A new study has shed light on the role of the regular huntingtin protein in the brain. For years, researchers have known that the faulty expanded huntingtin protein drives Huntington’s disease (HD), but this new study shows why the regular version matters for brain health. By lowering regular huntingtin (HTT) in brain cells, scientists discovered hidden changes inside nerve cells that might help explain why some past HD drug trials may have run into trouble. Far from being discouraging, these findings give researchers a clearer roadmap for designing future therapies that are safer and more precise. Let’s take a closer look.
The Role of Huntingtin in Huntington’s Disease
HD is caused by a change in a single gene called HTT. People with HD have a DNA “stutter,” a repeated stretch of the letters C-A-G, that is much longer than usual. Since everyone inherits two copies of each gene, one from their biological mom and one from their biological dad, people with HD typically carry one expanded HTT gene and one regular copy. This means that their cells produce two versions of the huntingtin protein: a faulty, expanded form that drives the disease and a regular form that supports brain health.
The Promise and Challenge of Huntingtin-Lowering
Most of the treatments currently being tested for HD in clinical trials aim to lower huntingtin protein (HTT) levels. The goal is to reduce the toxic expanded huntingtin protein, but many of these approaches also reduce the regular version.
In recent years, potential HTT-lowering therapies have faced challenges in clinical trials, with some not working as expected or raising safety concerns. There are many reasons why this may have happened, but one possible explanation is that reducing too much of the regular HTT protein could be harmful.
Several huntingtin-lowering therapies are now being tested in the clinic, using a variety of different approaches.
This has led scientists to ask an important question: what happens if too much regular HTT protein is lost? By understanding this, researchers can design safer trials and develop drugs that target the expanded form while sparing the healthy one.
In this new study, the researchers began to answer this by lowering expanded huntingtin in a type of brain cell, the nerve cell that transmits signals, and uncovered hidden changes that may explain why some past drug trials ran into trouble. Far from being discouraging, these findings offer a clearer roadmap for designing HD therapies that are safer and more precise.
Why Study the Hippocampus
Most research on regular HTT has looked at the developing brain, where regular HTT is essential, or at the striatum, the region that helps control movement and is most affected in HD. But most drugs circulate throughout the whole brain, not just one area. To better understand how lowering regular HTT affects overall brain health, scientists in this study turned to the hippocampus, a region of the brain that plays a central role in learning and memory.
How the Study Was Done
The researchers began by lowering regular HTT in nerve cells from a mouse hippocampus which were grown in a dish. To do this, they used a tool called siRNA, which works like a genetic “off switch” by telling cells to stop making a chosen protein. This allowed them to reduce regular HTT in a precise and controlled way.
The wiring between nerve cells, called synapses, looked fairly normal even when healthy huntingtin was lowered. The real changes were hidden deeper inside the nucleus.
After treatment, the researchers used special markers to label different parts of the nerve cells and then looked at them with microscopes. These microscopes can zoom in so closely that scientists can see all the intricate details of the nerve cells, including the synapses where nerve cells connect and communicate, and chromatin, the DNA-and-protein bundles that package up all our genetic material and help control whether genes are switched on or off. The team tracked how the structure of nerve cells changed as regular HTT levels dropped.
The researchers also created a mouse model to replicate the experiment and confirm the results. This step is important because findings in simple systems, such as cells grown in a dish, do not always translate to the complexity of a whole brain and body. In these mice, regular HTT was specifically removed from the hippocampus using a harmless virus that delivered a molecular switch that tells certain genes to turn off. In this case, the switch was designed to shut down the gene that makes regular HTT.
The Wiring Looks Pretty Normal
When the researchers looked at the wiring between nerve cells in these mice, they found that these structures remained mostly unchanged with less regular HTT around. That means reducing regular HTT levels did not immediately seem to disrupt how nerve cells connect to each other.
The Nucleus Reveals the Answer
The big changes were hidden deeper inside the cell. When the researchers looked at the nucleus, the control center where DNA is stored, they saw clear effects. After regular HTT was reduced, the nuclei grew larger compared to the nuclei of untreated cells.
Even more importantly, DNA in these nerve cells became less tightly packaged, making it harder for the cell to manage which genes were active.
