping when and how Huntington’s and other diseases progress. For the field, this shift in thinking has opened a new therapeutic frontier. For Carroll, however, it has landed as a gut punch.

As Carroll now understands all too well, the mutation he inherited isn’t static. It is still creeping longer, tacking on new CAG copies inside the very neurons it is destined to destroy. The genetic chain reaction has already produced subtle motor and cognitive symptoms he regards unmistakably as Huntington’s.

“It sucks as you think about it,” says Carroll, who will turn 49 in August. “Not only do I have this horrible mutation, but it’s getting worse over time.”

That’s the bad news. But fortunately for Carroll and others like him, the research into somatic expansion has revealed an unlikely silver lining. The expanding DNA repeat and the destruction of neurons do not appear to proceed in lockstep. Researchers now believe there may be a lengthy window, perhaps decades long, during which the repeats accumulate while much of the brain remains structurally and functionally intact.

A new generation of therapies aims to intervene at that gap between the disease’s molecular march and its neurological consequences. The first drug candidates designed to target somatic expansion are slated to enter clinical testing later this year. If those medicines can slow or halt the process before too many neurons cross the point of no return, researchers hope they may preserve much of the vulnerable brain tissue that remains in people like Carroll.

“It’s a beautiful intervention,” Carroll says. “There’s a good reason, based on the best science, to still be hopeful.”

Genetic gambit

Huntington’s has long carried a grim distinction: It is among the most clearly defined genetic tragedies in all of medicine.

Unlike complex disorders shaped by dozens of DNA variants, Huntington’s follows a brutally simple rule: Inherit one copy of mutant HTT, with its stuttering stretch of CAG repeats, and the disease will come.

Though the first signs of disease typically appear between the ages of 30 and 50, exactly when the illness strikes depends largely on the number of CAG repeats a person starts with. Any repeat count above 40 virtually guarantees the disease will develop. But the genetic hand dealt at birth also sets a rough timetable, with longer CAG tracts hastening symptoms and shorter ones buying more years of healthy life.

Scientists identified HTT and its corresponding protein, huntingtin, in 1993 — the culmination of a decade-long hunt involving research teams from around the world. The discovery remains one of the most celebrated achievements in human genetics research, a moment that finally revealed the cause of Huntington’s disease. It immediately raised hopes that an effective treatment would soon follow.

It did not.

The premise was hard to fault. Normally, the huntingtin protein encoded by HTT does vital work: guiding embryonic development, then helping neurons function in the adult brain. But the misshapen version churned out by the mutant gene builds up inside neurons and poisons them. So, the thinking went, clear out the toxic protein and the disease should loosen its grip. Yet one drug candidate after another stumbled in clinical trials.

The sharpest blow came in 2021, when late-stage trials of a drug called tominersen — once the field’s leading hope — had to be halted after investigators found the therapy not only didn’t work, it appeared to make patients worse.

Then came an unexpected revival of the huntingtin-depleting strategy. Last year, a gene therapy from the Dutch company uniQure became the first treatment to slow the progression of Huntington’s disease in a clinical trial. The therapy is designed to permanently dial down huntingtin production with a single infusion into the brain. When compared with matched controls from a database of untreated patients, the gene therapy showed at long last that “you can shift the dial” on the course of Huntington’s, says Sarah Tabrizi, a neurologist at University College London who served as lead scientific adviser on the trial.

But it wasn’t just the clinical results that convinced Tabrizi the effect was real. “It was the molecular evidence that nailed it for me,” she says. Spinal fluid analyses showed that levels of a protein called neurofilament light, which is released by dying neurons, had been reduced — the opposite of what typically happens as Huntington’s progresses.

The result was significant, though not without caveats. The therapy may have slowed the disease but did not stop it. Delivering it demands an hours-long brain surgery that only neurosurgeons at select medical centers can perform. And the evidence came from a small trial with no placebo-control arm, a methodological limitation that led some experts to question the strength of the conclusions.

In June, the U.S. Food and Drug Administration agreed that the data could support a new-drug application after all. Yet even this milestone reinforced a growing suspicion that the field has been aiming too far downstream. Lowering huntingtin may help, researchers say, but it may not fully address the deeper biology driving the disease.

That does not mean abandoning the protein-lowering strategy. Carroll sees it as a necessary piece of the puzzle. Were the uniQure therapy approved today, he says, he would take it himself, and “I would endorse my family doing it.”

For those wary of an invasive brain operation, other HTT-targeting therapies are coming, too. This year brought promising early-stage data on once-daily pills designed to throttle production of the toxic huntingtin protein.

