HDBuzz

This month brought new revelations across biomarkers, basic science and community gathering. In particular, we saw how DNA-repair targeting strategies are moving into focus, how gaps in diagnosis are being quantified, and how the annual Huntington’s Disease Clinical Research Congress 2025 deepened connections across the field. Together these developments reflect how far the HD research landscape has matured, and how many fresh paths remain to explore.

Therapeutic & Clinical Research Highlights

A Closer Look: One Month After the AMT-130 Headlines

Four weeks after uniQure’s landmark announcement, the HD community is still abuzz with the news. HDBuzz took a step back to break down what the data truly show, and what remains uncertain.

Early results from the small Phase 1/2 trial suggest AMT-130 may slow HD progression by about 75% in high-dose participants, marking the first evidence that a therapy could alter the course of disease. But promising doesn’t mean proven. The trial’s small size, use of an Enroll-HD comparator instead of a full placebo control, and lack of peer review mean we must interpret these results with caution, and unanswered questions remain about durability, safety, and access.

By untangling the hype from the headlines, a crucial point is reinforced: progress in HD research is real and accelerating, but it happens through steady, careful steps, not sudden leaps. While the news is hopeful, caution is urged when reading headlines about a “cure” or “treatment” that are too good to be true. 

Huntington Study Group (HSG) Clinical Research Congress 2025

The October meeting in Nashville offered a wide sweep of updates: new trial designs, biomarker deep dives, community-researcher interactions, and early-phase results that hint at shifting paradigms. And HDBuzz was there, front row, to cover it all. The gathering emphasised the value of sharing early data, aligning endpoints, and building collaborative momentum.

In a way, the congress acts as a greenhouse for ideas, nurturing the seedlings of innovation until they’re ready for field trials. The value here lies not just in the results presented, but in the relationships built and the priorities refined.

Biomarkers, Mechanisms & Population Research

Mechanistic Targeting of DNA Repair in CAG-Repeat Expansion

A study suggests that small molecules targeting the “DNA scanning machines” may slow the expansion of CAG repeats that are the genetic cause of HD. This finding brings insight into the mechanism that may drive onset and offers a potential new therapeutic angle.

This work combines molecules in a tube to get a better idea of how the error-repair processes that cause CAG expansion go awry in HD, giving researchers something tangible to aim drugs at. Of course, many questions remain: What’s the safety profile? How soon could this translate to humans? And in what disease stage could there be the biggest impact?

This month brought new revelations across biomarkers, basic science and community gathering.

How Big Is the Huntington’s Disease Iceberg?

A recent mathematical modelling study asked: how many people carry the HD gene and remain undiagnosed? This work tries to define the “hidden” portion of the iceberg — people with the gene for HD who aren’t diagnosed — insight critical for understanding the full disease impact.

Knowing the size of the unseen population helps us calibrate the real reach of therapeutic development since it’s not just those already diagnosed who are affected by HD, but those yet to be found. It can also help our community leaders better campaign for resources and recognition from their respective governments and healthcare systems. 

HDBuzz Prize-Winning Mechanistic Work

October also presented key early-career researcher contributions via the HDBuzz Prize, sponsored this year by the Huntington’s Disease Foundation (HDF):

One article from Gravity Guignard explored how lowering levels of unexpanded huntingtin protein, or the “good” versions, may complicate safe drug development. This work is a reminder that lowering levels of a target must be done with caution.

Another article from HDBuzz Prize winner Chloe Langridge highlighted the protein SGTA as a potential therapeutic target for HD, adding to the growing list of “support proteins” in the cell that may indirectly improve disease effects.

These mechanistic pieces reinforce that the field’s concept of “targeting huntingtin” is evolving into “impacting the molecular network around huntingtin.”

Early Clues in the HD Brain: Mapping Changes from Birth

A recent study used specialized techniques that examine where and how cells in the brains of mice are impacted by HD. They found there are changes at the level of individual cells long before symptoms appear.

The researchers found that gene activity shifts seem to start at birth in HD mice, especially in the striatum and cortex, the brain regions most affected in the disease. Medium spiny neurons may have early over-activation of key identity genes that later decline, while cortical development genes seem to be reduced from the start.

These findings suggest a time-lapse view of HD progression, highlighting that molecular changes begin early but evolve gradually, shaping which cells become most vulnerable.

Themes That Unified the Month

1. Mechanism first, translation next — There is a clear focus on understanding how HD works (DNA repair, protein networks). These insights will be critical as treatments that target the functioning of the huntingtin protein translate to the clinic.
2. Quantifying the unknown — Whether it’s undiagnosed carriers or untested protein networks, October emphasised measuring the hidden parts of the HD landscape.
3. Community and collaboration matter — Big meetings, transparency around complex mechanistic work, and the advancement of research projects with the help of the HD community reinforce that progress happens not in isolation, but through collective effort.
4. Cautious optimism with rigour — While the pace of HD research appears to be accelerating, researchers are dedicated to relaying an accurate message to the community and the field is appropriately mindful of safety signals, false leads, and the need for robust data.

Your support helps ensure families everywhere stay informed and empowered as science moves us all forward to an HD-free future. Thank you!

Falling Into Hope

Independent reporting by HDBuzz remains vital, particularly as we advance toward disease modifying drugs. The month of October continued our 8-week giving campaign, “Falling Into Hope”. 

With the generosity from the community, we were able to surpass our original fundraising goal of $30,000! Your support helps ensure families everywhere stay informed and empowered as science moves us all forward to an HD-free future. Thank you!

Summary

• New small-molecule work targets DNA‐repair machinery, which is promising but early.
• The Huntington Study Group (HSG) HD Clinical Research Congress 2025 fostered big-picture alignment and data sharing.
• Studies modelling undiagnosed gene carriers highlight hidden disease impact.
• Prize-winning mechanistic work on “good huntingtin” and SGTA show complexity of targets.
• The month emphasised measurement, mechanism and community, in balance.

A new study in mouse models reveals how Huntington’s disease (HD) disrupts brain development over time, even long before symptoms appear. Using advanced sequencing tools and spatial transcriptomics, a technique that maps where in the brain genes are activated, researchers discovered early warning signs that could help explain why some brain cells are more vulnerable than others in HD.

Why this matters

We know that HD is caused by a repetition of genetic letters that spell C-A-G in the huntingtin gene. People who won’t develop HD have 35 or fewer CAGs, whereas people who go on to develop HD have 36 or more.

And while every cell carries this genetic spelling mistake, certain brain cells are hit much harder, causing them to die early. What we still don’t fully understand is why those cells are more vulnerable, or what might be happening silently in the brain long before symptoms appear to make them more vulnerable.  

In a new study, led by Dr. Leslie Thompson and Dr. Mara Burns at the University of California Irvine, the team dove into that mystery. They used a powerful combination of techniques called “spatial transcriptomics” and “single-cell sequencing”. 