Every cell in our body contains 2 metres of DNA which is packaged into chromatin to compact it into the nucleus. How tightly it is packaged controls whether genes are switched on or off. When healthy huntingtin was reduced, these bundles became looser and fewer, suggesting problems with how genes are regulated.
The researchers also looked at proteins and chemical tags that help control whether genes are switched on or off. When regular HTT was lowered, their levels shifted from their usual balance. Together, these changes suggested the nucleus was less stable, even though the wiring of the nerve cells looked fine.
What This Means for the HD Community
At first, the idea that reducing regular huntingtin can affect the stability of nerve cells in the striatum might sound worrying. But in fact, these insights are good news for the HD community. For the first time, researchers know one of the possible reasons why some huntingtin-lowering drugs may have faced problems in earlier trials. Knowing this means the next generation of drugs can hopefully be designed to avoid those pitfalls. Instead of trial and error, scientists now have a roadmap showing what they should try to target and what to protect.
Importantly, this study lowered regular HTT by much more than what current drugs being tested are designed to do. In cells, levels dropped by about 86%. In comparison, clinical trials usually aim for a 30–50% reduction of regular HTT. The changes seen in this study potentially reflect what happens when the amount of HTT is lowered too far, giving researchers a clearer sense of the safe range to target.
This research also shows that not all changes are obvious at the surface. While the wiring between nerve cells looked normal, the nucleus revealed the hidden stresses that might come from lowering regular HTT. That insight gives scientists a powerful tool to check whether new drugs are safe before they move to larger trials.
A Step Closer to Safe and Effective Therapies
For families, the message is hopeful: every study, even those that uncover challenges, helps sharpen the path towards effective treatments. By understanding how regular HTT supports brain health, researchers can better design drugs that lower the harmful expanded HTT while minimizing effects on regular HTT.
Science is a step-by-step process. What we know today is built from the lessons of yesterday, and this study adds an important piece to the HD puzzle. With each discovery, the picture becomes clearer, and the future of safe and effective therapies comes into sharper focus.
Summary
Huntington’s disease is caused by expanded huntingtin (HTT), but regular HTT is essential.
Reducing regular HTT in hippocampal nerve cells left synapses intact but disrupted the nucleus, with looser DNA and weaker gene “off switches.”
These results help explain one of the possible reasons why some huntingtin-lowering drug trials didn’t work as we had hoped
Most importantly, they show the path forward: new drugs should take into consideration how much of the expanded HTT and regular HTT are reduced and find a balance that supports healthy brain function.
Gravity Guignard is in her final year of an Honours Bachelor of Science at Trinity College, University of Toronto, specializing in Fundamental Genetics. She conducts research in Dr. Derek van der Kooy’s laboratory, where she studies the development of neural stem cells.
Think about the last time you were stressed. What did you do to feel better? For many of us, it’s talking through our frustrations. Getting rid of things that stress out our cells also requires good communication. The central communicators? Chaperone proteins. Chaperone proteins are just like the chaperones at a school dance. They direct misbehaving proteins to where they need to go and keep them from causing more chaos in the cell. Proteins can be misbehaving in cells for many different reasons, but in diseases like HD, the expanded huntingtin protein is thought to misbehave because it isn’t folded properly and clumps together.
A study identified the co-chaperone SGTA as an expanded huntingtin interactor in HD model cells and mice. Co-chaperones are like the hall monitors that report to chaperones. SGTA is potentially a promising therapeutic target because it is not essential for cellular processes and increases survival of patients of other protein misfolding diseases. Let’s get into this study and what they found.
Finding the Troublemakers
In HD, expanded huntingtin clumps together into groups of misfolded proteins called aggregates. Chaperones target misfolded proteins to minimize the chaos in the cell. Expanded huntingtin aggregates are like magnets for chaperones. Despite this, chaperones fail to control the chaos caused by expanded huntingtin aggregates.
This is a key problem with using chaperones as a therapeutic target, but there are other issues too. Like the chaperones at a school dance, catching the chaos is not their only job, they also have to setup the dance. Chaperones help make new proteins, direct traffic in cells by sending specialized proteins to specific locations, and clean up by targeting old and damaged proteins to the cell’s trash can. Boosting the amount of a chaperone with a therapy doesn’t seem to help in HD. Having too many chaperones can be too much of a good thing and instead of productively removing the problem, we’ve introduced more chaos.
