Genes offer new clues to stopping Huntington’s disease

Jeff Carroll was in his 20s, fresh out of the U.S. Army, when a genetic test confirmed his worst fear: he would develop Huntington’s disease.

He had observed his mother’s illness for years; first the tremors, small enough to be explained, then the involuntary movements that almost seemed like dancing. The test revealed that the same mutation that caused his illness lived inside him: a three-letter fragment of DNA in a gene called HTTrepeated over and over dozens of times.

Carroll himself was not yet ill. He wouldn’t get sick for many years. But the countdown had begun. In fact, it had probably been operating all his life, deep within the vulnerable neurons of his brain. There, the mutant HTT the gene was growing slowly, its internal repetitions accumulate towards a threshold which, once crossed, would tip the cell into disarray.

The first outward signs of Huntington’s disease often begin with subtle mood changes and cognitive effects. The characteristic jerky movements come later. Eventually and relentlessly, patients lose the ability to speak, swallow or move. Most people die ten or twenty years after symptoms appear.

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

Carroll decided that the only rational response was to become one of the scientists searching for ways to defeat the disease. He was halfway through his undergraduate studies when he learned, in 2003, that he carried the mutation. He went on and earned a Ph.D. and completing postdoctoral training before starting his own research group dedicated to understanding and slowing the disease that stalks him from within.

Now a neurobiologist at the Allen Institute in Seattle, Carroll is part of a new initiative launched in June dedicated to fighting deadly neurodegenerative diseases. He leads the Huntington portion of this work, with a major focus on somatic expansion, the life-long growth of specific repetitive DNA sequences. In Huntington’s disease, this takes the form of CAG (encoding the nucleotides cytosine, adenine and guanine) in the HTT embarrassed.

Once considered a biological curiosity, somatic expansion is now seen as a key force determining when and how Huntington’s disease and other diseases progress. In the field, this change in mentality has opened a new therapeutic frontier. For Carroll, however, it was a real gut punch.

As Carroll understands only too well, the mutation he has inherited is not static. It continues to crawl longer, attacking new copies of CAG inside the very neurons it is designed to destroy. The genetic chain reaction has already produced subtle motor and cognitive symptoms that he undoubtedly sees as Huntington’s.

“It sucks when you think about it,” said Carroll, who turns 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, research into somatic expansion has revealed an unlikely glimmer of hope. DNA repeat expansion and neuron destruction do not appear to occur in parallel. Researchers now think there may be a long window, perhaps decades, during which repetitions accumulate while much of the brain remains structurally and functionally intact.

A new generation of therapies aims to bridge this gap between the molecular progression of the disease and its neurological consequences. The first drug candidates designed to target somatic expansion are expected to enter clinical trials later this year. If these drugs can slow or stop the process before too many neurons pass the point of no return, researchers hope they can preserve much of the vulnerable brain tissue that remains in people like Carroll.

“It’s a great intervention,” says Carroll. “There is good reason, based on the best science, to remain hopeful.”

Genetic bet

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

Unlike complex diseases shaped by dozens of DNA variants, Huntington’s disease follows an extremely simple rule: inherit one copy of the mutant. HTTwith his stuttering of CAG repetitions, and the disease will come.

Although the first signs of the disease usually appear between the ages of 30 and 50, exactly when the disease occurs depends largely on the number of CAG repeats a person starts with. Any number of repetitions greater than 40 virtually guarantees that the disease will develop. But the genetic hand exercised at birth also sets a rough timeline, with longer CAG pathways accelerating symptoms and shorter pathways achieving more years of healthy life.

The Regular Huntington Walk

People with Huntington’s disease go through distinct phases of somatic expansion (top), as CAG repeats accumulate. The disease severely affects specific neurons in the striatum (bottom), an area of ​​the brain that controls motor function and decision-making, among other crucial tasks. As CAG repeats accumulate, these neurons can experience a bout of depression, when many normally repressed genes begin to code for proteins, leading to neuron death.

Scientists identified HTT and its corresponding proteinhuntingtin, in 1993 — the culmination of a decade of hunting involving research teams from around the world. This discovery remains one of the most famous achievements in human genetics research, a moment that ultimately revealed the cause of Huntington’s disease. This immediately raised hopes that effective treatment would soon follow.

This is not the case.