Spatial transcriptomics sounds fancy (and it is!), but its name gives us clues into what it does. It spatially maps transcripts, or the short genetic messages created from DNA before they turn into protein, on a brain sample. So it can be used to show where genetic messages are on an image of the brain. The researchers used this technique to map changes across the lifetime of mice that model HD.

Single-cell sequencing looks at the genetic messages within a sample in each individual cell. Both of these techniques give a wealth of data and help create a detailed map of what’s going on inside the brain because of HD. 

Interestingly, they found some surprises! Their work suggests that changes in gene activity start from birth and evolve in a cell-type- and region-specific way, particularly affecting the striatum (central brain region that controls movement, motivation, and emotion) and cortex (outer wrinkly bit that controls things like perception, movement, and planning). These two brain regions are heavily impacted by HD. Knowing more about when and how changes happen in these brain regions can help us understand the mystery of selective vulnerability in HD.

The HD Brain’s Vulnerable Zones: Striatum and Cortex

We know that HD doesn’t affect all brain cells equally. Some types of cells, like glia cells which work to support neurons, aren’t vulnerable to death in the same way that neurons are. 

But even neurons themselves are selectively vulnerable. Some types are particularly vulnerable to death, while others remain surprisingly resilient, even in late stages. Among the most affected are medium spiny neurons (MSNs), which make up the bulk of the striatum — a brain region central to coordinating movement, motivation, and learning.

MSNs are critical “relay stations” in the brain’s circuitry, passing along dopamine signals and fine-tuning motor control. In HD, these neurons are among the first to show altered function and eventually die. The new study shows that even in newborn HD mice, MSNs begin to show abnormal gene activation, including increased levels of identity genes like Drd1 and Tac1, which later decline. This suggests the cells might be “overcompensating” early on before crashing.

Meanwhile, in the cortex, another brain region that governs higher thinking and decision-making, the researchers found reduced expression of Tcf4, a key genetic hub important for neuron development. These cortical changes start early and persist through disease progression, hinting that HD may also subtly disrupt how the cortex matures.

Using advanced sequencing tools and spatial transcriptomics, a technique that maps where in the brain genes are activated, researchers discovered early warning signs that could help explain why some brain cells are more vulnerable than others in HD.

A New Era of Brain Mapping

Until recently, if we wanted to know which genes were activated differently by HD, most studies relied on a method called “bulk RNA sequencing”. This technique is powerful, but it has a big drawback: to measure which genes are switched on, scientists first have to grind up brain tissue. That means the genetic messages from all cell types in the sample — vulnerable and resilient neurons, glia, and even cells from blood vessels — gets mixed together. 

Bulk RNA-seq is a bit like taking all the conversations in a city, recording them at once, and mixing them into a single audio track. You’ll hear the overall noise, but you can’t tell whether it came from a teacher in a classroom, a busker on the street, or a child in a playground. To get around this, the researchers in this study used two novel approaches:

• Spatial transcriptomics: This method is a big step forward because it measures gene activity while keeping the tissue slices intact. It’s like taking a bird’s-eye photo of the brain with colored spots showing which neighborhoods are “loud” or “quiet” in their genetic activity. The resolution doesn’t capture signals from each individual cell, but can from groups of dozens of cells. Critically, it preserves the “where” information that bulk methods erase.
• Single-nucleus RNA sequencing (aka, snRNA-seq): Here, scientists zoom in much closer. Instead of working with whole brain slices, they isolate individual cells and read out their genetic activity one by one. This reveals who is speaking in the city of the brain — neurons, astrocytes, microglia, or oligodendrocytes — and what each type of cell is saying. But the downside is that this method loses the spatial context: you know who is talking, but not where they are in the city.

By combining these two methods on a timeline of the HD mouse lifetime, the team got the best of both worlds: the “where” from spatial transcriptomics, and the “who” from single-cell sequencing. This allowed them to build a spatial map across time of how HD unfolds. With it, they linked gene changes to specific cell types and brain regions across three stages: birth, early symptoms, and late disease. This approach offers more nuance than previous techniques and opens new possibilities for understanding complex diseases, like HD.

Key findings

• Reorganization from the very start: Even at birth, HD mice already show altered gene activity. In the striatum, mitochondrial genes (those controlling energy production) were disrupted. In the cortex, a gene called Tcf4, crucial for brain development, was reduced. This may affect how cortical neurons organize and connect.
• Changes over time: MSNs showed early increases in identity genes that help define this specific type of neuron. Over time, this trend seems to change, and identity gene levels decrease. The researchers identified other changes that could contribute to MSN impairment, like mitochondrial deficits, seeming to originate in the striatum prior to overt symptom onset and spreading to other brain regions.
• Communication breakdown: By examining cell-cell signaling pathways, the team found time-dependent changes in neuropeptide Y (NPY) signaling, which may be involved in balancing energy use and neuron health.

Looking Ahead: New Paths for Understanding and Intervention

This study doesn’t just provide a snapshot of the HD brain, it offers a time-lapse map of how things changes as HD advances. By combining spatial and single-cell data, it shows Huntington’s early influence, perhaps beginning as early as birth and building slowly over time.

It’s important to note though, that even changes identified at birth don’t mean the brain can’t compensate. Clearly it can! People with the gene for HD generally live entirely healthy lives for decades. What it could mean is that these early, subtle changes may be setting these cells up for sensitivity later on that makes them more vulnerable to death. So while they can stave off molecular insults across those decades, over time it becomes too much. 

This study doesn’t just provide a snapshot of the HD brain, it offers a time-lapse map of how things changes as HD advances.

These insights offer several takeaways for the HD community:

• Therapeutic timing: If early gene changes contribute to vulnerability, treatments aimed at stabilizing brain development could be valuable, even before symptoms appear.
• Targeted strategies: Understanding which cells change first, and how, could help develop more precise therapies. Some changes may begin early but are balanced by the brain’s own mechanisms for compensation. Studying these natural defenses could reveal new ways to fight back from the start.
• Biomarker development: Patterns like mitochondrial stress or Tcf4 downregulation may one day help identify disease onset more accurately.

Most importantly, this work highlights the growing importance of big-data brain mapping tools, helping researchers move beyond bulk averages to truly understand what’s happening in individual cells, in real tissue, across time. While this study was done in a mouse model, it lays crucial groundwork for understanding the earliest molecular ripples of HD in the human brain, and how we might one day intervene before the map changes.

Summary 

• Advanced mapping tools: Combining spatial transcriptomics and single-cell sequencing reveals both where and which cells are altered in HD.
• Early beginnings: Gene activity changes start from birth in HD mice, particularly in the striatum and cortex, the brain’s most affected regions.
• Dynamic shifts over time: Neurons in vulnerable regions show early over-activation of identity genes that later decline as disease progresses.
• Energy and communication faults: Mitochondrial and neuropeptide signalling pathways are disrupted, affecting neuron health.
• A blueprint for early intervention: These findings highlight that subtle, early-life changes may shape later vulnerability, guiding future prevention and therapy strategies.

Learn More

Original research article, “Distinct molecular patterns in R6/2 HD mouse brain: Insights from spatiotemporal transcriptomics” (open access).

