HDBuzz

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. 

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.

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.

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. 

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

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

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

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

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

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

Composite Unified Huntington’s Disease Rating Scale (cUHDRS)

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

Total Functional Capacity (TFC)

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

Cognitive tests (thinking and processing speed)

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

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

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

Motor function (Total Motor Score, TMS)

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

Neurofilament light (NfL)

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

Safety

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

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

Next steps for AMT-130

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

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

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

What does this mean for the HD community?

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

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

Despite this success, some caution is still warranted 

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

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

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

Despite these caveats, the findings point to a potential disease-modifying effect, which is something the HD community has long hoped for. Prof. Sarah Tabrizi, Director of the University College London Huntington’s Disease Center, 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.

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

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

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

Summary

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

Learn more: 

uniQure press release – 24th Sept 2025

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. 

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. 

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. 

Learn More:

“Mutant huntingtin protein induces MLH1 degradation, DNA hyperexcision, and cGAS-STING-dependent apoptosis”, (open access).

Meet this 2025 HDBuzz Writing Competition Winner

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.

On September 17, 2025, we received an encouraging update from Skyhawk Therapeutics’ Phase 1 study, taking place in Australia. The recent update suggests that SKY-0515 can lower the huntingtin protein as well as PMS1, another protein which is thought might also drive Huntington’s disease (HD). Importantly, the drug also appears to be safe and well tolerated. A larger Phase 2/3 trial called FALCON-HD is already underway. Let’s get into what we learned from this latest update. 

What is SKY-0515 and how does it work?

SKY-0515 is a pill, taken by mouth, designed to change which proteins are made in the body. The drug works by targeting message molecules, or RNA, which are copied from the DNA code and have the instructions to make different types of proteins. SKY-0515 changes how cells process RNA messages. 

SKY-0515, like PTC Therapeutics’ votoplam, isn’t specific for huntingtin. The pill targets many different messages throughout the body, but huntingtin happens to be one that it targets quite strongly. Because it’s not specific, it also influences the levels of other proteins in the body. Two of the proteins whose levels are changed by the SKY-0515 drug are huntingtin and, perhaps serendipitously, PMS1. 

Lowering huntingtin levels is one of the main approaches companies are testing in the clinic to try and treat HD. The idea is that by reducing the levels of the toxic, expanded form of the protein made in people who have the gene for HD, we can target the root cause of the disease. SKY-0515 is actually a “total” huntingtin lowering drug, meaning it lowers both the expanded and regular forms of the huntingtin protein. 

With multiple huntingtin-lowering approaches now in clinical trials, the HD community is closer than ever to finding therapies that go beyond symptom management.

PMS1 also seems to be targeted by this drug. PMS1 is a DNA repair protein that, when reduced, is thought to slow the “somatic expansion” of CAG repeats. This is the molecular process that makes CAG repeats longer in some cells in the body over time. By reducing the toxic huntingtin protein and also potentially slowing down another one of the disease drivers, the scientists at Skyhawk think they might get a 2 for 1 effect with this drug. 

Testing the waters with SKY-0515

This Phase 1 trial is actually divided into three parts (A, B, and C) and the results we are learning about yesterday come from part C of the trial, which is testing the drug in people with HD. Parts A and B looked at the drug in healthy people without the gene for HD and we already learned about how the drug was working in a previous update from Skyhawk. That update showed the drug appeared safe and working as expected to lower huntingtin in the people in which it was tested. 

Part C of this trial tested 2 different doses of the drug, a low (3 mg) and high (9 mg) dose, and also included people who received a placebo sugar pill. Folks in the trial are then monitored and all sorts of measurements are made from samples, like blood, to see how well the drug might be working. Safety is the top priority in Phase 1 trials, but other data is collected too to give insights into designing the next round of trials and see if the drug appears to work as expected. 

So what’s new?

In this latest update, we got some interim data about Part C of the trial – where they test this drug in people with HD. Skyhawk reported that the drug appears to be generally safe at the doses tested – great news! SKY-0515 was also reported in this update to get into the brain very effectively, a critical challenge for HD therapies.

We also learned that the drug seems to do a good job of lowering the levels of the huntingtin protein, with data shared up to day 84 (12 weeks) into the study. In fact, the more drug participants got, the more lowering Skyhawk could measure in the blood. This “dose-dependent” lowering is a favourable hallmark researchers look out for when testing a new drug and fine-tuning what dose might work best. 

Why is this important?

The results so far suggest that SKY-0515 can lower huntingtin protein in people with HD to a greater extent than has been reported before with a pill. That’s exciting, because until now most huntingtin-lowering approaches have required injections or infusions into the spinal fluid, which are far less convenient and come with additional safety challenges. Having an oral drug that can reach the brain effectively and reduce huntingtin to this degree is a very encouraging step forward.

Another promising feature of SKY-0515 is that it does more than just lower huntingtin. It may also reduce levels of PMS1, a protein involved in the process that makes CAG repeats longer in some cells over time. By targeting both huntingtin and PMS1 at once, SKY-0515 could potentially tackle HD through two different disease mechanisms.

