In a very brief press release from uniQure on November 3, 2025 we learned that the company is no longer aligned with the FDA on moving their drug AMT-130 forward. Just a few weeks ago, positive news from their ongoing clinical trials took the world by storm. Their goal was to use those data to apply for a Biologics Licensing Application (BLA) to market AMT-130 as a disease modifying drug for Huntington’s disease (HD). However, that goal was reliant on remaining aligned with the FDA. So, what do we know? What does this mean for AMT-130? And where do we go from here?
What We Know
A BLA, or Biologics Licensing Application, is the formal dossier of information that a company uses to request permission to market a biologic, which is a therapy created from living organisms, like proteins, cells, or genetic material. AMT-130 is considered a biologic because it uses (harmless) virus to deliver genetic material – the instructions needed to lower huntingtin protein levels in cells in the brain.
UniQure had planned to submit their BLA to the FDA in just a few months, in early 2026. And until now, they were aligned with the FDA for submitting this application, with the most recent update of alignment in June of 2025. So what happened in the last 5 months to change that decision?
The timeline for developing drugs is never certain. While this announcement may cause a sidestep in the advancement of an effective drug for Huntington’s disease, the data remain the same and continue to look promising.
Unfortunately, we only have a 30,000 foot view of the update from uniQure’s meeting with the FDA, as minutes from that meeting haven’t been released or given to uniQure yet. The press release we’ve received from the company states that, “uniQure believes that the FDA currently no longer agrees that data from the Phase I/II studies of AMT-130 in comparison to an external control, as per the prespecified protocols and statistical analysis plans shared with the FDA in advance of the analyses, may be adequate to provide the primary evidence in support of a BLA submission.”
So it seems the major issue the agency currently has with the data they’ve received is around the use of an external control comparator group. This is a major shift from the latest update we had from uniQure this summer, which followed similar messaging dating back to November 2024, when they first shared that they maintained alignment with the FDA on clinical endpoints needed for a successful BLA application.
Why Does The Control Group Matter?
Many clinical trials test a drug against a placebo group, which is a group of participants that are given a mock treatment, like a sugar pill or, in this case, a mock surgery. This type of placebo group is considered a rigorous way for researchers to test if the effects they may be seeing are due to the drug, or are psychosomatic effects that hope for an effective treatment could bring on. The mind is incredibly powerful! And sometimes just thinking you’re receiving a treatment can have positive biological effects.
Initially, the AMT-130 clinical trials were tested against a placebo group – a small group of people who were given a mock surgery. They were followed for the first 12 months of the study, and after that they were given the option of receiving the drug. However, because of the progressive nature of HD and because gene therapy studies are quite long, some of those people no longer fit within the inclusion criteria used for the trial.
The reason for the change of heart by the agency is not currently clear. However, it makes the timeline for advancing AMT-130 less clear, with additional uncertainty as the US government shutdown continues.
Because of that, moving forward the study was designed to compare people who received AMT-130 against an “external control group”, who were made up of people who participated in Enroll-HD.
While an external control group is a less rigorous way to test a drug, some people consider it a more ethical way to test gene therapy drugs that are in early clinical stages. While these natural history comparator groups can give us an idea if a drug is meeting certain metrics, particularly early on, they may not be robust enough to provide conclusive evidence that a gene therapy may be effective. And this seems to be the crux of what is driving the current misalignment with the FDA, despite their previous agreement in this approach.
What Does This Mean For AMT-130?
The decision by the FDA to not agree that an external control group can be used to apply for a BLA doesn’t change the data. It simply means that the FDA would want to see more data, possibly from a trial designed with a placebo control group, before moving forward with a BLA for AMT-130.
We know this will come as a massive disappointment for many in the HD community, particularly since this decision seems a bit confusing. While a Breakthrough Therapy designation and a Regenerative Medicines Advanced Therapy (RMAT) designation was given to AMT-130 based on the use of a external control comparator group, this no longer appears to be sufficient for the agency.
The reason for the change of heart by the agency is not currently clear. However, it makes the timeline for advancing AMT-130 less clear, with additional uncertainty as the US government shutdown continues.
Scientific progress is iterative and advances in increments, not giant leaps forward. Everything we learn, from every trial, helps advance us toward our goal of an effective, disease-modifying drug against Huntington’s disease.
AMT-130 Will Continue To Advance
Despite this disappointing news, this doesn’t mean that this is the end of the road for AMT-130 and it doesn’t change what the data show. The data still indicate that AMT-130 appears to be largely safe and well tolerated and against an external control group it seems to be having a meaningful effect on HD progression. That continues to be the strongest evidence we have thus far that modifying the disease course of HD might be possible. This is what Dr. Ed Wild calls a “save point” in the story of HD drug development – a point of progress that the community can return to, learn from, and build upon, even when we encounter unexpected challenges along the way.
However, this could change the timeline for when AMT-130 could be expected to be available for the HD community. Their recent announcement states that, “uniQure expects to receive final minutes within 30 days of the meeting and plans to urgently interact with the FDA to find a path forward for the timely accelerated approval of AMT-130”. So we expect that uniQure will continue to forge forward in advancing AMT-130 for the HD community in the US.
Additionally, uniQure shared that they’re also working with regulatory agencies in Europe and the UK. And an advancement in one market would be an advancement for HD globally. Not only for the HD community members who live in those countries, but also because approval in other countries could ease the path to approval in others.
This is what Dr. Ed Wild calls a “save point” in the story of HD drug development – a point of progress that the community can return to, learn from, and build upon, even when we encounter unexpected challenges along the way.
We Push Forward – Together
This news will feel like a failure to some, particularly those who may have been swept up in the grandeur of the recent headlines about a “cure” or “treatment” for HD being found. But science always progresses incrementally, not in massive leaps. Sometimes that incremental progression isn’t linear, which is what we’re seeing now with the misalignment between uniQure and the FDA.