Yet the field’s center of gravity has continued to move upstream, toward the unstable DNA mutation and the cellular machinery that keeps making it worse.

Repair run amok

Almost as soon as the HTT gene was identified and genetic testing for Huntington’s became available, scientists noticed something that didn’t add up: Patients carrying nearly identical numbers of CAG repeats could develop symptoms years, sometimes decades, apart.

One person might start declining rapidly in his 40s while another might keep her faculties largely intact into her 60s. Same mutation, wildly different fates. Clearly, something else was at work.

That something began coming into focus around a decade ago, when an international consortium led by neurogeneticist Jim Gusella of Massachusetts General Hospital in Boston identified some of the first genes implicated in determining when Huntington’s strikes.

The research kept pointing to the same place: genes involved in DNA repair, the process cells use to correct the small copying errors that pile up as they read and maintain the genome. Subtle variations in these genes seemed to shift the age at which Huntington’s symptoms would begin, pushing onset earlier or later than the inherited repeat length would predict.

A new picture began to emerge. Though the mutant HTT gene might determine who develops Huntington’s, the DNA repair machinery seemed to help determine when the disease would set in. “It all fits together,” Gusella says.

The DNA-repair proteins encoded by these modifier genes normally patrol the genome for mistakes and damage. The mutant HTT gene, however, turns this protective machinery against itself. Its repetitive DNA sequence can confuse the very proteins tasked with preserving genetic integrity, causing some to make the sequence longer than they found it. The result is gradual accumulation of CAG repeats.

But even as the repeating DNA sequence gets nudged ever longer by the cell’s own repair machinery, the brain seems remarkably capable of absorbing the damage. It is only after the repeats cross a critical threshold that huntingtin turns lethal, pushing neurons into dysfunction and death.

Molecular biologist Nathaniel Heintz at the Rockefeller University in New York City and colleagues first laid out this logic in 2024 in Nature Genetics. That study showed the disease unfolds in two stages: first the slow expansion of the repeat, then a distinct toxic phase once the repeat has grown long enough.

In parallel, neurogeneticist Steve McCarroll at Harvard Medical School and colleagues had been examining individual neurons taken from post-mortem human brains. Reporting in February 2025 in Cell, they measured the exact number of CAG repeats inside each cell. What they found mapped almost perfectly to what the earlier gene-hunting studies had hinted at.

Once the repeat reached roughly 80 copies, its growth began to accelerate. Beyond about 150 copies, gene activity inside affected neurons started to go haywire. Degeneration followed soon thereafter. And within months of crossing that threshold, neurons entered a rapid downward spiral toward death.

“It’s like going over a waterfall,” McCarroll says — calm for a long while, until suddenly the plunge is unavoidable.

A new target emerges

Even before McCarroll’s team confirmed this tipping point, the discoveries about somatic expansion had steered Huntington’s researchers toward a new set of drug targets: components of the DNA-repair pathway that govern how quickly the CAG repeats expand.

Much of the drug discovery action has converged on a gene called MSH3, which encodes a key component of the DNA repair machinery. The protein recognizes small mismatches in DNA strands and recruits other repair proteins that can inadvertently lengthen the CAG sequence.

Natural variation in MSH3 impacts how quickly the sequence expands and, by extension, how quickly Huntington’s symptoms progress, Tabrizi and colleagues reported in 2017 in Lancet Neurology. That finding, along with similar activity in patients with myotonic dystrophy, another rare disorder caused by triplet DNA repeats, elevated MSH3 from a molecular curiosity to a prime therapeutic target.

In the years since, several research teams have shown that blocking MSH3 activity in mice can slow — and in some cases nearly stop — the runaway repeats inside neurons.

As the evidence mounted, so did interest from industry, ushering in the first wave of biotech ventures built on the premise that Huntington’s might be held at bay by preventing the mutant gene from growing more dangerous over time.

Anastasia Khvorova, a chemical biologist at the UMass Chan Medical School in Worcester, has studied long-term MSH3 suppression in mice. Up to a year of therapeutic silencing produced no obvious biological changes in these short-lived rodents, she and colleagues have found.

The findings don’t necessarily guarantee that the treatment is safe for people, Khvorova says. “But if you’re talking to Huntington’s patients, I think this risk is something people are willing to take.”

Promise and peril

As yet, no company has translated the promise of stopping somatic expansion into a proven therapy, in part because the road to clinical testing has been anything but straightforward.

Triplet Therapeutics was among the first to try. The Cambridge, Mass.–based startup, which was founded in 2018, burst onto the biotech scene with tens of millions of dollars in venture financing, plus a who’s who of scientific advisers including Gusella, Tabrizi, Carroll and other leaders in the field.