Chaperone proteins have lots of jobs in the cell separate from handling stressful situations. They are responsible for keeping all the other proteins in order like when chaperones keep track of students.
Getting Caught by the Hall Monitors
Here’s the good news. There’s a subset of helper proteins called co-chaperones that work with chaperones. The role of co-chaperones is to serve as the first response. Like hall monitors, they find the sneaky misfolded proteins and stop them from causing more problems. The sneaky protein is reprimanded by the co-chaperone and delivered to the chaperone. The chaperone is ultimately who decides what to do with the protein, but the co-chaperone often helps the chaperone find the protein, hence the name co-chaperone.
A study has identified the co-chaperone SGTA to be of particular interest as a new star hall monitor. Kubota and colleagues found that SGTA associates with the huntingtin aggregates in HD model cells and mice. They also found that SGTA associates with a large proportion of the huntingtin in cells models of HD that we would expect to be in the aggregated stage. Even though aggregates act like magnets for cochaperones like SGTA, the co-chaperone needs to be in range of the aggregate. The authors propose SGTA is acting on the aggregate and even identify the region of SGTA molecule that sticks to the huntingtin clumps. Now we’ve identified a hall monitor capable of reprimanding huntingtin before it takes it to the chaperone.
Strengthening the Frontlines
The big question now that we know SGTA interacts with huntingtin clumps is whether we can use it as a target for developing new medicines for HD. Researchers increased the amount of SGTA in HD model cells to see if it would reduce huntingtin clumps or cause more chaos. They found that increasing SGTA made expanded huntingtin less aggregated and more soluble. This suggests that SGTA isn’t just getting stuck on the huntingtin magnet but is intentionally acting on sneaky huntingtin.
SGTA fights against mHtt aggregates as a first responder. Increasing the amount of SGTA strengthens the initial response.
Boosting SGTA to change huntingtin solubility is a major finding. Huntingtin aggregates are big insoluble protein clumps, and SGTA overexpression shifts expanded huntingtin toward a more soluble state. SGTA seems to specifically target small immature aggregates rather than large mature ones. Because of this preference, SGTA may help determine whether immature or mature aggregates should be targeted to treat HD.
What’s Next
This study shows the importance of trusting the hall monitors of the cell. Researchers found not only that SGTA binds to expanded huntingtin, but also that when you increase the amount of SGTA in the cell, the properties of expanded huntingtin change to a less aggregated state. This suggests that SGTA is acting on expanded huntingtin to decrease its aggregation.
Where do we go from here? Increasing our cellular hall monitors shows promise as a therapeutic target, but there is still lots of work to be done. What is SGTA doing to decrease aggregation? Why is increasing the amount of it effective? Is it working with a chaperone or acting all on its own? These are vital questions for future research.
Summary
Chaperones target misbehaving proteins to prevent further chaos to the cell.
In HD, expanded huntingtin misbehaves into aggregates that are not effectively managed by chaperones.
Early studies find the co-chaperone SGTA to interact with expanded huntingtin.
Increasing the amount of SGTA reduces the aggregation of expanded huntingtin.
Co-chaperones may serve as an underutilized therapeutic target for managing HD.
Chloe is a PhD candidate in the lab of Dr. Emily Sontag in the department of Biological Sciences at Marquette University. Her dissertation work focuses on how quality control proteins interact with the huntingtin protein associated with HD when mutated. She hope this work can contribute to future therapeutics.
This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.
This month brought landmark therapeutic news, advances in biomarkers, deeper insights into what drives Huntington’s disease (HD), and fresh perspectives on mental health in HD. In particular among the developments, we learned from uniQure that the AMT-130 gene therapy appears to be slowing disease progression in their trial. Across the board, all of these updates speak to how far the field has come, and how many exciting directions remain.
A Big Milestone: AMT-130 Gene Therapy Offers Hope, but Caveats Remain
The headline story of the month was a press release from uniQure about their gene therapy, called AMT-130, which is designed to lower huntingtin protein levels in the brain. In this release we learnt that the trial met its primary endpoint as the data indicate approximately 75% slowing of disease progression based on cUHDRS, a clinical metric based on measures of lots of different signs and symptoms of HD. This is the first time a gene therapy for HD has shown the potential to modify disease progression in humans.
Like bees pollinating a field, the first signs of AMT-130 slowing Huntington’s disease may help seed progress for other therapies to grow. Each advance spreads hope across the research landscape.