What’s important is that nothing has fundamentally changed about what we know. The data around AMT-130 remain the same. It continues to be safe and well tolerated and the data suggest the drug could modify disease progression. Previous trial disappointments for the HD community involved safety or efficacy issues, which is not what is happening here. This disappointment comes from a misalignment between the drug maker and a single regulatory agency about what may be needed to progress the drug to the next step.
It’s currently unclear why the FDA no longer agrees that an external comparator group is sufficient after they determined that it was just 5 months ago. However, given the dedication of uniQure to advancing AMT-130, their stated plan to continue to interact with the FDA urgently, and ongoing work with regulatory agencies in Europe and the UK, this is merely a sidestep in the continued advancement of a disease modifying drug for HD.
Summary
UniQure Update: In a November 3, 2025 press release, uniQure announced it is no longer aligned with the FDA on how to advance its gene therapy AMT-130 for Huntington’s disease.
Key Issue: The FDA now disagrees with using an external control group (from Enroll-HD data) as the main comparison for efficacy in a Biologics Licensing Application (BLA).
Background: UniQure had been aligned with the FDA as recently as June 2025, with plans to file a BLA in early 2026. This shift changes that trajectory.
Why It Matters: External controls can be less rigorous than placebo groups, though some may consider them more ethical for invasive, one-time treatments like gene therapy. The FDA now appears to want more robust, controlled data.
Impact: The data themselves haven’t changed. AMT-130 still appears safe, well tolerated, and potentially disease-modifying, but the approval timeline is now uncertain.
Next Steps: UniQure will receive meeting minutes within 30 days and plans to “urgently” re-engage with the FDA to find a new approval path, while continuing work with regulators in Europe and the UK.
Big Picture: This is a regulatory misalignment, not a scientific setback. It reflects the slow, iterative nature of drug development. Progress continues, just on a different timetable.
This month brought new revelations across biomarkers, basic science and community gathering. In particular, we saw how DNA-repair targeting strategies are moving into focus, how gaps in diagnosis are being quantified, and how the annual Huntington’s Disease Clinical Research Congress 2025 deepened connections across the field. Together these developments reflect how far the HD research landscape has matured, and how many fresh paths remain to explore.
Therapeutic & Clinical Research Highlights
A Closer Look: One Month After the AMT-130 Headlines
Early results from the small Phase 1/2 trial suggest AMT-130 may slow HD progression by about 75% in high-dose participants, marking the first evidence that a therapy could alter the course of disease. But promising doesn’t mean proven. The trial’s small size, use of an Enroll-HD comparator instead of a full placebo control, and lack of peer review mean we must interpret these results with caution, and unanswered questions remain about durability, safety, and access.
By untangling the hype from the headlines, a crucial point is reinforced: progress in HD research is real and accelerating, but it happens through steady, careful steps, not sudden leaps. While the news is hopeful, caution is urged when reading headlines about a “cure” or “treatment” that are too good to be true.
October was an insight-rich month in Huntington’s disease research: additional clarity around uniQure’s AMT-130, mapping how and where HD changes the brain, early mechanistic studies targeting DNA repair, and a major meeting gathering the field.
Huntington Study Group (HSG) Clinical Research Congress 2025
The October meeting in Nashville offered a wide sweep of updates: new trial designs, biomarker deep dives, community-researcher interactions, and early-phase results that hint at shifting paradigms. And HDBuzz was there, front row, to cover it all. The gathering emphasised the value of sharing early data, aligning endpoints, and building collaborative momentum.
In a way, the congress acts as a greenhouse for ideas, nurturing the seedlings of innovation until they’re ready for field trials. The value here lies not just in the results presented, but in the relationships built and the priorities refined.
Biomarkers, Mechanisms & Population Research
Mechanistic Targeting of DNA Repair in CAG-Repeat Expansion
This work combines molecules in a tube to get a better idea of how the error-repair processes that cause CAG expansion go awry in HD, giving researchers something tangible to aim drugs at. Of course, many questions remain: What’s the safety profile? How soon could this translate to humans? And in what disease stage could there be the biggest impact?
This month brought new revelations across biomarkers, basic science and community gathering.
How Big Is the Huntington’s Disease Iceberg?
A recent mathematical modelling study asked: how many people carry the HD gene and remain undiagnosed? This work tries to define the “hidden” portion of the iceberg — people with the gene for HD who aren’t diagnosed — insight critical for understanding the full disease impact.
Knowing the size of the unseen population helps us calibrate the real reach of therapeutic development since it’s not just those already diagnosed who are affected by HD, but those yet to be found. It can also help our community leaders better campaign for resources and recognition from their respective governments and healthcare systems.
HDBuzz Prize-Winning Mechanistic Work
October also presented key early-career researcher contributions via the HDBuzz Prize, sponsored this year by the Huntington’s Disease Foundation (HDF):
One article from Gravity Guignard explored how lowering levels of unexpanded huntingtin protein, or the “good” versions, may complicate safe drug development. This work is a reminder that lowering levels of a target must be done with caution.
Another article from HDBuzz Prize winner Chloe Langridge highlighted the protein SGTA as a potential therapeutic target for HD, adding to the growing list of “support proteins” in the cell that may indirectly improve disease effects.
These mechanistic pieces reinforce that the field’s concept of “targeting huntingtin” is evolving into “impacting the molecular network around huntingtin.”
The themes that unified the month ranged from understanding mechanisms so we can translate research to the clinic to understanding just how many people are affected by Huntington’s disease.
Early Clues in the HD Brain: Mapping Changes from Birth
A recent study used specialized techniques that examine where and how cells in the brains of mice are impacted by HD. They found there are changes at the level of individual cells long before symptoms appear.
The researchers found that gene activity shifts seem to start at birth in HD mice, especially in the striatum and cortex, the brain regions most affected in the disease. Medium spiny neurons may have early over-activation of key identity genes that later decline, while cortical development genes seem to be reduced from the start.
These findings suggest a time-lapse view of HD progression, highlighting that molecular changes begin early but evolve gradually, shaping which cells become most vulnerable.