Professor Ed Wild, HDBuzz Editor Emeritus, who is involved in the study, summed it up by saying:

“This is what success looks like at the 3-month timepoint, setting the stage for meaningful impact for people living with HD across the world – for whom an orally administered huntingtin-lowering treatment such as SKY-0515 would be truly transformative.”

What we still don’t know

It’s worth pointing out that this update from Skyhawk is still quite limited in details. While the company shared a graph showing reductions in huntingtin protein levels by dose, they didn’t provide all the details behind some of the claims. 

The most recent press release suggests that SKY-0515 lowers PMS1, but we’ve not yet seen this data. This would be fantastic if it lowered PMS1 to a meaningful level! But without the data, we don’t know if the levels to which PMS1 are lowered would be considered significant. So the questions remain: How much is PMS1 being lowered by SKY-0515? Is PMS1 being lowered to a level that would be meaningful? Is the lowering of PMS1 significant enough to influence somatic expansion of the CAG repeat within the huntingtin gene?

This kind of early communication is sometimes called “science by press release.” The full picture, including the more complete results from this trial, won’t be available until mid-2026. So, while these first signs are encouraging, it’s important to keep expectations realistic and remember that there’s still a lot we don’t yet know.

So what happens next?

After the first 3 months, people in the study will keep taking SKY-0515 in a longer follow-up, where everyone stays on treatment at a low or a high dose for up to a year. We should hear the main results from this part of the trial in mid-2026.

At the same time, a bigger Phase 2/3 study called FALCON-HD is already underway across 10 sites in Australia and New Zealand. This trial will involve about 120 people with stage 2 or early stage 3 HD, as per the HD Integrated Staging System or HD-ISS, and will test different doses of SKY-0515 to be compared with placebo. Importantly, this study will not just look at effects beyond safety and levels of huntingtin and PMS1. It will also see if the drug can help with symptoms like movement, thinking, and daily life, and whether it influences how the brain structure changes with HD.

What does this mean for the HD community?

For people affected by HD, these results are both hopeful and cautious news. On the hopeful side, SKY-0515 is the first oral therapy to achieve such strong huntingtin lowering in people with HD that can be fine-tuned by changing the dose of the drug. SKY-0515 also seems to target PMS1, potentially tackling an additional potential driver of HD. Most importantly, the drug appears to be generally safe. 

By reducing the toxic huntingtin protein and also potentially slowing down another one of the disease drivers, the scientists at Skyhawk think they might get a 2 for 1 effect with this drug. 

That said this is very early data in a small group of people with HD. The trial is also focused on safety and whether the drug is working as expected, but not whether it can slow, halt, or reverse symptoms of HD. It will take larger, longer trials to know if SKY-0515 actually slows or improves the course of HD.

Still, this is a big step forward for the field. With multiple huntingtin-lowering approaches now in clinical trials, the HD community is closer than ever to finding therapies that go beyond symptom management.

Summary

• SKY-0515 is an oral drug that alters RNA processing, lowering levels of huntingtin and potentially PMS1, a DNA repair protein linked to CAG repeat expansion in Huntington’s disease (HD).
• Phase 1 results show safety and brain penetration, with dose-dependent reductions in huntingtin protein—greater than previously achieved with an oral therapy.
• Dual targeting of huntingtin and PMS1 could provide a “two-for-one” therapeutic effect, addressing both toxic protein buildup and CAG repeat expansion, though PMS1 data remain limited.
• Next steps: Full Phase 1 results are expected in mid-2026, while the larger Phase 2/3 FALCON-HD trial is already underway to test effects on symptoms, brain changes, and overall disease progression.

Learn More

Skyhawk’s September 17, 2025 press release.

People living with Huntington’s disease (HD) experience changes in their thinking, memory, and behaviours. This is anarea of HD that is widely studied and fairly well understood. However, sometimes people with HD don’t realize these changes are happening. This is actually a symptom known as anosognosia. This symptom isn’t the same as being in denial, where a person avoids reality while still being aware of it.

A recent study used MRI to explore why anosognosia happens in people with HD and what parts of the brain are involved. The findings help explain why people with HD don’t see or feel the symptoms that the people around them notice and why that is important for safety and understanding of the disease. Let’s get into what the researchers found, and what this means for the HD community.

Ignorance isn’t always bliss

Anosognosia can be mislabelled as stubbornness or laziness and dismissed as denial of a diagnosis. It can create major challenges for people with HD, their families, and caregivers. If a person does not realise they are sick, they may refuse or delay medical support, make unsafe decisions, or perhaps strain their relationships with family members and caregivers who are trying to help.

This study aimed to understand what is going on physically in the brain when this challenge presents itself. If these scientists can see physical changes that could be linked to anosognosia, they can help physicians, caregivers, and researchers better support people with

HD and understand why they might be unable to recognize their own symptoms. With this knowledge we could reduce the tendency to blame the impacted person and break the “stubbornness” stigma.

