The First Domino Falls: AMT-130 Gene Therapy Slows Huntington’s in Landmark Trial

UniQure has announced positive top-line results from its Phase I/II trial of AMT-130, a one-time gene therapy being tested in people with Huntington’s disease (HD). Topline data is a summary of the key results from a study that is released quickly after data becomes available to the company at a specified timepoint. In this update, uniQure reports that symptom progression is being significantly slowed by the drug, and the primary endpoint of the trial was met. This is the first time any drug has been shown to alter the course of HD in people in a clinical trial. HDBuzz caught up with uniQure’s Chief Medical Officer Walid Abi-Saab and CEO Matt Kapusta to get clarity for the HD community around this update. Let’s get into the details of this drug and the update uniQure have shared.

What is AMT-130 and how does it work?

HD is caused by a faulty copy of the huntingtin gene, which contains an expanded stretch of DNA “letters” that repeat C-A-G over and over. This expansion leads to the production of an expanded form of the huntingtin protein, which is thought to be harmful and gradually damage brain cells. 

The idea behind AMT-130 is to reduce the amount of huntingtin protein that cells produce. It belongs to a class of drugs known as huntingtin-lowering drugs, for which many trials are underway. Some of those approaches are delivered by pill (e.g., SKY-0515 and votoplam) or by spinal tap (e.g., WVE-003 and tominersen), but all need repeat dosing. 

AMT-130 is the very first gene therapy designed specifically for HD that has made it into human clinical trials. Instead of being taken as a pill or an injection, AMT-130 is delivered directly into the brain through a surgical procedure. uniQure believes that AMT-130 has the potential to be a treatment that lasts for life.

AMT-130 is packaged in a specially-designed harmless virus called AAV5. Think of this virus like a Trojan Horse – a shell used as a package to deliver something (good this time!) into the brain. This virus contains the blueprints to make a special genetic molecule that sticks to the instructions cells normally use to make the huntingtin protein. By binding to these instructions, AMT-130 essentially marks them for destruction. With fewer instructions around, cells make less huntingtin protein overall, including the harmful version linked to HD. The treatment lowers levels of both the expanded and regular huntingtin protein.

Brave steps towards a gene therapy for HD

The effects of gene therapies, like AMT-130, are irreversible and its delivery by brain surgery carries many risks. Because of this and following many studies in different animal models of HD, uniQure began testing AMT-130 in people with cautious, small-cohort trials and stringent safety monitoring. Early on, some serious adverse events in participants receiving the high dose led to a temporary pause, safety reviews, and adjustments. 

But by mid-2024, the picture had begun to look much more encouraging. In July 2024, uniQure released an update sharing data from trial participants who were 24 months post-surgery. In this interim update it appeared that disease progression was slowing, biomarker levels that track brain cell health, like neurofilament light (NfL), were headed in a favourable direction, and there were no major safety issues. Along with other positive trial updates around this time, this gave us the first indication that HTT lowering as an approach to treat HD, may be able to slow disease progression. 

Earlier this year, uniQure shared an encouraging update about their discussions with the U.S. Food and Drug Administration (FDA) on the development of AMT-130. They reported continued alignment with the agency and outlined next steps, including preparations for manufacturing, statistical planning for the data from the clinic, and defining the appropriate comparison control group.

AMT-130 is the very first gene therapy designed specifically for HD that has made it into human clinical trials.

These updates were an important boost of optimism for the HD community, but all eyes remained on the topline data which would provide the most definitive insights yet into AMT-130’s potential. That’s the update we got today – let’s get into it! 

AMT-130 can slow signs and symptoms of HD in people

Yep – you read that right. The key finding from this topline data is that AMT-130 appears to be slowing down the course of HD. But how do we know that is happening? The study focused on several measures widely used in HD research and care. All of the findings were compared to data from Enroll-HD, a natural history control sample, allowing scientists to judge whether treated participants were declining more slowly than expected if they weren’t taking the drug. Here’s what uniQure reported:

Composite Unified Huntington’s Disease Rating Scale (cUHDRS)

This is a “combined score” that brings together several measures of HD progression: movement, thinking skills, daily functioning, and independence. It’s considered a sensitive way to track how HD changes over time. In this study, people receiving the high dose of AMT-130 declined much more slowly than the matched control group with a 75% slowing of disease progression overall, as measured by cUHDRS. This means that the decline you would normally expect in one year would take four years after treatment with AMT-130. The change to cUHDRS was the primary endpoint of the trial, which was met. This is great news for forthcoming regulatory review.