Themes That Unified the Month
Mechanism first, translation next — There is a clear focus on understanding how HD works (DNA repair, protein networks). These insights will be critical as treatments that target the functioning of the huntingtin protein translate to the clinic.
Quantifying the unknown — Whether it’s undiagnosed carriers or untested protein networks, October emphasised measuring the hidden parts of the HD landscape.
Community and collaboration matter — Big meetings, transparency around complex mechanistic work, and the advancement of research projects with the help of the HD community reinforce that progress happens not in isolation, but through collective effort.
Cautious optimism with rigour — While the pace of HD research appears to be accelerating, researchers are dedicated to relaying an accurate message to the community and the field is appropriately mindful of safety signals, false leads, and the need for robust data.
Your support helps ensure families everywhere stay informed and empowered as science moves us all forward to an HD-free future. Thank you!
Falling Into Hope
Independent reporting by HDBuzz remains vital, particularly as we advance toward disease modifying drugs. The month of October continued our 8-week giving campaign, “Falling Into Hope”.
With the generosity from the community, we were able to surpass our original fundraising goal of $30,000! Your support helps ensure families everywhere stay informed and empowered as science moves us all forward to an HD-free future. Thank you!
Summary
New small-molecule work targets DNA‐repair machinery, which is promising but early.
The Huntington Study Group (HSG) HD Clinical Research Congress 2025 fostered big-picture alignment and data sharing.
A new study in mouse models reveals how Huntington’s disease (HD) disrupts brain development over time, even long before symptoms appear. Using advanced sequencing tools and spatial transcriptomics, a technique that maps where in the brain genes are activated, researchers discovered early warning signs that could help explain why some brain cells are more vulnerable than others in HD.
Why this matters
We know that HD is caused by a repetition of genetic letters that spell C-A-G in the huntingtin gene. People who won’t develop HD have 35 or fewer CAGs, whereas people who go on to develop HD have 36 or more.
And while every cell carries this genetic spelling mistake, certain brain cells are hit much harder, causing them to die early. What we still don’t fully understand is why those cells are more vulnerable, or what might be happening silently in the brain long before symptoms appear to make them more vulnerable.
In a new study, led by Dr. Leslie Thompson and Dr. Mara Burns at the University of California Irvine, the team dove into that mystery. They used a powerful combination of techniques called “spatial transcriptomics” and “single-cell sequencing”.
Spatial transcriptomics sounds fancy (and it is!), but its name gives us clues into what it does. It spatially maps transcripts, or the short genetic messages created from DNA before they turn into protein, on a brain sample. So it can be used to show where genetic messages are on an image of the brain. The researchers used this technique to map changes across the lifetime of mice that model HD.
Single-cell sequencing looks at the genetic messages within a sample in each individual cell. Both of these techniques give a wealth of data and help create a detailed map of what’s going on inside the brain because of HD.
Interestingly, they found some surprises! Their work suggests that changes in gene activity start from birth and evolve in a cell-type- and region-specific way, particularly affecting the striatum (central brain region that controls movement, motivation, and emotion) and cortex (outer wrinkly bit that controls things like perception, movement, and planning). These two brain regions are heavily impacted by HD. Knowing more about when and how changes happen in these brain regions can help us understand the mystery of selective vulnerability in HD.
Researchers tracked changes caused by Huntington’s disease in the brains of mice across their lifespan: from newborn pups to adult mice.
The HD Brain’s Vulnerable Zones: Striatum and Cortex
We know that HD doesn’t affect all brain cells equally. Some types of cells, like glia cells which work to support neurons, aren’t vulnerable to death in the same way that neurons are.
But even neurons themselves are selectively vulnerable. Some types are particularly vulnerable to death, while others remain surprisingly resilient, even in late stages. Among the most affected are medium spiny neurons (MSNs), which make up the bulk of the striatum — a brain region central to coordinating movement, motivation, and learning.
MSNs are critical “relay stations” in the brain’s circuitry, passing along dopamine signals and fine-tuning motor control. In HD, these neurons are among the first to show altered function and eventually die. The new study shows that even in newborn HD mice, MSNs begin to show abnormal gene activation, including increased levels of identity genes like Drd1 and Tac1, which later decline. This suggests the cells might be “overcompensating” early on before crashing.
Meanwhile, in the cortex, another brain region that governs higher thinking and decision-making, the researchers found reduced expression ofTcf4, a key genetic hub important for neuron development. These cortical changes start early and persist through disease progression, hinting that HD may also subtly disrupt how the cortex matures.
Using advanced sequencing tools and spatial transcriptomics, a technique that maps where in the brain genes are activated, researchers discovered early warning signs that could help explain why some brain cells are more vulnerable than others in HD.
A New Era of Brain Mapping
Until recently, if we wanted to know which genes were activated differently by HD, most studies relied on a method called “bulk RNA sequencing”. This technique is powerful, but it has a big drawback: to measure which genes are switched on, scientists first have to grind up brain tissue. That means the genetic messages from all cell types in the sample — vulnerable and resilient neurons, glia, and even cells from blood vessels — gets mixed together.
Bulk RNA-seq is a bit like taking all the conversations in a city, recording them at once, and mixing them into a single audio track. You’ll hear the overall noise, but you can’t tell whether it came from a teacher in a classroom, a busker on the street, or a child in a playground. To get around this, the researchers in this study used two novel approaches:
Spatial transcriptomics: This method is a big step forward because it measures gene activity while keeping the tissue slices intact. It’s like taking a bird’s-eye photo of the brain with colored spots showing which neighborhoods are “loud” or “quiet” in their genetic activity. The resolution doesn’t capture signals from each individual cell, but can from groups of dozens of cells. Critically, it preserves the “where” information that bulk methods erase.