Despite this hopeful news, key questions remain: what is the durability of effect? How about the long-term safety? What stage of disease might, or might not, benefit from this treatment? The underlying data for the conclusions made by the company in the release have not yet been shared or gone through the peer review proceed. There are sure to be more updates, and lots of discussion, on uniQure’s approach in the coming months.
Huntingtin-Lowering and Other Therapeutic Strategies
SKY-0515 Trial Update:
This small molecule therapy, a pill taken by mouth, showed dose-dependent lowering of huntingtin in people with HD and was reported to have a possible secondary effect on the DNA repair protein PMS1. It is early, but the results from Skyhawk Therapeutics add momentum to other approaches which aim to lower huntingtin levels, like AMT-130.
PROOF-HD Revisited:
The results of the PROOF-HD trial were published in a peer reviewed journal. PROOF-HD set out to test pridopidine, to see if this drug might improve signs and symptoms of HD but did not meet its endpoints. In this publication, the data were dissected, highlighting some possible subgroup effects, potential variables which could have confounded the effect of pridopidine, and lessons for future trial design.
Together, these studies show that multiple therapeutic strategies, with very different approaches, are progressing, with some showing promise.
Biomarkers, Brain Imaging, and Drivers of Disease
DNA Repair and Expanded Huntingtin:
September featured several articles from the HDBuzz Prize for young science writers, sponsored this year by the Huntington’s Disease Foundation (HDF). In a winning article by Mustafa Mehkary, we learned how expanded huntingtin may disrupt some aspects of the DNA repair process. What should be a protective cellular process instead becomes a liability, leaving nerve cells vulnerable to accumulating damage.
Electrophysiology: Early Clues in Brainwaves
Another prize winning article from Eva Woods focused on brain activity, showing how EEG recordings reveal differences in people who carry the HD gene before symptoms appear. These subtle brainwave changes could become useful biomarkers for identifying early disease features and testing new treatments.
A field of ideas: this year’s HDBuzz Prize winners explored EEG, MRI, DNA repair, and mental health in HD, showing how researchers from across different disciplines can help the field grow in many directions.
MRI and Awareness (Anosognosia)
A third prize article from Jenna Hanrahan highlighted how MRI scans may help explain anosognosia, the reduced self-awareness some people with HD experience. Linking brain structure changes with this symptom bridges neuroscience with the lived reality of HD, opening the door to better support and interventions.
These mechanistic and biomarker advances will be essential both for understanding disease and for powering future clinical trials.
Mental Health, Care, and Lived Experience
Another winning HDBuzz prize article from Nicolo Zarotti explored a case study of Acceptance and Commitment Therapy (ACT). In this instance, ACT improved psychological well-being for both a person with HD and their caregiver. It underscores how mental health strategies can complement biomedical advances, helping families navigate the challenges of HD with resilience and support.
Themes That Unified the Month
1. Therapies have the potential to change the course of HD reality
With the cautious optimism we have for AMT-130’s success and encouraging data from SKY-0515, HD is no longer just a target for future therapies but now entering a new era of interventions that might tangibly move the needle.
2. Biomarkers and mechanisms setting the stage
Development of biomarkers such as EEG, MRI, and molecular marker measurements, as well as mechanistic insights into the drivers of HD, like DNA repair disruption, are paving a clearer path for how we design, test and understand new treatments.
3. Holistic care matters
Therapeutics are vital, but mental health, caregiver support, and quality of life perspectives continue to be crucial complements to scientific advances.
4. Transparency and trust
Open publication of trial results, such as the PROOF-HD study, allows the HD community to scrutinize findings and learn from them. We hope to see the same level of openness for AMT-130.
Independent reporting by HDBuzz, sustained through September’s Falling Into Hope fundraising campaign, is a crucial part of building trust and keeping the community informed. If you are able, please consider making a donation.
Falling Into Hope
HDBuzz has launched “Falling Into Hope”, an 8-week campaign to raise $30,000 by October 28, 2025. This pivotal year in HD research brings us closer than ever to disease-modifying treatments, and independent, unbiased reporting has never been more important.
Unlike many organizations in the HD landscape, we make a deliberate choice not to accept funding from pharmaceutical companies. That independence means you can trust us to remain unbiased, especially as we get closer to having disease-modifying drugs.