The past 4 weeks have been a whirlwind in the Huntington’s disease (HD) community. On September 25th we had an update from uniQure about a drug they’re testing for HD in ongoing clinical trials. The news was positive and it took the world by storm, producing jaw dropping headlines from news sources around the world, generating global interest in HD, and prompting many people within the HD community to reach out to neurologists and care centers around the world with various questions. 

Now that the dust has settled, we can take a step back to break down what we know, where the uncertainties lie, and address and answer some of the questions we’ve heard from the HD community. Given past disappointments, it’s natural for the HD community to approach new developments carefully. We share this caution, as well as optimism, and want to frame the buzz that the recent news has generated through a realistic lens. 

uniQure’s Announcement

Just a few weeks ago, uniQure announced positive topline results from their Phase 1/2 trial of AMT-130, a gene therapy being tested in people with HD. The therapy, delivered directly into the brain through a ~10 hour surgery, is designed to permanently lower production of the HTT protein that causes HD. 

According to uniQure’s update, trial participants receiving the high dose of AMT-130 who have been followed for 3 years have experienced a 75% slowing in overall disease progression as measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS). The cUHDRS is a collection of tests that assess how well people with HD are functioning day-to-day through memory, movement, and mood tests. The improvement on the cUHDRS scale meant that the trial met its primary endpoint. 

This positive news represents a milestone, showing for the first time that a drug can alter the course of HD in people. uniQure shared that their next steps are to meet with the U.S. drug regulator, the FDA, later this year, aiming to file for accelerated approval in early 2026.

However, we’re not across the finish line yet and don’t yet have a bona fide HD treatment in hand. This is a Phase 1/2 trial, so it’s only being tested in a small group of people. Even with these critical caveats that should elicit some caution, many media outlets headlined the exciting part of the news without doing much to temper excitement. 

Given past disappointments, it’s natural for the HD community to approach new developments carefully. We share this caution, as well as optimism, and want to frame the buzz that the recent news has generated through a realistic lens.

Overhyped & Misleading Media Coverage

Unfortunately, many news outlets are driven by attention. They want your eyes on their website. So the more clicks they get the better. And big, over-the-top headlines generate a lot of clicks. Thus, when fantastic research news about a devastating brain disorder, like HD, comes out for the first time, the splashier headlines are a common tactic for some news outlets. But this can be detrimental to the very populations that the news is intended to serve. Let’s get into some of the flagrant headlines that made our eyes pop and jaws drop.

HD “Successfully Treated”?

Some of the more egregious headlines claimed that HD was “successfully treated” for the first time, even pairing this news with pictures of world-renowned, incredibly reputable HD researchers. Because of that, it’s understandable that anyone with HD, from an HD family, or who even knows anyone affiliated with HD would immediately get on the phone to call or text about the next steps. 

First and foremost – was HD successfully treated for the first time? The jury is still out on this one; the data are promising, but not conclusive. The recent news from uniQure does not yet show that we have a successful treatment for HD. It shows in a small number of people being given AMT-130 that metrics measuring signs and symptoms of HD are moving in a favorable direction that suggests the drug may be able to slow disease progression. 

Is this good news? Undoubtedly. Is it conclusive? By no means. AMT-130 is currently being tested in a Phase 1/2 trial. Even if this trial is wildly successful and surpasses every expectation, we will still need more data to conclusively say that it is a successful drug in treating HD. 

uniQure has always been transparent about the fact that even if this trial is successful, the next steps could include accelerated regulatory approval, which is different from a fully approved drug on the traditional path. Drugs that receive accelerated approval can be marketed with the understanding that more data will be collected in larger trials with more trial participants to ensure that the drug can do what everyone hopes it will do. If it doesn’t, the accelerated approval label will be revoked, the drug will be pulled from market, and it will no longer be sold. Fully approved drugs have been tested in a sufficient number of people to conclusively show that they work as intended, and they likely won’t be pulled from market for efficacy reasons. 

A “Breakthrough Cure”?

Other conclusive-sounding headlines suggested that the world had found a “breakthrough cure” for HD. Similar to headlines claiming we’ve “successfully treated” HD, the data do not yet support the conclusion that we have a cure for HD. 

A cure implies that someone who once had HD no longer has the disease, which suggests that there has been a reversal of symptoms or elimination of all signs of HD. The data from uniQure do not suggest that HD has been cured or that HD signs and symptoms are being reversed. The data suggest that progression of HD is being slowed. While this is still fantastic news, it’s an incredibly critical difference.

Some Weren’t So Bad

Not every news source put out a headline that exaggerated the results. Some of the more level-headed articles underscored that the results “show promise”, were “a cause for hope”, were “preliminary but promising”, and “slowed progression”. 

Science is rarely cut and dry, especially when it’s in earlier stages like a Phase 1/2 trial, so headlines that are more cautious and avoid conclusive sounding language are usually more in line with a level interpretation of the findings. 

Navigating Headlines 

A sure fire way to spot articles that you should view with some skepticism are those with huge claims, like a successful treatment or cure for HD. At HDBuzz, we recently updated an article with 10 golden rules you can use to navigate HD research news. With all the news swirling about, if you haven’t checked this article out, now would be a fantastic time to give it a glance so that you’re brushed up on your HD media literacy. 

Some of the more level-headed articles underscored that the results “show promise”, were “a cause for hope”, were “preliminary but promising”, and “slowed progression”.

The Key Caveats

We mentioned that there are some key caveats that should elicit caution around these results. So, what are they?

Small number of participants

As stated above, this is an early, small trial. Phase 1/2 trials by design are intended to be small because we don’t want to test unproven drugs in large numbers of people without more evidence that they may be successful. Trials are designed to include increasing numbers of participants as evidence mounts that the drug is likely to work. 

Because of that, this ongoing trial has just 29 participants – 12 in the low dose group, and 17 in the high dose group. Of those 17 receiving the high dose, 12 have made it to the 3 year mark, so the exciting data currently being scrutinized is from just those 12 people. This isn’t a very big group. 

Trials with larger numbers of people evoke more confidence because it’s less likely that a larger group of people would all have some sort of biological anomaly chosen by chance. For example, it could be possible that 12 randomly selected people may all have some factor (biological, pharmalogical, or otherwise) that may make them perform better on a certain drug, but this chance decreases if you have 100 people, for example. Inclusion and exclusion criteria try to account for some of this, but smaller sample sizes still have this probabilistic risk. 

The comparator group

Very robust clinical trials are compared against a placebo group – a group of people that are similar to the participants being given the drug that are instead given a sugar pill, or a mock surgery, as it would be in this case. While the first 12 months of this study were tested against such a group, after that initial year, those people were given the option of receiving the drug. Unfortunately because this study, and any gene therapy study, is long term, some of those people were no longer eligible for the drug based on the inclusion and exclusion criteria for the trial. 

Thus, moving forward the trial was controlled against data from Enroll-HD, which is an observational study that follows people with HD as they naturally live and age. For this reason, the comparator group in this trial is much larger, following over 1500 people, 940 of whom are being compared against the high dose group. 