Single-nucleus RNA sequencing (aka, snRNA-seq): Here, scientists zoom in much closer. Instead of working with whole brain slices, they isolate individual cells and read out their genetic activity one by one. This reveals who is speaking in the city of the brain — neurons, astrocytes, microglia, or oligodendrocytes — and what each type of cell is saying. But the downside is that this method loses the spatial context: you know who is talking, but not where they are in the city.
By combining these two methods on a timeline of the HD mouse lifetime, the team got the best of both worlds: the “where” from spatial transcriptomics, and the “who” from single-cell sequencing. This allowed them to build a spatial map across time of how HD unfolds. With it, they linked gene changes to specific cell types and brain regions across three stages: birth, early symptoms, and late disease. This approach offers more nuance than previous techniques and opens new possibilities for understanding complex diseases, like HD.
Advanced analysis techniques used in the study let researchers narrow in on where and when Huntington’s disease alters the brain, like pinpointing people in a city having a specific conversation.
Key findings
Reorganization from the very start: Even at birth, HD mice already show altered gene activity. In the striatum, mitochondrial genes (those controlling energy production) were disrupted. In the cortex, a gene called Tcf4, crucial for brain development, was reduced. This may affect how cortical neurons organize and connect.
Changes over time: MSNs showed early increases in identity genes that help define this specific type of neuron. Over time, this trend seems to change, and identity gene levels decrease. The researchers identified other changes that could contribute to MSN impairment, like mitochondrial deficits, seeming to originate in the striatum prior to overt symptom onset and spreading to other brain regions.
Communication breakdown: By examining cell-cell signaling pathways, the team found time-dependent changes in neuropeptide Y (NPY) signaling, which may be involved in balancing energy use and neuron health.
Looking Ahead: New Paths for Understanding and Intervention
This study doesn’t just provide a snapshot of the HD brain, it offers a time-lapse map of how things changes as HD advances. By combining spatial and single-cell data, it shows Huntington’s early influence, perhaps beginning as early as birth and building slowly over time.
It’s important to note though, that even changes identified at birth don’t mean the brain can’t compensate. Clearly it can! People with the gene for HD generally live entirely healthy lives for decades. What it could mean is that these early, subtle changes may be setting these cells up for sensitivity later on that makes them more vulnerable to death. So while they can stave off molecular insults across those decades, over time it becomes too much.
This study doesn’t just provide a snapshot of the HD brain, it offers a time-lapse map of how things changes as HD advances.
These insights offer several takeaways for the HD community:
Therapeutic timing: If early gene changes contribute to vulnerability, treatments aimed at stabilizing brain development could be valuable, even before symptoms appear.
Targeted strategies: Understanding which cells change first, and how, could help develop more precise therapies. Some changes may begin early but are balanced by the brain’s own mechanisms for compensation. Studying these natural defenses could reveal new ways to fight back from the start.
Biomarker development: Patterns like mitochondrial stress or Tcf4 downregulation may one day help identify disease onset more accurately.
Most importantly, this work highlights the growing importance of big-data brain mapping tools, helping researchers move beyond bulk averages to truly understand what’s happening in individual cells, in real tissue, across time. While this study was done in a mouse model, it lays crucial groundwork for understanding the earliest molecular ripples of HD in the human brain, and how we might one day intervene before the map changes.
Summary
Advanced mapping tools: Combining spatial transcriptomics and single-cell sequencing reveals both where and which cells are altered in HD.
Early beginnings: Gene activity changes start from birth in HD mice, particularly in the striatum and cortex, the brain’s most affected regions.
Dynamic shifts over time: Neurons in vulnerable regions show early over-activation of identity genes that later decline as disease progresses.
Energy and communication faults: Mitochondrial and neuropeptide signalling pathways are disrupted, affecting neuron health.
A blueprint for early intervention: These findings highlight that subtle, early-life changes may shape later vulnerability, guiding future prevention and therapy strategies.
The past 4 weeks have been a whirlwind in the Huntington’s disease (HD) community. On September 25th we had an update from uniQure about a drug they’re testing for HD in ongoing clinical trials. The news was positive and it took the world by storm, producing jaw dropping headlines from news sources around the world, generating global interest in HD, and prompting many people within the HD community to reach out to neurologists and care centers around the world with various questions.
Now that the dust has settled, we can take a step back to break down what we know, where the uncertainties lie, and address and answer some of the questions we’ve heard from the HD community. Given past disappointments, it’s natural for the HD community to approach new developments carefully. We share this caution, as well as optimism, and want to frame the buzz that the recent news has generated through a realistic lens.
While the recent update from uniQure about AMT-130 is indeed exciting, we want to be cautious about how we interpret their findings. The results don’t yet suggest that we have a treatment for Huntington’s disease, even though they are encouraging.
uniQure’s Announcement
Just a few weeks ago, uniQure announced positive topline results from their Phase 1/2 trial of AMT-130, a gene therapy being tested in people with HD. The therapy, delivered directly into the brain through a ~10 hour surgery, is designed to permanently lower production of the HTT protein that causes HD.
According to uniQure’s update, trial participants receiving the high dose of AMT-130 who have been followed for 3 years have experienced a 75% slowing in overall disease progression as measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS). The cUHDRS is a collection of tests that assess how well people with HD are functioning day-to-day through memory, movement, and mood tests. The improvement on the cUHDRS scale meant that the trial met its primary endpoint.
This positive news represents a milestone, showing for the first time that a drug can alter the course of HD in people. uniQure shared that their next steps are to meet with the U.S. drug regulator, the FDA, later this year, aiming to file for accelerated approval in early 2026.
However, we’re not across the finish line yet and don’t yet have a bona fide HD treatment in hand. This is a Phase 1/2 trial, so it’s only being tested in a small group of people. Even with these critical caveats that should elicit some caution, many media outlets headlined the exciting part of the news without doing much to temper excitement.
Given past disappointments, it’s natural for the HD community to approach new developments carefully. We share this caution, as well as optimism, and want to frame the buzz that the recent news has generated through a realistic lens.