Total Functional Capacity (TFC)

TFC is part of the cUHDRS and looks at how well a person can manage everyday activities like handling finances, working, or living independently. It’s especially relevant to families because it reflects real-world abilities. AMT-130 treatment significantly slowed decline of TFC by about 60%, and this was a key secondary endpoint, adding weight to the cUHDRS endpoint result.

Cognitive tests (thinking and processing speed)

One of the cognitive tests they used is called the Symbol Digit Modality Test (SDMT). This checks mental processing speed, which often declines early in HD. AMT-130 treatment suggested an 88% slowing of decline compared with controls (though the result just missed “statistical significance”).

The key finding from this topline data is that AMT-130 appears to be slowing down the course of HD.

Another test was the Stroop Word Reading Test (SWRT). This test measures attention span and language. People in the trial receiving the high dose of AMT-130 showed 113% slowing as per this metric in the uniQure analysis. 

Motor function (Total Motor Score, TMS)

TMS tracks movement symptoms such as chorea (involuntary movements), coordination, and eye movements. Folks on the high dose seemed to worsen more slowly than controls, with a 59% slowing, though this result was not statistically significant. This change could mean that AMT-130 may help across types of symptoms. 

Neurofilament light (NfL)

NfL is a protein released when brain cells are stressed or damaged. In HD, higher NfL levels usually mean faster disease progression. At 36 months, people treated with high-dose AMT-130 actually had lower NfL than when they started (about an 8% drop). This is encouraging because it suggests less ongoing damage in the brain, and it lines up with the clinical benefits seen on other measures.

Safety

Overall, AMT-130 appears to be generally well tolerated and safe. No new serious side effects linked to the drug have been seen since late 2022 when enrollment in the trial was temporarily paused. The most common side effects were related to the surgical procedure itself, and all of these issues have since resolved in the people affected.

Taken together, all these results point towards AMT-130 being beneficial for function, movement, thinking, and biomarkers in the high-dose group. The low-dose group showed more mixed findings, which the company interprets as evidence that dose strength is important.

Next steps for AMT-130

uniQure plans to meet with the FDA later this year to discuss the data and hopes to file a Biologics License Application (BLA) in early 2026. If these interactions and applications prove successful and everything moves forward smoothly, AMT-130 could be launched in the U.S. later on in 2026. uniQure also confirmed to HDBuzz that they are keen to engage with other regulators, including the EMA, who oversee drug approvals in Europe. 

“These data indicate that AMT-130 has the potential to meaningfully slow disease progression – offering long-awaited hope to individuals and families impacted by this devastating disease” – Prof. Sarah Tabrizi

In parallel, more participants are being treated in ongoing study cohorts, which will add more data to help scientists better understand the effects of AMT-130 in a broader cross-section of people. In particular, uniQure are now recruiting people with HD who would not have been eligible for their previous versions of the trial, because the part of their brain where the drug would be administered was too small. This will help the company understand if people at different stages of HD might benefit from receiving AMT-130. 

What does this mean for the HD community?

This is a monumental day for scientific research, for HD families, and for every person within the HD community. September 24, 2025 is the first time the world has learned that disease progression of Huntington’s can be modified with a drug. Undoubtedly, these findings have a weighted momentum, like the first domino falling in a chain, that will act as the tipping point for other breakthroughs in HD research.  

This is the very first time any drug for HD has shown statistically significant slowing of disease progression on clinical measures accepted and in alignment with the FDA. That makes the results very encouraging (and the HDBuzz editorial team reach for a tissue as we happy cry our way through writing this article). 

Despite this success, some caution is still warranted 

Even with all of this good news, it’s important to be cautious. Firstly, the number of people treated in this trial is still very small. All of the statistics reported in this update relate to data from less than 30 participants, only a portion of whom received the high dose of the drug that seems to show benefit. Further, many of the comparisons made to show how well this drug is working were against an external control group, not participants within the same trial. Although carefully matched, this kind of comparison is not as strong as a classic placebo-controlled study. 

There are also some pieces of the puzzle which are missing. This drug is designed to lower huntingtin levels, but there is no report in this update that the drug is working to do that – a feature of a drug known as target engagement. In part, this is perhaps because the current tools we have to measure huntingtin levels are quite noisy, which can make the results confusing. We also didn’t learn anything about how this drug might impact different regions of the brain structure from imaging analyses like MRI. 

Even if everything continues to look positive, making AMT-130 available to large numbers of people with HD will be a challenge. Delivering a one-time gene therapy is very different from prescribing pills or injections. It requires major planning, organisation, and scaling up. uniQure has disclosed they are already working on expanding their manufacturing capacity, and are planning to partner with specialist neurosurgery teams to perform the brain surgery required to deliver the treatment. And then there’s the issue of cost: like other gene therapies already on the market, the price is likely to be extremely high. These practical hurdles don’t lessen the excitement about AMT-130, but they remind us that turning promising trial results into real-world treatments is a long and complex journey.