This is a less rigorous way to test a drug for several reasons. Firstly, there’s no easy way to determine that “the placebo effect” isn’t improving their symptoms. The mind is incredibly powerful over the body! Ample research shows us that the suggestive powers of just thinking you’re taking something that might help you get better and can actually reduce symptoms. Secondly, people who are frequently seen and looked after by doctors, nurses, social workers, and therapists, like participants of a clinical trial, often have improved symptoms, regardless of what drugs they are receiving. The people in this trial could be going to the clinic more frequently than those in the Enroll-HD comparator group, causing a medical response bias that improves their symptoms. 

However, while comparator groups are a less rigorous way to test a drug, they’re often considered a more ethical way to test a gene therapy drug in early stages. As drugs advance through the regulatory process and reach later clinical phases, double-blinded, placebo-controlled trials could be required. So for a Phase 1/2 trial like this one for AMT-130, a natural history comparator can give us an idea if a drug is meeting certain metrics, but isn’t robust enough to conclusively tell us if a gene therapy is effective. 

Other considerations 

There are also a variety of other considerations that researchers are pondering, but don’t yet have the data to support or produce conclusive results around. 

Are there people who will respond well to this treatment while others won’t? Given the small number of people in this trial, it’s possible they could be “super responders” – people who respond particularly well to a specific treatment. If so, what might be the delineating factors that define these subgroups? Is it developmental brain stage, disease stage, age, etc? We’ve not seen data from individuals treated with AMT-130 yet, only the group averaged together. Once we have this data, we could get some clarity around these questions.

Even with the permanence of this treatment, how durable will it be? Will it wear off over time? Might additional treatments be needed in the future? If so, how far out and at what dose? This is complicated because we don’t have satisfactory tools or surrogates to accurately measure HTT lowering, particularly in brain tissue. 

We’ve not yet seen all the data collected from this trial and it’s not yet been peer-reviewed or published. How will these data measure up when examined by other researchers? 

With any gene therapy, accessibility will be an issue. Would this treatment be covered by insurance companies? If not, how will HD families afford such treatments that can run into the millions of dollars?

In all, there are still many outstanding questions to consider for which we just don’t yet have answers. 

Treatment-associated risks

Even if all the other considerations prove favorable, there are still two large potential treatment-associated risks that should be considered around AMT-130. This is a permanent gene therapy that is delivered via brain surgery. 

Firstly, while there are very skilled brain surgeons carrying out these surgeries, brain surgery is never without risk. This is a highly invasive procedure. We understand that the risks around brain surgery are something that many in the HD community are willing to tolerate for a potential treatment against this disease, however it still must be stated that brain surgery always comes with a risk. 

Secondly, this is a permanent treatment. Once AMT-130 is delivered to the brain, there is no going back, good or bad. While a one time treatment could be viewed as desirable by many within the HD community, this type of non-reversible change for an unproven treatment also carries risks that must be acknowledged. 

It is for these reasons that gene therapy trials, like uniQure’s AMT-130, are rolled out slowly and carefully in a very small number of people in a staggered way. Initially, the surgery was given to only 1 person, who was followed for several months before a second person was inducted into the trial. This specific trial design was devised to mitigate safety risks around brain surgery and permanence of this treatment approach. 

So far, the data suggests there is a slowing of disease in people on the high dose of AMT-130, but the disease in those people is still progressing.

Reaction From The Community 

With the exciting results from this trial and the abundance of hyped up headlines, the HD community has understandably had a lot of questions. We’d like to address some of the more frequently asked questions we’ve heard.

Does this mean there’s finally a cure for HD?

No. But this is an important step forward. 

A “cure” implies that someone who had signs and symptoms of HD no longer does. That would require reversal of disease worsening, which is not what we’ve seen. So far, the data suggests there is a slowing of disease in people on the high dose of AMT-130, but the disease in those people is still progressing.

So, has HD been successfully treated for the first time?

We don’t know yet. But this is some of the most encouraging data we’ve seen from a clinical trial thus far. While we need data from a larger group of people to have conclusive evidence that a drug has treated HD, the recent data from uniQure is the first to show that any drug is slowing disease progression, which is incredibly encouraging.

Where can I get access to AMT-130?

AMT-130 is not yet an approved treatment, so it’s not readily available at trial sites for the general public, hospitals, or doctors offices. 

AMT-130 is still being actively tested in clinical trials. If you are interested in participating in a trial for AMT-130, you can check if the trial is enrolling at a site near you using HDSA’s HD Trial Finder and speak to your neurologist and medical care team.  

When will AMT-130 be approved?

uniQure has stated that they plan to speak to the FDA about accelerated approval for AMT-130 in early 2026. While uniQure and the FDA have had alignment on moving AMT-130 forward thus far, the path forward is not guaranteed. The FDA will determine if the data are strong enough for accelerated approval.

If the data continue to look promising and the FDA grants accelerated approval, AMT-130 could potentially be approved by the end of 2026. However it would still take time to roll this out to the general public. Additionally, if more data are required prior to approval, this timeline could be extended. 

How much will AMT-130 cost?

uniQure has not yet released the price point for AMT-130, but has stated that it will be in line with other gene therapies. Given the nature of gene therapies, they are incredibly expensive, ranging from about $2 to $4.25 million dollars for the drug alone. Depending on your country’s healthcare system, there could also be additional medical care costs to consider associated with hospital stays, anaesthesia, and brain surgery. 

It is not yet clear what costs may be covered by different national healthcare providers, insurance companies, or other health programs around the world. However, uniQure has stated that they plan to discuss the value of the drug with the different agencies who may cover costs, which could improve access if AMT-130 is approved by regulators. 

Who will be eligible to receive AMT-130 if approved?

Currently, AMT-130 is being tested in people with fairly early symptoms of HD. If the drug is approved by regulatory agencies, people who have a similar disease stage to those tested in the trial would likely be eligible initially. The goal for any drug that could successfully treat one subset of people with HD would be to broaden who may successfully be eligible, so uniQure is very likely to do subsequent studies to test the limits on who AMT-130 may successfully treat – moving both earlier and later in disease stage. 

What if I’m not eligible for AMT-130?

While we understand that not being eligible for AMT-130 could elicit strong emotions for many, there are many other treatments being developed and tested right now in a whole suite of clinical trials. The goal of every researcher working on HD is to bring a treatment for this disease forward to help as many people as possible. 

If I’m at risk, should I get tested for HD?

Getting tested for HD is a deeply personal decision. If the recent news from uniQure has made you wonder if you should get tested, we encourage you to reach out to a genetic counsellor who can help you weigh your options, as there are emotional, legal, and financial implications to consider. 

If you are based in the US, there are also considerations around eligibility for various types of insurance, including life, disability, and long-term care. 

If you are considering getting tested, you can reach out to HD Genetics, a company specializing in genetic testing for individuals at risk for Huntington’s disease, to learn more.