Overhyped & Misleading Media Coverage
Unfortunately, many news outlets are driven by attention. They want your eyes on their website. So the more clicks they get the better. And big, over-the-top headlines generate a lot of clicks. Thus, when fantastic research news about a devastating brain disorder, like HD, comes out for the first time, the splashier headlines are a common tactic for some news outlets. But this can be detrimental to the very populations that the news is intended to serve. Let’s get into some of the flagrant headlines that made our eyes pop and jaws drop.
HD “Successfully Treated”?
Some of the more egregious headlines claimed that HD was “successfully treated” for the first time, even pairing this news with pictures of world-renowned, incredibly reputable HD researchers. Because of that, it’s understandable that anyone with HD, from an HD family, or who even knows anyone affiliated with HD would immediately get on the phone to call or text about the next steps.
First and foremost – was HD successfully treated for the first time? The jury is still out on this one; the data are promising, but not conclusive. The recent news from uniQure does not yet show that we have a successful treatment for HD. It shows in a small number of people being given AMT-130 that metrics measuring signs and symptoms of HD are moving in a favorable direction that suggests the drug may be able to slow disease progression.
Is this good news? Undoubtedly. Is it conclusive? By no means. AMT-130 is currently being tested in a Phase 1/2 trial. Even if this trial is wildly successful and surpasses every expectation, we will still need more data to conclusively say that it is a successful drug in treating HD.
uniQure has always been transparent about the fact that even if this trial is successful, the next steps could include accelerated regulatory approval, which is different from a fully approved drug on the traditional path. Drugs that receive accelerated approval can be marketed with the understanding that more data will be collected in larger trials with more trial participants to ensure that the drug can do what everyone hopes it will do. If it doesn’t, the accelerated approval label will be revoked, the drug will be pulled from market, and it will no longer be sold. Fully approved drugs have been tested in a sufficient number of people to conclusively show that they work as intended, and they likely won’t be pulled from market for efficacy reasons.
Particularly as we near disease-modifying drugs for Huntington’s disease, popular press articles about research findings must be read and interpreted carefully.
A “Breakthrough Cure”?
Other conclusive-sounding headlines suggested that the world had found a “breakthrough cure” for HD. Similar to headlines claiming we’ve “successfully treated” HD, the data do not yet support the conclusion that we have a cure for HD.
A cure implies that someone who once had HD no longer has the disease, which suggests that there has been a reversal of symptoms or elimination of all signs of HD. The data from uniQure do not suggest that HD has been cured or that HD signs and symptoms are being reversed. The data suggest that progression of HD is being slowed. While this is still fantastic news, it’s an incredibly critical difference.
Some Weren’t So Bad
Not every news source put out a headline that exaggerated the results. Some of the more level-headed articles underscored that the results “show promise”, were “a cause for hope”, were “preliminary but promising”, and “slowed progression”.
Science is rarely cut and dry, especially when it’s in earlier stages like a Phase 1/2 trial, so headlines that are more cautious and avoid conclusive sounding language are usually more in line with a level interpretation of the findings.
Navigating Headlines
A sure fire way to spot articles that you should view with some skepticism are those with huge claims, like a successful treatment or cure for HD. At HDBuzz, we recently updated an article with 10 golden rules you can use to navigate HD research news. With all the news swirling about, if you haven’t checked this article out, now would be a fantastic time to give it a glance so that you’re brushed up on your HD media literacy.
Some of the more level-headed articles underscored that the results “show promise”, were “a cause for hope”, were “preliminary but promising”, and “slowed progression”.
The Key Caveats
We mentioned that there are some key caveats that should elicit caution around these results. So, what are they?
Small number of participants
As stated above, this is an early, small trial. Phase 1/2 trials by design are intended to be small because we don’t want to test unproven drugs in large numbers of people without more evidence that they may be successful. Trials are designed to include increasing numbers of participants as evidence mounts that the drug is likely to work.
Because of that, this ongoing trial has just 29 participants – 12 in the low dose group, and 17 in the high dose group. Of those 17 receiving the high dose, 12 have made it to the 3 year mark, so the exciting data currently being scrutinized is from just those 12 people. This isn’t a very big group.
Trials with larger numbers of people evoke more confidence because it’s less likely that a larger group of people would all have some sort of biological anomaly chosen by chance. For example, it could be possible that 12 randomly selected people may all have some factor (biological, pharmalogical, or otherwise) that may make them perform better on a certain drug, but this chance decreases if you have 100 people, for example. Inclusion and exclusion criteria try to account for some of this, but smaller sample sizes still have this probabilistic risk.
The comparator group
Very robust clinical trials are compared against a placebo group – a group of people that are similar to the participants being given the drug that are instead given a sugar pill, or a mock surgery, as it would be in this case. While the first 12 months of this study were tested against such a group, after that initial year, those people were given the option of receiving the drug. Unfortunately because this study, and any gene therapy study, is long term, some of those people were no longer eligible for the drug based on the inclusion and exclusion criteria for the trial.
Thus, moving forward the trial was controlled against data from Enroll-HD, which is an observational study that follows people with HD as they naturally live and age. For this reason, the comparator group in this trial is much larger, following over 1500 people, 940 of whom are being compared against the high dose group.
This is a less rigorous way to test a drug for several reasons. Firstly, there’s no easy way to determine that “the placebo effect” isn’t improving their symptoms. The mind is incredibly powerful over the body! Ample research shows us that the suggestive powers of just thinking you’re taking something that might help you get better and can actually reduce symptoms. Secondly, people who are frequently seen and looked after by doctors, nurses, social workers, and therapists, like participants of a clinical trial, often have improved symptoms, regardless of what drugs they are receiving. The people in this trial could be going to the clinic more frequently than those in the Enroll-HD comparator group, causing a medical response bias that improves their symptoms.