Your gift makes the difference between simply reporting on progress and ensuring every HD family, everywhere, has the knowledge they need to face the future with the knowledge they’ll need as we advance toward disease-modifying therapies. Please consider donating if you’re able.
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.
The HD community is deeply grateful to the participants who took the brave first steps by being the first people dosed with AMT-130. Their courage opened the door for other people to participate in testing of this gene therapy.
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:
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.
All of the data reported in the update from uniQure give news the HD community has waited so long to hear. The data suggests that AMT-130 is slowing down progression of signs and symptoms of HD.
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, who was involved in the trial, 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.
uniQure’s update is good news for other huntingtin-lowering trials. All that we learn from AMT-130 can help guide scientists working on other therapies for HD.
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.
Every cell in our body is constantly fixing DNA damage that happens throughout our lifetime. Like a city sending out crews to mend roads and power lines, our cells rely on specialized proteins to keep our genetic code in a state of good repair.
The huntingtin (HTT) protein has been a bit of a mystery in terms of precisely figuring out the many functions it participates in. However, there have been some clues about its link with DNA repair. In this study by Dr. Guo Min-Li’s group, researchers built on these clues to uncover more details about HTT: figuring out its involvement in the cell’s DNA repair crew, and how this crew alls apart when HTT is expanded in Huntington’s disease (HD). The result is unchecked DNA damage, activation of the cell’s internal immune alarms and ultimately cell death, suggesting HTT is a key player in DNA repair. Let’s get into the study.
Workers of the Cell, Unite!
HD is caused by an expansion of the DNA code in a repeating C-A-G letter stretch of the HTT gene. The expansion changes the HTT protein, producing a longer toxic version known as expanded HTT.
While scientists have long known that the expanded version is harmful, researchers are still uncovering exactly how the expansion disrupts the many roles of HTT in cell function and what happens when those roles go unfulfilled.
The expanded repeat isn’t stable, and can grow longer in certain types of cells, especially in the brain, through a process called somatic expansion. This means that even more expanded versions of the HTT protein are made in these cells too.
Scientists have been homing in on DNA damage and how DNA repair functions in individuals with HD. One way that DNA can be damaged is called a double strand break – serious damage where both strands of DNA are severed, like when a falling tree takes out a power line or blocks a road. To fix these breaks, the cell recruits DNA repair proteins. To repair these breaks the team of proteins collaborate, with each protein having specific tasks and responsibilities. In this study, researchers focused on 3 members of this DNA repair team in HD:
EXO1- a protein that trims broken DNA ends to get them ready for repair. Think of it as the excited rookie with a jackhammer or axe, great at shaping the site for a proper fix, but in need of guidance to avoid over-cutting.
MLH1- works together with its PMS2 partner to help coordinate the DNA repair and rein in the DNA trimming performed by EXO1. MLH1 is like an experienced crew member who keeps the rookie in check and makes sure the repair project stays on track.
HTT- the big boss themselves! HTT is at the DNA repair site according to this study. It keeps the whole crew running smoothly by giving orders and interacting directly with EXO1 to keep its activity in check. HTT also contacts MLH1 so the team can finish the job properly.
The repair crew works together to fix road damage just like HTT works alongside DNA repair partners to ensure DNA damage is repaired properly.
When the repair crew falls apart
So, what happens when HTT is expanded in HD? In a healthy cell, HTT is like the big boss at a busy repair site, keeping the DNA repair crew working in harmony. To investigate how this changes in HD, the researchers used “co-immunoprecipitation” – a fancy way to say they yanked HTT out from cells, to see which other proteins come along for the ride. In mouse and human cells without the HD expansion, EXO1 and MLH1 were both found together with HTT indicating a tight knit crew working together.
However, when they examined mouse brain cells as well as human cells with the HD expansion, the repair crew was nowhere to be found near expanded HTT. In these cells, expanded HTT seems to be a slacker and ignores the responsibilities of keeping EXO1 in check nor does it contact MLH1, leading the entire repair crew to collapse.
Without the boss in charge, EXO1 trims DNA ends too aggressively leaving the repair site in poor shape. The researchers found that MLH1 drops off, a bit like it walking off the job, further weakening the entire repair operation. In the human and mouse cell models assessed by the researchers, this double blow left broken DNA ends flagged by a DNA damage marker called γ-H2AX and a pile of DNA “debris” scattered around the worksite.