It was difficult to criticize the premise. Normally, the huntingtin protein encoded by HTT performs vital work: guiding embryonic development, then helping neurons function in the adult brain. But the distorted version produced by the mutant gene accumulates inside neurons and poisons them. So, it was thought, remove the toxic protein and the disease should loosen its grip. Yet one drug candidate after another has failed in clinical trials.

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

Then came an unexpected resurgence of the huntingtin depletion strategy. Last year, a gene therapy from 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 reduce huntingtin production with a single infusion into the brain. Compared with matched controls from a database of untreated patients, gene therapy has finally shown that “you can make a difference” in the course of Huntington’s disease, says Sarah Tabrizi, a neurologist at University College London who served as lead scientific advisor for the trial.

But it was not only the clinical results that convinced Tabrizi of the reality of the effect. “It was the molecular evidence that convinced me,” she says. Scans of the spinal fluid showed that levels of a protein called neurofilament lumen, released by dying neurons, had been reduced – the opposite of what typically occurs as Huntington’s disease progresses.

The result was significant, but not without reservations. Therapy may have slowed the disease but not stopped it. To achieve this, it requires brain surgery lasting several hours that only neurosurgeons at certain medical centers can perform. And the evidence came from a small trial without a placebo control arm, a methodological limitation that led some experts to question the strength of the findings.

In June, the U.S. Food and Drug Administration acknowledged that the data could ultimately support a new drug application. Yet even this milestone reinforced growing suspicion that the field was aiming too far downstream. Reducing huntingtin could help, researchers say, but it might not fully address the deeper biology behind the disease.

This doesn’t mean abandoning the protein reduction strategy. Carroll sees this as a necessary piece of the puzzle. If UniQure therapy were approved today, he said, he would take it himself and “I would approve of my family doing it.”

For those wary of invasive brain surgery, others HTT-targeted therapies are also arriving. This year brought promising preliminary data on once-daily pills designed to limit production of the toxic huntingtin protein.

Yet the center of gravity of the field has continued to shift upward, toward the unstable mutation of DNA and the cellular machinery that keeps making things worse.

The repair has gone crazy

Almost as soon as the HTT When the gene was identified and genetic testing for Huntington’s disease became available, scientists noticed something wrong: Patients carrying a nearly identical number of CAG repeats could develop symptoms years, sometimes decades, apart.

A person may begin to decline rapidly in the qua age, while another may retain their faculties largely intact into their sixties. Same mutation, very different destinies. Clearly, something else was at work.

This phenomenon began to emerge about a decade ago, when an international consortium led by neurogeneticist Jim Gusella of Massachusetts General Hospital in Boston identified some of the first genes involved in determining when Huntington’s disease strikes.

Research kept pointing to the same point: genes involved in DNA repair, the process cells use to correct the small copying errors that accumulate during genome reading and maintenance. Subtle variations in these genes appeared to alter the age at which Huntington’s symptoms would begin, pushing the onset earlier or later than the hereditary repeat length would predict.

A new picture began to emerge. Although the mutant HTT If this gene could determine who would develop Huntington’s disease, the DNA repair mechanism seemed to help determine when the disease would take hold. “Everything fits together perfectly,” Gusella explains.

The DNA repair proteins encoded by these modifier genes normally patrol the genome looking for errors and damage. The Mutant HTT However, the gene turns this protective machinery against itself. Its repetitive DNA sequence can confuse the very proteins responsible for preserving genetic integrity, leading some people to make the sequence longer than they found it. The result is a progressive accumulation of CAG repeats.

But even as the repetitive DNA sequence is pushed longer and longer by the cell’s own repair mechanism, the brain seems remarkably capable of absorbing the damage. Only once the repeats cross a critical threshold does huntingtin become lethal, pushing neurons toward dysfunction and death.

Molecular biologist Nathaniel Heintz of Rockefeller University in New York and his colleagues first laid out this logic in 2024 in Natural genetics. This study showed the disease occurs in two stages: first the slow expansion of the repetition, then a dis tinted toxic phase once the repetition has increased sufficiently.

At the same time, neurogeneticist Steve McCarroll of Harvard Medical School and his colleagues were examining individual neurons taken from post-mortem human brains. Report in February 2025 in Cellthey measured the exact number of CAG repeats inside each cell. What they found matched almost perfectly what previous gene-hunting studies had suggested.

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

“It’s like going over a waterfall,” McCarroll says: calm for a long time, until suddenly the plunge is inevitable.