Scientists at Triplet quickly zeroed in on a type of drug known as an antisense therapy, which uses short strands of synthetic DNA or RNA to block production of a target protein. They developed one such drug that turned down MSH3 expression in the brains of mice and monkeys, setting the stage for what would have been the first human trial of a therapy targeting somatic expansion. “We had everything ready,” says neuropsychiatrist Irina Antonijevic, who led Triplet’s drug development efforts.

But the company needed fresh capital to fund a clinical trial. And just as Antonijevic and colleagues were preparing to raise it, the disappointing results from trials of tominersen and another Huntington’s antisense drug rattled confidence across the field. Investors suddenly grew reluctant to place more bets on Huntington’s research, especially another antisense drug candidate.

Triplet shut down in 2022. The collapse came down to bad timing, not any crack in the biological case for targeting MSH3, says Antonijevic, who is now chief medical officer of the startup Trace Neuroscience. “I have no doubt about the science,” she says.

Genetic evidence continues to tie the repair genes to how fast the disease unfolds, Gusella’s consortium reported last June in Nature Genetics. And mouse studies have validated the idea that switching off the genes blunts runaway DNA growth and eases the disease’s mark on the brain, according to a study published in 2025 in Cell.

Now, Latus Bio of Philadelphia and Boston has secured millions in funding and is on track to become the first company to test the strategy in humans using a new type of gene therapy. Possible approaches to slowing repeat expansion vary. Among companies targeting MSH3, some like Latus Bio are developing biological drugs that must be injected directly into the brain or spinal fluid to reach their target. Others are pursuing small-molecule pills in which the drug is so tiny that it can easily cross from the bloodstream into the brain, no invasive procedures needed.

Other targets within the DNA-repair pathway are under investigation as well, including proteins that genetic and molecular studies suggest should be boosted, rather than blocked, to keep repeat expansion in check.

A determined push forward

None of this means the original strategy of targeting the huntingtin protein is obsolete. Such a therapy could still play an important role late in the disease course, after the DNA repeats have already expanded and when neurons are faltering but not yet gone, says David Howland, head of preclinical biology at the CHDI Foundation, a nonprofit research organization dedicated to Huntington’s.

The ideal, Howland suspects, may be to pair the two approaches in a one-two punch — first freezing the genetic expansion to stop the disease at its source, then clearing the toxic protein already damaging neurons.

But a combination attack on Huntington’s is probably years away. Drugs that achieve each half of the strategy generally have to be established on their own before the two can be brought together. In the meantime, researchers face a choice about where to place their bets.

“Five years ago, probably 95 percent of people would have said huntingtin-lowering is the top priority target by a long way,” says neurologist Ed Wild of University College London. Now, Wild says, that consensus has dissolved, and experts are hard-pressed to say whether lowering huntingtin or modulating DNA repair should come first.

And the implications reach well beyond a single disease. A drug that freezes repeat expansion in Huntington’s could, in principle, work against myotonic dystrophy, spinocerebellar ataxia and a wide range of other diseases that follow similar genetic dynamics.

“Huntington’s is the disorder for which we have the most compelling data,” says Darren Monckton, a geneticist at the University of Glasgow in Scotland who studies these conditions. “But all the mouse and tissue-culture data say it’s the same players [in the DNA-repair pathway] and absolutely we should be thinking about targeting them to treat these other disorders as well.”

For the scientists closest to this work, success or failure won’t be measured only in trial data. It will be measured in people, and one person in particular: Jeff Carroll.

“If we can save Jeff’s brain, then we’ve done our job,” says Wild, who has known Carroll since they were graduate students. “If we can’t, then we probably should have stayed a few more nights late at work.”

Carroll himself holds a clear-eyed view. He still has research to do and a life to live. Despite his symptoms, he is producing some of the strongest science of his career, colleagues say. In the last year, his lab reported that one type of huntingtin-depletion therapy can also curb the expansion of repeats, a finding that knits together the field’s two leading bets.

He is also a father to twin 20-year-olds — both conceived via IVF and with genetic screening to spare them the Huntington’s mutation — and he helps shoulder the care of his siblings who also inherited it. “It’s very clear that Jeff’s reserves are far from empty,” Wild says.

But they are steadily depleting. Inside Carroll’s brain, the mutant DNA continues lengthening. The slow neurological countdown set in motion by his genetic inheritance is advancing, even as the science is trying to stop it. Through it all, he keeps moving forward — for himself, for his family and for the tens of thousands of others living with the same diagnosis.

“We have to hurry,” Carroll says. “We have to keep pushing.”