What can I do right now?

If the recent news from uniQure has compelled you to get involved in HD research, a great starting point can be to participate in Enroll-HD. It’s the largest observational trial (meaning no drug is given) that follows people with and without HD to collect data as they naturally live and age. 

Researchers from around the globe use the Enroll-HD database to ask and answer various questions that are consistently teaching us more about HD. Your involvement in Enroll, and any trial, helps researchers understand HD better to improve clinical trial design and advance us toward disease modifying treatments more quickly. 

Getting tested for HD is a deeply personal decision. If the recent news from uniQure has made you wonder if you should get tested, we encourage you to reach out to a genetic counsellor who can help you weigh your options, as there are emotional, legal, and financial implications to consider. 

Science Advances In Steps, Not Leaps

We know that science is incremental and often moves more slowly than anyone hopes. But it does advance. And we’ve met many milestones that have gotten us to this point. One of those is undoubtedly the September data update from uniQure about AMT-130. 

However, while we celebrate this progress, let’s do so under a realistic lens – we don’t have a treatment in hand, yet. We have to continue reading popular press articles with a critical eye, being wary of headlines that promise we’ve crossed the finish line. Getting updates about HD research from reputable sources is more important now than ever before as we near disease modifying drugs. Communicating clearly to the HD community about what results show, what it means, and what we still need to learn is critical as we move forward.

With that in mind though, please remember that HD research is moving faster than ever. Each step we’ve taken – from the description of the disease in 1872, to the discovery of the gene in 1993, to now having evidence of what we need to do to slow HD in 2025 – is taking us to the top of the mountain. It hasn’t been great leaps that have gotten us here, but rather steady progress toward a goal and a commitment from the entire HD community. With that momentum behind us, we’re nearing the final stretch. It will still take time, teamwork, and persistence, but the path is clearer than it’s ever been, and every step forward brings us one step closer to treatments that change lives.

Summary

• uniQure announced encouraging results from its Phase 1/2 trial of AMT-130, a gene therapy designed to lower huntingtin in people with HD.
• High-dose participants followed for 3 years showed a ~75% slowing in disease progression on the cUHDRS, meeting the trial’s primary endpoint.
• This marks the first time any therapy has shown the potential to alter HD progression in people, a historic milestone for the field.
• However, the study is small (29 participants, 12 in the 3-year high-dose group), and results have not yet been peer-reviewed or published.
• Some media headlines overstated the findings, with claims of a “cure” or “successful treatment.” The data show slowing of symptoms, not reversal or elimination of disease.
• The trial used a comparator group from Enroll-HD instead of a full placebo control after year one, so results should be interpreted cautiously.
• AMT-130 delivery requires brain surgery and involves permanent changes, which carry inherent risks.
• Key questions remain: durability of benefit, variability of response, affordability, and future accessibility.
• uniQure plans to seek accelerated FDA approval in 2026, but this would still require confirmatory studies and regulatory review.
• AMT-130 is not yet approved or available outside clinical trials. Interested participants should discuss enrollment options with their neurologist or consult the HDSA trial finder.
• Progress is real but incremental. This isn’t a leap forward to a cure, but a meaningful step forward on the long road to disease-modifying treatments.

Huntington’s disease (HD) is caused by repeating C-A-G letters of genetic code that are too long. Everyone who develops HD is born with 36 or more CAG repeats, but not everyone with 36 or more CAG repeats is actually diagnosed with HD. That’s because either they are not old enough yet to have symptoms, or because they have symptoms but have not been given a correct diagnosis by a doctor. Because of this, mathematical models of how many people have HD don’t match up with how many people have been predictively tested or diagnosed in the clinic. Researchers have attempted a new way of calculating how many people have HD but are not diagnosed.

Three repeating letters – and 36 or more cause HD

The repeating C-A-G letters in the huntingtin gene that cause HD are like three letters repeated on a specific page of a book. People who develop HD are born with 36 or more CAG repeats, one after the other, like this: …CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG …  (That’s 40 CAGs by the way.)

The genetic cause of HD means that everyone who develops the disease has an identical and easily identified region in their genetic code that can be used for diagnostic or predictive testing. When a doctor suspects someone has HD, based on their symptoms, they will order a test that counts the number of CAG repeats a person has. If that test comes back with 36 or more CAG repeats in the huntingtin gene, then that person is formally diagnosed with HD. Counting up all these people with formal diagnosis of HD is how we measure the prevalence of HD.

However, not everyone who has 36 or more repeats is diagnosed with HD. For one thing, someone might decide to get the test predictively, because they may have inherited 36 or more repeats, but are not old enough yet to have symptoms of HD. Someone like this who receives a test result with 36 or more CAG repeats, but does not yet have symptoms of HD, is usually called gene-positive. They are not counted in prevalence, because they don’t yet have symptoms of HD.

But there are also people who have 36 or more CAG repeats and symptoms of HD who have not been tested. This could be because they don’t have adequate access to health care, because of the negative social stigma of HD, or because of insurance concerns. Or, perhaps they’ve never even suspected they may have HD. This could be because they either don’t know about their family history of HD or they are the first person in their family to develop the disease. This begs the question, how many people with 36 or more CAG repeats have symptoms of HD but don’t get counted in the prevalence data for HD?

Finding everyone with 36 or more CAG repeats – how big is the iceberg?

Figuring out how many people have 36 or more CAG repeats, but never show up to a doctor, is a bit like an iceberg. There’s a visible part above water and an unknown part hidden out of view. The visible part of the iceberg is like the people who get a positive test for 36 or more CAG repeats – we can see and count them.

The size of the iceberg below the water is the many people who have 36 or more CAG repeats but are never tested. Most of these people in the hidden part of the iceberg are too young to have symptoms of HD, even though they have 36 or more CAG repeats. But at least some of the hidden part of the iceberg are people with symptoms of HD who are never tested or diagnosed.

HD researchers have tried to figure out how many people have 36 or more CAG repeats, but are never tested, and they are getting close to an answer. Some scientists have anonymously tested thousands of people from the general public to determine how many have 36 or more CAG repeats within their huntingtin gene. Researchers with newer technology and bigger pools of DNA have further refined these numbers. The consensus is that about 1 in 400 people has 36 or more CAG repeats in Europe and North America, where HD is most common. 

The size of the iceberg below the water is the many people who have 36 or more CAG repeats but are never tested.

How many people have HD but are never tested?

Ok, so 1 in 400 people has 36 or more CAG repeats. But remember, some of these are people who are too young to develop symptoms of HD. How many people with 36 or more CAG repeats actually have symptoms of HD, but haven’t been tested or diagnosed? 

This question has been surprisingly hard to answer, because we don’t know how many people in that underwater part of the iceberg actually have symptoms of HD. We can only count people with symptoms of HD in the visible part of the iceberg, who get tested and diagnosed in a doctor’s office. 

Some researchers think a large portion of people in the hidden part of the iceberg don’t have HD and will never get HD. A tantalizing thought for HD families! But why do they think this? Because 1 in 400 is already a lot more people than ever get diagnostically tested. 