However, while comparator groups are a less rigorous way to test a drug, they’re often considered a more ethical way to test a gene therapy drug in early stages. As drugs advance through the regulatory process and reach later clinical phases, double-blinded, placebo-controlled trials could be required. So for a Phase 1/2 trial like this one for AMT-130, a natural history comparator can give us an idea if a drug is meeting certain metrics, but isn’t robust enough to conclusively tell us if a gene therapy is effective.
Some media outlets reporting on the recent AMT-130 news made it seem like we had a treatment or cure for Huntington’s disease, but we haven’t crossed the finish line yet. The results are hopeful, but not conclusive.
Other considerations
There are also a variety of other considerations that researchers are pondering, but don’t yet have the data to support or produce conclusive results around.
Are there people who will respond well to this treatment while others won’t? Given the small number of people in this trial, it’s possible they could be “super responders” – people who respond particularly well to a specific treatment. If so, what might be the delineating factors that define these subgroups? Is it developmental brain stage, disease stage, age, etc? We’ve not seen data from individuals treated with AMT-130 yet, only the group averaged together. Once we have this data, we could get some clarity around these questions.
Even with the permanence of this treatment, how durable will it be? Will it wear off over time? Might additional treatments be needed in the future? If so, how far out and at what dose? This is complicated because we don’t have satisfactory tools or surrogates to accurately measure HTT lowering, particularly in brain tissue.
We’ve not yet seen all the data collected from this trial and it’s not yet been peer-reviewed or published. How will these data measure up when examined by other researchers?
With any gene therapy, accessibility will be an issue. Would this treatment be covered by insurance companies? If not, how will HD families afford such treatments that can run into the millions of dollars?
In all, there are still many outstanding questions to consider for which we just don’t yet have answers.
Treatment-associated risks
Even if all the other considerations prove favorable, there are still two large potential treatment-associated risks that should be considered around AMT-130. This is a permanent gene therapy that is delivered via brain surgery.
Firstly, while there are very skilled brain surgeons carrying out these surgeries, brain surgery is never without risk. This is a highly invasive procedure. We understand that the risks around brain surgery are something that many in the HD community are willing to tolerate for a potential treatment against this disease, however it still must be stated that brain surgery always comes with a risk.
Secondly, this is a permanent treatment. Once AMT-130 is delivered to the brain, there is no going back, good or bad. While a one time treatment could be viewed as desirable by many within the HD community, this type of non-reversible change for an unproven treatment also carries risks that must be acknowledged.
It is for these reasons that gene therapy trials, like uniQure’s AMT-130, are rolled out slowly and carefully in a very small number of people in a staggered way. Initially, the surgery was given to only 1 person, who was followed for several months before a second person was inducted into the trial. This specific trial design was devised to mitigate safety risks around brain surgery and permanence of this treatment approach.
So far, the data suggests there is a slowing of disease in people on the high dose of AMT-130, but the disease in those people is still progressing.
Reaction From The Community
With the exciting results from this trial and the abundance of hyped up headlines, the HD community has understandably had a lot of questions. We’d like to address some of the more frequently asked questions we’ve heard.
Does this mean there’s finally a cure for HD?
No. But this is an important step forward.
A “cure” implies that someone who had signs and symptoms of HD no longer does. That would require reversal of disease worsening, which is not what we’ve seen. So far, the data suggests there is a slowing of disease in people on the high dose of AMT-130, but the disease in those people is still progressing.
So, has HD been successfully treated for the first time?
We don’t know yet. But this is some of the most encouraging data we’ve seen from a clinical trial thus far. While we need data from a larger group of people to have conclusive evidence that a drug has treated HD, the recent data from uniQure is the first to show that any drug is slowing disease progression, which is incredibly encouraging.
Where can I get access to AMT-130?
AMT-130 is not yet an approved treatment, so it’s not readily available at trial sites for the general public, hospitals, or doctors offices.
AMT-130 is still being actively tested in clinical trials. If you are interested in participating in a trial for AMT-130, you can check if the trial is enrolling at a site near you using HDSA’s HD Trial Finder and speak to your neurologist and medical care team.
If the data continue to look promising and the FDA grants accelerated approval, AMT-130 could potentially be approved by the end of 2026. However it would still take time to roll this out to the general public. Additionally, if more data are required prior to approval, this timeline could be extended.
Each step we’ve taken in understanding Huntington’s disease – from the first description of the disease, to the discovery of the genetic cause, to the recent news of potential disease slowing – gets us closer to the top of the mountain, where we’ll have a clear view of what we need to do to treat HD.
How much will AMT-130 cost?
uniQure has not yet released the price point for AMT-130, but has stated that it will be in line with other gene therapies. Given the nature of gene therapies, they are incredibly expensive, ranging from about $2 to $4.25 million dollars for the drug alone. Depending on your country’s healthcare system, there could also be additional medical care costs to consider associated with hospital stays, anaesthesia, and brain surgery.
It is not yet clear what costs may be covered by different national healthcare providers, insurance companies, or other health programs around the world. However, uniQure has stated that they plan to discuss the value of the drug with the different agencies who may cover costs, which could improve access if AMT-130 is approved by regulators.
Who will be eligible to receive AMT-130 if approved?
Currently, AMT-130 is being tested in people with fairly early symptoms of HD. If the drug is approved by regulatory agencies, people who have a similar disease stage to those tested in the trial would likely be eligible initially. The goal for any drug that could successfully treat one subset of people with HD would be to broaden who may successfully be eligible, so uniQure is very likely to do subsequent studies to test the limits on who AMT-130 may successfully treat – moving both earlier and later in disease stage.
What if I’m not eligible for AMT-130?
While we understand that not being eligible for AMT-130 could elicit strong emotions for many, there are many other treatments being developed and tested right now in a whole suite of clinical trials. The goal of every researcher working on HD is to bring a treatment for this disease forward to help as many people as possible.
If I’m at risk, should I get tested for HD?
Getting tested for HD is a deeply personal decision. If the recent news from uniQure has made you wonder if you should get tested, we encourage you to reach out to a genetic counsellor who can help you weigh your options, as there are emotional, legal, and financial implications to consider.