When the repair crew fails, fragments of DNA “debris” result. This triggers the cell’s immune alarm systems.
Ouch, That cGAS-STINGs
To a cell, loose DNA “debris” is like finding suspicious material dumped in the middle of town; it sets off immune system alarms. With expanded HTT unable to coordinate the repair crew and the cell being full of broken DNA fragments, it triggers the cGAS-STING signalling pathway. This pathway is an in-built response system that normally detects foreign DNA, like that from viruses or bacteria. When triggered, it launches an inflammatory response to these “invaders”. In HD, the cell mistakes the DNA debris as foreign and the cGAS-STING induced response triggers the destruction and death of the cell.
The researchers tested this in several models. They used mouse cells in a dish engineered with the HD expansion, human cells from HD patients and neuron-like cells from mice. In every case, cells with expanded HTT had higher levels of DNA “debris” and thus cGAS-STING pathway activation which led to cell death. When they removed cGAS or STING from the cell, the alarms stayed quiet, the inflammation dropped and cell survival improved! Similar observations occurred when EXO1 was removed with the added benefit of less DNA “debris”.
These findings show that expanded HTT is unable to coordinate EXO1 and MLH1. This failure not only leaves DNA damage unrepaired but also actively triggers the cGAS-STING pathway which can result in cell death.
Loose ends at the repair site for HTT
So where does that leave us and what do these findings mean for future work? This study offers a new explanation for how expanded HTT contributes to harm cells in HD. Expanded HTT fails to do a critical job when it comes to DNA repair, but much still remains unknown. While expanded HTT throws the DNA repair crew into disarray at double stranded DNA breaks, we don’t yet know if or how this problem might feed into somatic expansion, a process thought to drive HD progression.
Another open question is when this breakdown in DNA repair occurs. Does the failure of expanded HTT in coordinating repair happen from birth, slowly adding stress to the cells of people with HD or does it emerge suddenly after a certain disease stage or trigger? We still don’t know whether this disruption due to expanded HTT is a gradual process or one that accelerates at specific points during HD.
From a therapeutic standpoint the findings open up some intriguing questions and possibilities. Could targeting cGAS-STING pathway activation help prevent harmful immune activation and cell death in HD? Additionally, what do these findings mean for HTT-lowering approaches currently being tested in the clinic?
The challenge ahead is curbing the damage caused by expanded HTT while preserving the normal HTT protein’s essential jobs. By uncovering a potential role of HTT in DNA repair, this study underscores how critical it is to unravel the basic biology of HTT. Each new insight builds the foundation that will ultimately pave the way for possible therapies capable of changing the course of HD.
TL;DR: The major takeaways
The problem: In HD, the expanded HTT protein loses some of its normal functions. One newly identified role of HTT is supervising DNA repair and keeping DNA repair proteins working together to fix DNA breaks safely. Without HTT and its oversight, DNA repair goes awry.
The insight: Expanded HTT can’t keep EXO1 in check or stabilize MLH1, leading to over-trimming of DNA ends during DNA repair and breakdown of repair coordination. This creates stray DNA fragments or “debris” in the cell, which the cell mistakes for an infection. This DNA “debris” triggers the cGAS-STING immune pathway, causing harmful inflammation and cell death.
The breakthrough: Researchers showed that HTT is a direct player in a particular DNA damage repair pathway called double strand break repair while interacting with MLH1 and EXO1.
In the lab: This chain of events was seen in multiple systems including mouse and human cell lines as well as mouse neuron like cells. In all cases, mHTT led to higher DNA damage, more DNA “debris” and stronger immune activation.
Turning it off: Knocking out cGAS, STING or EXO1 reduced DNA fragments, quietened the immune response and improved cell survival.
Why it matters: This work links faulty DNA repair to immune activation in HD and points to the critical involvement of HTT in DNA repair. Therapies lowering HTT must find the sweet spot of balance between preserving function and therapeutic benefit.
Mustafa Mehkary is a PhD candidate at the University of Toronto studying the biology of Huntington’s disease, with a focus on targeting DNA repair and somatic expansion for therapeutic benefit. Mustafa is also the founder of the Huntington’s Disease Society of Pakistan, working to provide support and resources for HD families in Pakistan.
This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.