The prevalence of HD – meaning people with HD in the visible part of the iceberg – is about 1 in 8000. This is how many people actually get diagnosed with HD by a doctor, which is  way less (about one-tenth!) than the number of all people who have 36 or more CAG (1 in 400). Even after accounting for people who are gene-positive and too young to have symptoms, that would leave a huge number of unknown cases of HD, which some researchers think doesn’t make sense. Other researchers think most people with 36 or more CAGs will eventually develop HD symptoms if they live long enough, but just aren’t getting tested and appropriately diagnosed. They may have symptoms that simply don’t get noticed as HD, especially if they are very old. This concept of people having symptoms of HD but not getting diagnosed is called underascertainment. Literally this means that some people with HD are undercounted from prevalence.

Using clever math to tackle the problem

A well-known research group at Massachusetts General Hospital has recently tackled this question, using a new mathematical approach to explore underascertainment. They started with the question above: how many people have HD but are not diagnosed?

To estimate how many people have 36 or more CAG and might have symptoms of HD, the researchers used an interesting feature of CAG repeats across people: there are fewer and fewer of each CAG as they get longer and longer. 17 is the most common number of CAG repeats in people, but there are fewer people with 18 CAG repeats, then still fewer with 19 CAG repeats, and fewer and fewer all the way up to 36 CAG repeats. 

This is part of why HD is a relatively rare disease: because repeats of 36 or more CAG are actually pretty uncommon among people in general. Dr. Jong-Min Lee and his team used this observation to estimate how many CAG repeats with 36 or more should be found among millions of people.

More than expected – but still just an estimate

The researchers estimated that about 1 in 325 people have 36 or more CAG repeats. That’s a bit more than reported in the anonymized studies mentioned earlier. But it’s important to note this is a simulated number, and not directly tested from people, so we don’t know if it’s any more accurate than 1 in 400.

The researchers then did some further calculations to simulate ages of people, estimate how many people should have developed symptoms of HD, and also estimate how many would have died of HD or other causes. This complex math is needed given that people develop HD at different ages and also pass away at different ages. They applied these calculations to the total number of people with 36 or more CAG repeats and – Voila! This calculation yielded an estimate of the number of people with 36 or more CAG  who actually have symptoms of HD. Finally, the researchers then compared this estimate of how many people have HD to the published prevalence of HD, or how many people have been formally counted from a clinical diagnosis. Surprisingly, they estimate that only about 50% of people with symptoms of HD might be counted in prevalence.

Why might half of people estimated to have HD not be diagnosed and appropriately counted? There are many potential explanations.

What about the rest?

Why might half of people estimated to have HD not be diagnosed and appropriately counted? There are many potential explanations. One explanation is that some people have symptoms but don’t recognize them, or don’t seek to be tested. Another is that some people have subtle symptoms later in life that are just mistaken for old age. Or perhaps CAG repeats between 36 and 39 – repeats found in a grey zone known as reduced penetrance – don’t lead to symptoms of HD as often as we thought. CAG repeats between 36 and 39 are found in the general public, but aren’t that common in people diagnosed with HD. We still don’t know how often these CAG repeats between 36 and 39 might lead to symptoms of HD.

But you can be sure that researchers like these are hard at work to figure out how many people have HD and how to find them. Having a better understanding of how many people there are that have the gene for HD, but who don’t develop symptoms of the disease, or only do so very late in their lives, could help scientists prolong the healthspan and/or lifespan of people with HD and help develop future treatments. 

Summary

• HD is caused by 36+ CAG repeats in the huntingtin gene, but not everyone with this expansion is diagnosed.
• Prevalence estimates don’t match reality because many people with the gene aren’t tested or diagnosed.
• Population studies suggest ~1 in 400 (and possibly as high as 1 in 325) people in Europe/North America carry 36+ repeats — far more than the ~1 in 8,000 clinically diagnosed.
• This mismatch raises two possibilities: either many carriers never develop HD, or many people with symptoms remain undiagnosed (underascertainment).
• A new mathematical model suggests only ~50% of people with HD symptoms are formally diagnosed.
• Reasons for undercounting may include lack of testing, subtle late-onset symptoms, misdiagnosis, or reduced penetrance at 36–39 repeats.
• Understanding the full “iceberg” of HD prevalence is critical for preparing treatments and supporting families.

Learn More

Original research article, “Significant underascertainment in Huntington’s disease” (open access).

Welcome back for the final day of the Huntington’s Disease (HD) Clinical Research Congress in Nashville, Tennessee!

Translational issues in HD

The first session will focussed on translational issues in HD – how we get research to people that need it most, HD families. Dr. Sarah Tabrizi from UCL opened with an introduction discussing translational issues in HD. Translational science bridges lab discoveries from the bench to clinic, with the aim that research findings impact patient lives sooner. She started by highlighting some of the challenges in translating research to the clinic. Things like finding good biomarkers, creating scales to rate disease stages, applying imaging technology, responsibly testing new treatments, and developing different models to test potential drugs. 

We’ve heard about the HD-ISS (integrated staging system) from several people so far at this meeting. Sarah shared that a large collaborative team is working on a 2nd iteration of this scaling system to better capture how HD progresses. A scaling system that accurately captures the progression of HD will help with participant selection for clinical trials, allowing researchers to better understand which groups of people may most benefit from potential treatments. 

Sarah pointed out several biomarkers that people are advancing to track HD progression: NfL, expanded HTT from the CSF, and lesser known biomarkers like proenkephalin. She also gave a high level view of another topic we’ll dive into in this session – moving potential treatments from “mice to men.” Making sure drugs work once they move out of animal models of HD is critical for developing treatments. 

Up next was Dr. Sam Frank, a clinician from Harvard. His talk will detail how the HD-ISS – developed solely for research – might someday guide patient care, from early detection to clinical decisions. The question of how the HD-ISS should be used comes up a lot for families and clinicians. 

Sam spoke about how patients often ask him what stage they are, with the hope that this information could help to determine how to view their own HD. Should they get an MRI? Can they participate in research? How long might they have until they stop working, driving, walking, or need 24 hour care? These are challenging questions and Sam believes the ISS could help with answers. 

Sam highlighted the differences between staging systems and rating scales, and says he doesn’t feel we have enough clinical data yet to use the HD-ISS in clinic, still considering it a research tool. He points out that the patients he sees with HD are quite savvy and they’re tuned in to what the HD-ISS is. He underscores that the HD-ISS is intended for research – we’re getting there for clinical use, but we’re not quite there yet. 

Sam emphasized that the HD-ISS plays a role in inclusion criteria which in turn has implications for who will have access to a drug and how insurance companies could handle reimbursement. It also means companies can begin to target people at earlier disease stages with this granular understanding of HD. 

So, how does Sam address the question when his patients ask him what stage they are? He prefers to look at their total functional capacity (TFC) instead of the HD-ISS to help them understand their progression and trajectory. He also tries to understand why they want to know. Do they want to participate in research? Or are they going to scour the internet and fall into a rabbit hole of scientific literature?  