If you are based in the US, there are also considerations around eligibility for various types of insurance, including life, disability, and long-term care.
If you are considering getting tested, you can reach out to HD Genetics, a company specializing in genetic testing for individuals at risk for Huntington’s disease, to learn more.
What can I do right now?
If the recent news from uniQure has compelled you to get involved in HD research, a great starting point can be to participate in Enroll-HD. It’s the largest observational trial (meaning no drug is given) that follows people with and without HD to collect data as they naturally live and age.
Researchers from around the globe use the Enroll-HD database to ask and answer various questions that are consistently teaching us more about HD. Your involvement in Enroll, and any trial, helps researchers understand HD better to improve clinical trial design and advance us toward disease modifying treatments more quickly.
Getting tested for HD is a deeply personal decision. If the recent news from uniQure has made you wonder if you should get tested, we encourage you to reach out to a genetic counsellor who can help you weigh your options, as there are emotional, legal, and financial implications to consider.
Science Advances In Steps, Not Leaps
We know that science is incremental and often moves more slowly than anyone hopes. But it does advance. And we’ve met many milestones that have gotten us to this point. One of those is undoubtedly the September data update from uniQure about AMT-130.
However, while we celebrate this progress, let’s do so under a realistic lens – we don’t have a treatment in hand, yet. We have to continue reading popular press articles with a critical eye, being wary of headlines that promise we’ve crossed the finish line. Getting updates about HD research from reputable sources is more important now than ever before as we near disease modifying drugs. Communicating clearly to the HD community about what results show, what it means, and what we still need to learn is critical as we move forward.
With that in mind though, please remember that HD research is moving faster than ever. Each step we’ve taken – from the description of the disease in 1872, to the discovery of the gene in 1993, to now having evidence of what we need to do to slow HD in 2025 – is taking us to the top of the mountain. It hasn’t been great leaps that have gotten us here, but rather steady progress toward a goal and a commitment from the entire HD community. With that momentum behind us, we’re nearing the final stretch. It will still take time, teamwork, and persistence, but the path is clearer than it’s ever been, and every step forward brings us one step closer to treatments that change lives.
Summary
uniQure announced encouraging results from its Phase 1/2 trial of AMT-130, a gene therapy designed to lower huntingtin in people with HD.
High-dose participants followed for 3 years showed a ~75% slowing in disease progression on the cUHDRS, meeting the trial’s primary endpoint.
This marks the first time any therapy has shown the potential to alter HD progression in people, a historic milestone for the field.
However, the study is small (29 participants, 12 in the 3-year high-dose group), and results have not yet been peer-reviewed or published.
Some media headlines overstated the findings, with claims of a “cure” or “successful treatment.” The data show slowing of symptoms, not reversal or elimination of disease.
The trial used a comparator group from Enroll-HD instead of a full placebo control after year one, so results should be interpreted cautiously.
AMT-130 delivery requires brain surgery and involves permanent changes, which carry inherent risks.
Key questions remain: durability of benefit, variability of response, affordability, and future accessibility.
uniQure plans to seek accelerated FDA approval in 2026, but this would still require confirmatory studies and regulatory review.
AMT-130 is not yet approved or available outside clinical trials. Interested participants should discuss enrollment options with their neurologist or consult the HDSA trial finder.
Progress is real but incremental. This isn’t a leap forward to a cure, but a meaningful step forward on the long road to disease-modifying treatments.
Huntington’s disease (HD) is caused by repeating C-A-G letters of genetic code that are too long. Everyone who develops HD is born with 36 or more CAG repeats, but not everyone with 36 or more CAG repeats is actually diagnosed with HD. That’s because either they are not old enough yet to have symptoms, or because they have symptoms but have not been given a correct diagnosis by a doctor. Because of this, mathematical models of how many people have HD don’t match up with how many people have been predictively tested or diagnosed in the clinic. Researchers have attempted a new way of calculating how many people have HD but are not diagnosed.
Three repeating letters – and 36 or more cause HD
The repeating C-A-G letters in the huntingtin gene that cause HD are like three letters repeated on a specific page of a book. People who develop HD are born with 36 or more CAG repeats, one after the other, like this: …CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG … (That’s 40 CAGs by the way.)
The genetic cause of HD means that everyone who develops the disease has an identical and easily identified region in their genetic code that can be used for diagnostic or predictive testing. When a doctor suspects someone has HD, based on their symptoms, they will order a test that counts the number of CAG repeats a person has. If that test comes back with 36 or more CAG repeats in the huntingtin gene, then that person is formally diagnosed with HD. Counting up all these people with formal diagnosis of HD is how we measure the prevalence of HD.
However, not everyone who has 36 or more repeats is diagnosed with HD. For one thing, someone might decide to get the test predictively, because they may have inherited 36 or more repeats, but are not old enough yet to have symptoms of HD. Someone like this who receives a test result with 36 or more CAG repeats, but does not yet have symptoms of HD, is usually called gene-positive. They are not counted in prevalence, because they don’t yet have symptoms of HD.
But there are also people who have 36 or more CAG repeats and symptoms of HD who have not been tested. This could be because they don’t have adequate access to health care, because of the negative social stigma of HD, or because of insurance concerns. Or, perhaps they’ve never even suspected they may have HD. This could be because they either don’t know about their family history of HD or they are the first person in their family to develop the disease. This begs the question, how many people with 36 or more CAG repeats have symptoms of HD but don’t get counted in the prevalencedata for HD?
Scientists think more people may have symptoms of Huntington’s disease than are tested by a doctor. But detailed math is needed to estimate exactly how many people this might be.
Finding everyone with 36 or more CAG repeats – how big is the iceberg?
Figuring out how many people have 36 or more CAG repeats, but never show up to a doctor, is a bit like an iceberg. There’s a visible part above water and an unknown part hidden out of view. The visible part of the iceberg is like the people who get a positive test for 36 or more CAG repeats – we can see and count them.