Despite these caveats, the findings point to a potential disease-modifying effect, which is something the HD community has long hoped for. Prof. Sarah Tabrizi, Director of the University College London Huntington’s Disease Center said “These data indicate that AMT-130 has the potential to meaningfully slow disease progression – offering long-awaited hope to individuals and families impacted by this devastating disease”. We’ll take that for sure!

What about other huntingtin lowering therapies? 

This update is also excellent news for other companies developing huntingtin-lowering drugs. If AMT-130 can slow progression by reducing huntingtin protein levels, it strengthens the case that lowering this protein is a valid strategy to treat HD and that other approaches to do so may also succeed. Indeed, we have had positive updates from other companies in this direction earlier this year. 

That said, nearly all the drugs in development work in slightly different ways. AMT-130 is delivered directly into the striatum, the brain region most affected by HD, while other therapies reach the brain through spinal fluid or even through the bloodstream as pills taken by mouth. 

“We have written a new future together – now we must make it a reality for everyone who needs it” – Prof. Ed Wild

They also vary in how much lowering of huntingtin they achieve and and how widely throughout the brain and body they act. At this stage, we still don’t know what level of lowering is optimal, which brain regions must be targeted for the best effect, or who at which stage of HD will benefit most from each approach. 

These are questions the field will need to answer, but for now, the AMT-130 results provide a welcome boost of optimism across the entire huntingtin-lowering pipeline, showing that this approach has the potential to slow disease progression and modify the course of HD.

A step forward made possible by the commitment of the HD community

The AMT-130 results mark a major milestone: for the first time, any drug has shown signs it may slow Huntington’s disease progression in people.

This progress didn’t happen in isolation. It was made possible by the extraordinary commitment of the HD community. Families, advocacy groups, and research participants have all given their time, energy, and voices to push the field forward. People with HD and their loved ones have participated for years in natural history studies like Enroll-HD, building the world’s largest dataset tracking how HD progresses in the absence of treatment. That investment is now paying off in a profound way as the AMT-130 trial relied on Enroll-HD data as a critical comparator.

Beyond data, the willingness of individuals with HD to step into early clinical trials, including undergoing complex brain surgery for AMT-130, represents an extraordinary act of courage. Each participant, and their families, made a choice that carries personal risk but advances knowledge for the entire community. Coupled with tireless advocacy from HD organizations around the world, this collective commitment has kept gene therapy research moving, attracting investment, and ensuring regulators understand the urgency of bringing treatments to families.

Prof. Ed Wild, HDBuzz editor emeritus who was involved in the trial, sent us his thoughts on today’s news: “Today we get to move Huntington’s disease into the column headed “treatable”. We are here because of the astonishing bravery of the volunteers in this gene therapy trial – and everyone who ever signed up for a trial that disappointed but got us a little closer – and everyone who ever donated spinal fluid, or blood, or had an MRI scan for HD research, or took part in Enroll-HD or drove a loved one to a clinic visit or baked a batch of muffins for HD. You did this. We have written a new future together – now we must make it a reality for everyone who needs it.” 

More work is needed to confirm the findings, ensure safety, and understand long-term effects. But for now, this news offers genuine hope that gene therapy could change the future of HD treatment, hope made possible by the community’s determination to keep showing up, contributing, and believing in progress.

Summary

• AMT-130, delivered via brain surgery using an AAV5 viral vector, is designed to reduce production of huntingtin protein (both expanded and unexpanded forms), offering the potential for a one-time treatment.
• uniQure’s gene therapy AMT-130 met its primary endpoint in a Phase I/II trial, showing for the first time that a drug can significantly slow Huntington’s disease (HD) progression in people.
• High-dose participants showed substantial slowing of decline across multiple measures, including 75% slower progression on the composite HD scale (cUHDRS), ~60% slowing in the decline of daily function, and favorable biomarker changes (notably reduced neurofilament light).
• These results come from fewer than 30 participants and comparisons rely on external controls, so some caution is still warranted. uniQure will meet the FDA later in 2025, aiming to file for approval in early 2026, while scaling up manufacturing and surgical capacity.
• The findings bring unprecedented hope to the HD community, further support huntingtin-lowering as a therapeutic strategy, and boost prospects for other treatments in development, all made possible by the extraordinary commitment of trial participants and the broader HD community.

Learn more: 

uniQure press release – 24th Sept 2025