He cautioned providers in the room to be careful about their language in the clinic, to avoid making folks feel excluded when discussing clinical trials. This is particularly important for the HD-ISS because it is currently a research tool, not a clinical classification for HD. He then went through some of the limitations of the HD-ISS, one of which is that most people with HD are cared for by doctors who aren’t familiar with HD. Sam wrapped up by stating that the HD-ISS is a critical tool for research right now, but cautioned physicians who aren’t HD specialists against using it in the clinic. 

The next speaker was Dr. Joel Braunstein from C2N Diagnostics. Joel started by sharing some info about C2N Diagnostics. They are a clinical diagnostic lab, meaning they analyse biological samples, from companies trying to understand how their drugs may be working, and from patient biofluids. Early research that launched C2N involved injecting a tracer molecule into people to deeply examine newly created proteins from the fluid that bathes the brain (CSF). This allowed them to better understand the formation and the “lifespan” of disease proteins. 

Joel shared that economics are playing an increasing role in determining if technologies and treatments will advance, underscoring the need to have a reasonable price point and working with “payers,” i.e. insurance companies. He shared that a few weeks ago they filed with the FDA for their blood test to measure proteins that detect Alzheimer’s disease. They overcame “a number of firsts” to get there, a process which took 7 years. Being the first to market a new technology is exciting, but it requires breaking through many glass ceilings. This typically paves the path and makes it easier for others to follow suit.  

Joel discussed some parallels between AD and HD – it can take months to years for someone to get an accurate diagnosis. 85% of dementia diagnoses are made in primary care environments, rather than with a neurologist, and it can be hard to tease out the symptoms from the underlying biological changes. 

Clinical benefit is highest when diseases like AD are treated early and by specialists. That window closes when time to proper diagnosis is delayed, which can happen when people are initially seen and screened by primary care physicians rather than a neurologist. Having accurate and fast diagnostic testing can speed this process up drastically. The AD blood test developed by C2N Diagnostics is 90% sensitive and 90% accurate, meaning there is a low rate of false negatives and the test results are very likely to be correct. 

In the US there are about 7 million with dementia and another 13 million with mild cognitive impairment. If they can identify people with early pathological features of disease, early intervention steps can be taken to give the highest level of care. 

Next, Joel is dove into some of the specifics of the blood test, including that it assesses two biomarker proteins that suggest that someone is likely to have brain pathology features related to AD. C2N asked clinicians how this has impacted their diagnosis of AD, and it has come up from about 62-71% to 90% accuracy. Getting a diagnosis as fast as possible for people with early HD symptoms is important for getting them the best level of care. The AD field is now working on staging systems, similar to the oncology field, in the same way that the HD field is moving forward with the HD-ISS. 

Looking at what’s happening in other brain diseases can help us advance how we think about HD. While we have a blood test for the causative gene, one could envision a blood panel test to help us better understand staging, progression, and drug development for HD – a reason that accurate and reliable biomarkers are so critical. 

Our last speaker for this session was Dr. Dirk Keene from the University of Washington, presenting on neuropathology needs in HD. Research on human research is essential for understanding what drives neuronal loss in HD and how we might stop it. Dirk is a neuropathologist, so he is a super brain geek who examines how diseases affect the structure of human brains. He opens by showing the tremendous size difference between a human brain and mouse brain. While mice are critical for us to understand biological pathways and the mechanisms of drugs, to really understand any human disease, we need to look at human brains. 

About 10 years ago, an emergent technology allowed researchers like Dirk to study the genetic profiles within brains at the single cell level. This massive library of information allows researchers to build intricate maps of the human brain to understand how it’s built and how it works. To apply this technology to human brains, Dirk and his team had to rethink how they are collected and stored. If you’ve ever taken an anatomy class, you may remember the noxious smell of formaldehyde-preserved tissue, which isn’t compatible with these single cell techniques. 

So for the past 8 years, they’ve been “modernizing neuropathology” so that it’s compatible with new techniques like single cell analyses. This greatly expands what we can learn about the human brain. With this data, they’re building a “human brain cell atlas” that gives researchers a framework for studying the human brain during health and disease at the level of genes, proteins, and cells. 

Currently, Dirk’s team is applying this approach to Alzheimer’s disease. They are working to analyze brain pathology across the entire spectrum of the disease, from the very earliest changes to late stage. While Dirk and his team are specifically focused on AD right now, this type of deep analysis is something people are working toward applying to HD as well. 

Brain donations are truly the most generous gift an HD family can give to science. While it’s a deeply personal decision, if it’s something you’re interested in, you can learn more in our previous article on this topic. The Allen Institute for Brain Science, which has created the brain atlas for AD, will soon launch the Human Brain Accelerator Initiative which will help apply new technologies to the study of human brain tissue. This initiative for HD will be called HD-BRIDGE – Brain Resource Initiative for Discovery and Global Engagement. This will give every HD family the opportunity to donate their brain for this initiative at any brain bank. 

Dirk ended by thanking the brain donors and their families, saying that each donation is a true gift which he tries to honor by learning as much as possible about that brain so all scientists can advance disease knowledge. That’s a sentiment that we want to echo to all HD families who donate brains, tissue, and cells, and who participate in observational and clinical trials. The massive advancements that we’ve made, particularly this year, are because of you. Thank you! 

Science for Clinicians: Hot Topics That Are Important to Communicate in the Clinic

Dr. Davina Hensman-Moss from UCL was the first speaker in this session. She started by going over some basics of somatic instability that frequent HDBuzz readers will be familiar with – CAG repeats over 40 will cause disease, those between 27 and 35 are a gray area, and those below 27 aren’t associated with disease. HD is just one of many diseases caused by a repeated expansion of the genetic letter code. Together this family of diseases are mostly neurological and together affect about 1 in 3,000 people worldwide. 

While every cell in our bodies has the same genetic information overall, there are small differences, like the number of the CAG repeat size. In someone with HD their blood cell may have 42 repeats, but some cells in the brain may have many more. These numbers can change even more as people age. The biological phenomenon of increasing CAG repeat size in the HTT gene in people with HD is known as somatic instability. 

Davina shared a recent model in the field that HD pathology might be a 2 part process: somatic expansion in brain cells drives how quickly the disease begins, then HTT protein produced from the gene with the CAG expansion drives toxicity of the disease in those cells. CAG repeat expansion doesn’t happen in all affected cells at the same time, but in each cell on its own timeline. This means that impacted cells aren’t lost all at once, but rather there is a slow loss of each cell as it reaches the toxic threshold. 

There are also genetic variants that affect HD onset and progression that were discovered in a large genetic study called GeM-HD, where genetic information from over 16,000 people with HD was collected and analyzed. Interestingly, many of the genes that modify when HD signs and symptoms will appear are involved in DNA repair. This is the same process that controls somatic instability. That means the same genetic variants that can control onset of HD symptoms also control expansion of the CAG repeat, which seems to be a driver of toxicity and cell death. This suggests that if we can harness these modifiers, we may be able to control the onset of HD symptoms. 