The size of the iceberg below the water is the many people who have 36 or more CAG repeats but are never tested. Most of these people in the hidden part of the iceberg are too young to have symptoms of HD, even though they have 36 or more CAG repeats. But at least some of the hidden part of the iceberg are people with symptoms of HD who are never tested or diagnosed.
HD researchers have tried to figure out how many people have 36 or more CAG repeats, but are never tested, and they are getting close to an answer. Some scientists have anonymously tested thousands of people from the general public to determine how many have 36 or more CAG repeats within their huntingtin gene. Researchers with newer technology and bigger pools of DNA have further refined these numbers. The consensus is that about 1 in 400 people has 36 or more CAG repeats in Europe and North America, where HD is most common.
The size of the iceberg below the water is the many people who have 36 or more CAG repeats but are never tested.
How many people have HD but are never tested?
Ok, so 1 in 400 people has 36 or more CAG repeats. But remember, some of these are people who are too young to develop symptoms of HD. How many people with 36 or more CAG repeats actually have symptoms of HD, but haven’t been tested or diagnosed?
This question has been surprisingly hard to answer, because we don’t know how many people in that underwater part of the iceberg actually have symptoms of HD. We can only count people with symptoms of HD in the visible part of the iceberg, who get tested and diagnosed in a doctor’s office.
Some researchers think a large portion of people in the hidden part of the iceberg don’t have HD and will never get HD. A tantalizing thought for HD families! But why do they think this? Because 1 in 400 is already a lot more people than ever get diagnostically tested.
The prevalence of HD – meaning people with HD in the visible part of the iceberg – is about 1 in 8000. This is how many people actually get diagnosed with HD by a doctor, which is way less (about one-tenth!) than the number of all people who have 36 or more CAG (1 in 400). Even after accounting for people who are gene-positive and too young to have symptoms, that would leave a huge number of unknown cases of HD, which some researchers think doesn’t make sense. Other researchers think most people with 36 or more CAGs will eventually develop HD symptoms if they live long enough, but just aren’t getting tested and appropriately diagnosed. They may have symptoms that simply don’t get noticed as HD, especially if they are very old. This concept of people having symptoms of HD but not getting diagnosed is called underascertainment. Literally this means that some people with HD are undercounted from prevalence.
Not all people with Huntington’s disease are appropriately tested and counted in the clinic. Some may not know they have HD, or they may not have been correctly diagnosed, especially if they are very old.
Using clever math to tackle the problem
A well-known research group at Massachusetts General Hospital has recently tackled this question, using a new mathematical approach to explore underascertainment. They started with the question above: how many people have HD but are not diagnosed?
To estimate how many people have 36 or more CAG and might have symptoms of HD, the researchers used an interesting feature of CAG repeats across people: there are fewer and fewer of each CAG as they get longer and longer. 17 is the most common number of CAG repeats in people, but there are fewer people with 18 CAG repeats, then still fewer with 19 CAG repeats, and fewer and fewer all the way up to 36 CAG repeats.
This is part of why HD is a relatively rare disease: because repeats of 36 or more CAG are actually pretty uncommon among people in general. Dr. Jong-Min Lee and his team used this observation to estimate how many CAG repeats with 36 or more should be found among millions of people.
More than expected – but still just an estimate
The researchers estimated that about 1 in 325 people have 36 or more CAG repeats. That’s a bit more than reported in the anonymized studies mentioned earlier. But it’s important to note this is a simulated number, and not directly tested from people, so we don’t know if it’s any more accurate than 1 in 400.
The researchers then did some further calculations to simulate ages of people, estimate how many people should have developed symptoms of HD, and also estimate how many would have died of HD or other causes. This complex math is needed given that people develop HD at different ages and also pass away at different ages. They applied these calculations to the total number of people with 36 or more CAG repeats and – Voila! This calculation yielded an estimate of the number of people with 36 or more CAG who actually have symptoms of HD. Finally, the researchers then compared this estimate of how many people have HD to the published prevalence of HD, or how many people have been formally counted from a clinical diagnosis. Surprisingly, they estimate that only about 50% of people with symptoms of HD might be counted in prevalence.
Why might half of people estimated to have HD not be diagnosed and appropriately counted? There are many potential explanations.
What about the rest?
Why might half of people estimated to have HD not be diagnosed and appropriately counted? There are many potential explanations. One explanation is that some people have symptoms but don’t recognize them, or don’t seek to be tested. Another is that some people have subtle symptoms later in life that are just mistaken for old age. Or perhaps CAG repeats between 36 and 39 – repeats found in a grey zone known as reduced penetrance – don’t lead to symptoms of HD as often as we thought. CAG repeats between 36 and 39 are found in the general public, but aren’t that common in people diagnosed with HD. We still don’t know how often these CAG repeats between 36 and 39 might lead to symptoms of HD.
But you can be sure that researchers like these are hard at work to figure out how many people have HD and how to find them. Having a better understanding of how many people there are that have the gene for HD, but who don’t develop symptoms of the disease, or only do so very late in their lives, could help scientists prolong the healthspan and/or lifespan of people with HD and help develop future treatments.
Summary
HD is caused by 36+ CAG repeats in the huntingtin gene, but not everyone with this expansion is diagnosed.
Prevalence estimates don’t match reality because many people with the gene aren’t tested or diagnosed.
Population studies suggest ~1 in 400 (and possibly as high as 1 in 325) people in Europe/North America carry 36+ repeats — far more than the ~1 in 8,000 clinically diagnosed.
This mismatch raises two possibilities: either many carriers never develop HD, or many people with symptoms remain undiagnosed (underascertainment).
A new mathematical model suggests only ~50% of people with HD symptoms are formally diagnosed.
Reasons for undercounting may include lack of testing, subtle late-onset symptoms, misdiagnosis, or reduced penetrance at 36–39 repeats.
Understanding the full “iceberg” of HD prevalence is critical for preparing treatments and supporting families.