A new target emerges

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

Much of the drug discovery activity has converged on a gene called MSH3which encodes a key element 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 of MSH3 impacts how quickly the sequence develops and, by extension, how quickly Huntington’s symptoms progress, Tabrizi and colleagues reported in 2017 in Neurology Lancet. This discovery, as well as similar activity in patients with myotonic dystrophyanother rare disease caused by triplet DNA repeats, elevated MSH3 from a molecular curiosity to a first-rate therapeutic target.

Since then, several research teams have shown that the blocking MSH3 activity in mice can slow down – and in some cases almost stop – the uncontrollable repetitions inside neurons.

As evidence accumulated, so did industry interest, paving the way for the first wave of biotechnology companies based on the principle that Huntington’s disease could be kept at bay by preventing the mutant gene from becoming more dangerous over time.

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

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

Promise and peril

So far, no company has translated the promise of stopping somatic expansion into proven therapy, in part because the path to clinical testing has been anything but straightforward.

Triplet Therapeutics was among the first to try. The Cambridge, Massachusetts-based startup, founded in 2018, burst onto the biotech scene with tens of millions of dollars in venture funding, along with a who’s who of scientific advisors, including Gusella, Tabrizi, Carroll and other leaders in the field.

Triplet scientists quickly focused on a type of drug known as antisense therapy, which uses short strands of synthetic DNA or RNA to block the production of a target protein. They developed one of these drugs that was rejected MSH3 expression in the brains of mice and monkeys, paving the way 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 new capital to finance a clinical trial. And just as Antonijevic and his colleagues were preparing to talk about it, disappointing trial results for tominersen and another Huntington’s antisense drug shook confidence in the field. Investors suddenly became reluctant to bet more on Huntington’s research, particularly on another antisense drug candidate.

Triplet closed in 2022. The collapse was due to poor timing and a lack of flaw in the biological case for targeting. MSH3says Antonijevic, now chief medical officer of the startup Trace Neuroscience. “I have no doubt about the science,” she says.

Genetic evidence continues to link repair genes the speed at which the disease is spreading, the Gusella consortium reported last June in Natural genetics. And mouse studies validated the idea that silencing genes slows the uncontrolled growth of DNA and reduces the traces of disease on the brain, according to a study published in 2025 in Cell.

Now, Latus Bio of Philadelphia and Boston has secured millions of dollars in funding and is poised to become the first company to test this strategy in humans using a new type of gene therapy. Possible approaches to slowing repeated expansion vary. Among the companies targeting MSH3some like Latus Bio are developing biological drugs that must be injected directly into the brain or cerebrospinal fluid to reach their target. Others are looking for small-molecule pills in which the drug is so small that it can easily pass from the bloodstream to the brain, without the need for invasive procedures.

Other targets in the DNA repair pathway are also being studied, including proteins that genetic and molecular studies suggest should be enhanced, rather than blocked, to control repeat expansion.

Determined progress

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

The ideal, Howland suspects, might be to combine the two approaches in one fell swoop: first freezing genetic expansion to stop the disease at its source, then eliminating the toxic protein already damaging neurons.

But a combined attack on Huntington is likely years away. Drugs that achieve each half of the strategy generally need to be developed individually before the two can be brought together. In the meantime, researchers must choose where to place their bets.

“Five years ago, probably 95 percent of people would have said that lowering huntingtin was by far the priority goal,” says neurologist Ed Wild of University College London. Today, Wild says, that consensus has dissolved and experts struggle to say whether reducing huntingtin or modulating DNA repair should be the priority.

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

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

For the scientists closest to this work, success or failure will not be measured solely by trial data. It will be measured in people, and in 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, we probably should have stayed a few nights later at work.”

Carroll himself has a lucid vision. He still has research to do and a life to live. Despite his symptoms, he produced some of the strongest science of his career, his colleagues say. Last year, his laboratory reported that a type of treatment for huntingtin depletion may also curb the expansion of repeats, a finding that brings the field’s two main bets closer together.

He is also the father of 20-year-old twins – both conceived through IVF and with genetic screening to spare them the Huntington’s mutation – and he helps care for his siblings who also inherited them. “It’s very clear that Jeff’s reserves are far from empty,” Wild says.

But they are gradually running out. In Carroll’s brain, the mutant DNA continues to lengthen. The slow neurological countdown triggered by his genetic inheritance advances, even as science attempts to stop it. Despite it all, he continues to move forward – for himself, for his family, and for the tens of thousands of others living with the same diagnosis.

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