A photoshoot for your brain

To investigate anosognosia, researchers looked at MRI (short for magnetic resonance imaging) scans from 570people (males and females). These scans came from two large research projects, the PREDICT-HD and TRACK-HD studies. Many participants were premanifest HD (HD-ISS stage 0), or in early stages of the disease (HD-ISS stage 1). 

The MRI scans are essentially detailed pictures of the different structures inside the brain. Think of it like a super high-quality camera that uses magnets and radio waves to take pictures. Getting an MRI can be scary – it’s large, loud,and intimidating. But it is also powerful!

Here’s how it works: the machine is like the magnets on your fridge, except much larger and stronger. The hydrogen atoms that make up the water in our bodies act like micro magnets that are spinning in every direction (each one like a tiny Earth spinning on its own axis). When you enter the MRI machine, the big magnet makes the spins of the hydrogen atoms align. Then it sends out radio waves that push the hydrogen atoms out of place. Eventually they fall back to their original positions, giving off signals that the computer can detect. The computer takesall those signals and turns them into an image. All the thumping and buzzing sounds you hear are the quick electrical changes happening to the coils of the machine (the wires carrying the 

electricity) to get the best images. It causes no damage, emits no radiation, and teaches us a lot about what’s happening inside our bodies – an all-round win!

But how do you measure a symptom someone is unaware of?

Since anosognosia means not being aware of your own symptoms, it can’t be measured directly. They used a questionnaire called the Frontal Systems Behaviour Scale (FrSBe). The person with HD and a companion who knows them well (caregiver or family member) filled out the survey. The questionnaire asked about things like behaviour, thinking and emotions. Comparing how the two responded to questions allowed them to observe the differences in how they view the symptoms (e.g., loss of energy, impulsivity, problems with organization).

Think of it like using two weather apps, where the app you use consistently misreports the temperature. If your weather app says it’s 20°C, and a friend’s app says 0°C for the same location, you may go outside without a sweater because you didn’t get an accurate reading of what the temperature really is. In the same way, a person with HD may think they are fine and rate their symptoms low, while a caregiver who sees what the symptoms truly are will rate their symptoms high. The bigger the gap in scores, the more unaware the person is of their symptoms, potentially impacting the person’s care.

The group used this gap to measure how much anosognosia the person with HD was experiencing. Then they ran the numbers, looking for connections between these score differences and saw is this tallied with what they saw in the MRI scans.

What did the study find?

The study found that seven brain regions were closely linked to anosognosia in people with HD – the globus pallidus, putamen, caudate, basal forebrain, substantia nigra, angular gyrus, and cingulate cortex. Each of these regionshas a special job, but many of them help with movement, learning, memory and emotion.

Through further investigation, one region in particular stood out: the globus pallidus. This region was thestrongest predictor of anosognosia in the study. This means that people with more globus pallidus atrophy (shrinkage) tended to be less aware of their symptoms.

The globus pallidus helps in controlling movements and makes sure our movements are smooth and efficient. In many HD studies and in the clinic, researchers tend to focus on the caudate and putamen, but this study suggests that changes to the globus pallidus could contribute to some of the symptoms of HD, especially when it comes to anosognosia.

What does this mean for HD families?

This research shows that anosognosia in HD is not about having a bad attitude, it’s linked to real brain changes. Being able to recognize the neurological side of things gives families and caregivers a better understanding of why people might not see their symptoms. It reduces the stigma and blame that is often misunderstood, and empowers safer decision making, and opens doors to new care strategies in the future. When we recognise that someone isn’t ignoring their illness on purpose, we can replace frustration with compassion. 

Finally, a huge thank you to all the participants and families who contributed to the data sets used in this study. Your donation of brain data is a generous decision that will continue to provide new information and advance research. The studies you help build, like this one, stress the importance of working with the brain, and not against it and brings us one step closer to fully understanding the HD brain!

TL;DR 

• People with HD often experience anosognosia (a lack of awareness of their own symptoms).
• A recent study used MRI data from over 500 people to explore brain regions linked to anosognosia.
• Researchers used a questionnaire to compare perspectives of caregivers and people with HD across different symptoms and used the gap between the two to measure anosognosia. 
• Seven brain regions were linked to anosognosia, with the globus pallidus standing out as the most significant. 
• These findings show that anosognosia in HD is linked to biological changes, not behavioral concerns. Knowing this can help families and caregivers respond with more empathy and better care. 

Learn more

“Structural MRI Correlates of Anosognosia in Huntington’s Disease.” (paid access).

Meet this 2025 HDBuzz Writing Competition Winner

Jenna Hanrahan is a PhD student at Memorial University in Newfoundland, Canada, under the supervision of Dr. Lindsay Cahill. Her research focuses on using medical imaging techniques such as MRI and ultrasound to better understand brain changes associated with HD. Jenna hopes her findings will contribute to the development of novel therapies for the disease.

This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.