Every week neurologist Victor Sung sees people with Huntington’s disease, a rare and devastating neurodegenerative disorder, at his clinic at the University of Alabama at Birmingham. But last Wednesday was a day unlike any other.
“I cried with every single patient,” Sung says. “It just was this crazy feeling that, for the patients and families, almost can’t feel real.” That day the results of important phase 1/2 clinical trials had finally been released: an experimental gene therapy drug was the first treatment shown to slow the progression of Huntington’s disease.
The treatment, known as AMT-130, is delivered deep into the brain during an eight- to 10-hour surgery. The trials were small; the three-year follow-up results were based on just 24 participants who received the treatment. These results showed a 75 percent slower progression of disease among treated patients than that of external control participants who were not given the treatment, according to the new therapy’s developer uniQure, which posted the results ahead of their review by the Food and Drug Administration (FDA). The company hopes to receive accelerated approval from the FDA, which could allow the drug to be approved by the end of 2026 without the need for phase 3 trials, according to a uniQure spokesperson.
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Because the therapy is still in clinical trials, it is not yet approved or available for wider use. The patients that Sung saw last Wednesday hadn’t received it and likely won’t be able to anytime soon. But this early success has given the Huntington’s disease community measured hope after years of disappointments.
“We’ve had so many failures, and there’s been a lot of heartbreak over many years in this community,” Sung says. “So to have something that at least really appears to be having [an] impact is really significant.”
Other researchers also praised the development. “This is a community that has been waiting for so long for some kind of breakthrough,” says Rachel Harding, a toxicologist at the University of Toronto, who helps develop therapies that target the cause of Huntington’s disease and was not involved in the uniQure trials. “This news has really buoyed everyone’s expectations of what might be possible.”
A “Simple” Cause
When someone is diagnosed with Huntington’s disease, their treatment options are limited. Doctors can offer patients medications to treat their symptoms, such as reducing chorea (involuntary, unpredictable muscle movements) and depression. But until now, nothing could slow or halt the progression of the disease itself. People usually exhibit their first symptoms between the ages of 30 and 50 and can expect to live another 10 to 30 years after that. Because the gene that causes Huntington’s runs in families, people affected by the disease have often watched many loved ones struggle and die from it, too.
In some ways, Huntington’s disease seems like it should be the easiest neurodegenerative condition to treat. Unlike Parkinson’s and Alzheimer’s, scientists know exactly what causes Huntington’s: a mutation of the HTT gene in which a short, three-letter DNA sequence is repeated many times, causing it to produce a faulty version of the huntingtin protein. These faulty proteins accumulate in a deep brain structure called the striatum and cause symptoms such as uncontrollable movements, muscle spasms and cognitive decline that worsen over time.
Although the cause of Huntington’s is a simple genetic mutation, preventing that mutation from resulting in disease is a challenge. Researchers have traditionally focused on treatments that can lower the levels of abnormal huntingtin protein in the brain. For years, the most promising treatments were antisense oligonucleotides (ASOs), which are delivered by recurring injections into a patient’s cerebrospinal fluid. These drugs contain small pieces of genetic material that bind to and "silence" the messenger RNA molecules that carry instructions for building the mutant huntingtin protein.
But in 2021 clinical trials of three ASOs were abruptly halted. One phase 3 trial of a drug produced by Roche called tominersen was stopped because the condition of participants in the trial’s treatment group was no better than that of those that received a placebo. In some cases, it appeared to actually worsen symptoms—an outcome a neurologist called “the saddest possible result” for a drug that so many in the Huntington’s community had pegged their hopes on.
While this development was devastating at the time, Sung sees it as an inevitable part of the scientific process. “If a technology is completely brand-new, we still need to test it. And with each failure, we learn something,” he says. Developers of new therapies targeting genes often try to tackle Huntington’s disease first because of its straightforward genetic cause—meaning it’s the site of both failure and innovation. “Sometimes the first generation of the thing doesn’t work out, and we move to the next,” he says.
The New Treatment
Unlike ASOs, the new gene therapy drug AMT-130 is a one-time treatment, but it also involves lengthy and invasive brain surgery. Physicians insert catheters into deep parts of the brain where they can deliver the AMT-130 drug right to the neurons in the striatum that produce the abnormal huntingtin protein. The medication is transported through “shuttles” called adeno-associated viruses—noninfectious viral shells that can be packaged with genetic material. This genetic payload enters neurons, where it continuously produces tiny pieces of genetic code called microRNA. These microRNA specifically target and degrade messenger RNA carrying the instructions to build more huntingtin protein, therefore lowering the amount of huntingtin protein in the cell.
Three years after participants received the treatment, their disease had progressed 75 percent more slowly compared with that the of people in the control group. Disease progression was measured by the participants’ combined results on many tests measuring their motor and cognitive functioning. “75 percent disease-slowing—that’s better than we would have hoped for,” Sung says.
The treatment was tested in patients who were administered either a high dose or low dose of the drug. Their results were compared with the progression of the disease among a database of matched control participants that has been built through the hard work of the Huntington’s disease community, Harding explains. (Because of the invasive nature of the surgery, it was not considered ethical to give a placebo version of the drug, but three years is generally thought to be an implausibly long time for a placebo effect to persist, Sung says.)
Three of the participants who received high doses of AMT-130 experienced serious neurological side effects, such as swelling and severe headache. The trial was paused in August 2022, but was resumed after the participants recovered and the data were reviewed. Since then, no serious adverse events have been reported. Most adverse events were related to the initial surgery, uniQure said, and those all eventually resolved.
Who Will Get the Treatment?
Next, the FDA will review results from the phase 1/2 study, and uniQure plans to apply for accelerated approval, an expedited FDA-approval process for treatments that address serious conditions or meet an unmet medical need. If this is granted, the company expects that approval could come by the end of 2026, a spokesperson said. This would forego the need for a larger phase 3 study, though other trials may be done to confirm the treatment’s efficacy.
It is not clear at this stage how much the treatment would cost or how it would be paid for, although it will almost certainly be very expensive, experts say. This, in addition to the invasive nature of the treatment, means it likely won’t be available to most people around the world who have Huntington’s or carry the faulty HTT gene. Even if the drug wins FDA approval, “this is not a therapy that will be available for everyone” with this disease, says Harding, who is also an editor in chief of HDBuzz, a Huntington’s disease news site that tracks research developments for the community. But “what it does is give us hope that perhaps Huntington-lowering is a really viable therapeutic strategy.”
Other huntingtin-lowering therapies are currently in development, and some are in clinical trials. SKY-0515 from Skyhawk Therapeutics is currently in phase 2/3 clinical trials, and Novartis is planning to develop phase 3 trials of PTC-518, now called votoplam. Both are taken by pill. Roche’s tominersen is back in trials with a more restricted group of people who may benefit most from the therapy, and another ASO called WVE-003 from Wave Life Sciences may soon be entering phase 2/3 trials. Both drugs are delivered through a spinal tap.
Along with the AMT-130 results, this competitive field brings Harding hope. “I don’t think it’s that the others haven’t succeeded. It’s just they haven’t succeeded yet,”she says—and if they do, they could allow even more people to access treatment.