When CAG repeat expansions occur, the DNA has to take on a loop structure. Understanding this structure and that of the proteins involved in the process of DNA repair and expansion may also lead to a therapeutic opportunity to control these expansions. With a list from the GeM-HD study of potential modifiers, researchers are tasked with deciding which would be best to target. 

DNA repair genes play many roles in health and disease, and in particular, fiddling with them could lead to cancer, so we have to be careful. Several of the genes identified as modifiers of HD can also contribute to a type of cancer called Lynch Syndrome, which causes many cancerous tumors to grow in people who have variations in some of the DNA repair genes. Nevertheless, scientists working on safely targeting HD genetic modifiers have shown encouraging results in mice when they lower the DNA repair genes MSH3 and PMS1. What we’ve learned from HD mice is that targeting these genes might help us control somatic instability, but there is a “sweet spot”, where we have to treat before the toxicity threshold is crossed. 

After we figure out what genes to target, Davina suggests the next big question is when we should treat. Dr. Sarah Tabrizi’s HD-YAS (Young Adult Study) has generated data about the early appearance of symptoms, giving researchers a timeline for when to treat prior to disease onset. Davina ended by thanking all the people who have participated in studies that have contributed to knowledge about genetic modifiers somatic instability. Without HD community partnership between researchers and families, we wouldn’t know about the findings Davina shared today.  

Next up was Dr. David Howland from CHDI. David starts with a “nomenclature check” to make sure everyone is on the same page as far as the different forms of the HTT protein. While we often talk about unexpanded and expanded HTT, there are different forms and fragments of expanded HTT that contribute to disease. One form is a fragment of expanded HTT called HTT1a. This is a toxic piece of the HTT protein created from the first little bit of the expanded HTT genetic code, which includes the expanded CAG region of the gene. 

This toxic HTT1a fragment is created through a biological process called “splicing” – you can think of this as similar to how movie reels can be cut and spliced together to alter scenes, ultimately piecing together the final product. When the cell does this, it splices the rest of the HTT product. Many different types of HTT fragments can be made from the same gene, and it’s not known which bits of the protein are actually driving toxicity within cells. 

The HTT1a fragment is highly prone to forming sticky protein clumps. Mice designed to produce only this fragment show signs and symptoms reminiscent of HD, suggesting that this fragment specifically can cause disease. David believes that the HTT1a fragment itself acts as a driver of HD pathology. Current data seems to suggest that HTT1a is a key to toxicity. But there are still questions around how much of it is needed to cause disease, and limitations to how we can measure HTT1a. 

Because it’s part of a larger protein, specific tools are needed to measure levels of HTT1a. David and the team at CHDI have developed a protein visualization tool, called an antibody, that targets a region within HTT1a. This antibody is already helping researchers examine levels of HTT1a in tissue samples of people who have HD. So far they’ve found that it shows up in protein clumps, and seems to be more rare in people with HD compared to mice that model the disease. 

This type of data will help answer questions around the contribution that HTT1a has to HD pathology. While researchers still can’t measure levels of the HTT1a fragment in people while they’re alive, this is something they’re working toward. Researchers are asking (so far just in mice) whether lowering levels of the HTT1a fragment can provide a therapeutic benefit. In mice with long CAG repeats who can’t produce HTT1a, there are fewer protein clumps, lower NfL, and more regulated cell signaling. 

Some of the caveats around this work involve the fact that the mice we use to model HD have very high CAG repeat lengths, starting at 190 CAGs. This helps researchers to get answers faster, but may not accurately represent what we see in human disease. This is why it’s critical to work with tools that closely represent the human condition: cells from people, postmortem human tissue, and ultimately people living with HD. 

David ended by sharing his perspective that lowering HTT1a and full length expanded HTT are desirable paths toward treatment, but we still don’t have conclusive evidence. He hopes that the future of therapy could involve some combination of addressing mHTT and somatic instability. 

HD Insights of the Year: Emerging evidence for disproportionate benefit of HTT1a lowering

Kicking off the afternoon programming was Dr. Jeff Carroll, HDBuzz Editor Emeritus and HD researcher. Jeff has a personal and professional interest in HD; he comes from an HD family. His first publication came out in 2011, and today his lab does translational HD research. His original question was whether targeting just the expanded copy of HTT (“allele selective lowering”) was a better strategy than lowering all forms of huntingtin, both toxic and healthy. 

Jeff works with a type of HD mouse where he can study different CAG repeat lengths by inserting a part of the human genetic code. He reminds us that mice with long repeats are a great tool to understand relationships between biology and symptoms, which is much harder to do in people. His lab worked with Wave Life Sciences to develop a genetic tool, called an ASO (antisense oilgonucleotide), that targets all forms of HTT (known as a panASO) or expanded HTT alone (mHTT). Treating HD mice with the latter eliminates clumps of HTT that are normally seen in these models. 

Jeff detailed work from Gill Bates’s team that we heard about in the last session, showing that splicing creates a toxic Htt1a fragment, and also reminds us of work from Steve McCarroll’s lab showing that there’s a proposed threshold of CAG repeats (150) that becomes toxic. Treating with the ASO that specifically targets expanded HTT eliminated the toxic Htt1a fragment and reversed a lot of genetic changes that occur in these mice, whereas the panASO didn’t have these beneficial effects. Jeff summarizes his work on ASOs by reminding us that the way that HTT-lowering is approached can make a big difference in terms of effectiveness (at least in mice). 

Jeff believes that it will be important to consider how and whether different HTT lowering strategies target HTT in different ways. For example, whether they target the beginning of the gene where the CAG repeats occur and/or the supportive genetic code around it. This could have implications for current ongoing clinical trials, which Jeff separates into two groups based on how they target the HD gene. 

Young People and Huntington’s Disease

Dr. Erin Furr Stimming from UTHealth Houston Neurosciences introduced the next session focused on young people and HD. This was a vital discussion on youth, development, and inclusion. 

Dr. Bruce Compas, a psychologist from Vanderbilt University, was up first. He began by noting that we are shifting from talking about genetics and biology to symptoms and behaviour. His work focuses on several questions about how expanded HTT affects the developing brain, and he’s highlighting cognitive symptoms as one example. 

There are different schools of thought around how thinking symptoms emerged in HD research. One theory says that cognitive issues emerge alongside movement symptoms. Another holds that CAG repeats actually confer an initial benefit for cognitive function in early life before a decline in HD. Yet a third theory says that impairments in thinking emerge early, with some apparent during adolescence. Bruce is showing evidence from different areas of HD research for each of these ideas. They all have different types of tests and approaches. 

When theories conflict so strongly, it’s important to gain an understanding of the underlying causes. Bruce is interested in the effects of expanded HTT on the developing brain, guided by what we know about brain development in the presence and absence of the HD gene expansion. He reviewed what we know about the developmental ages at which different brain regions, features, and networks mature to drive different functions, some of which don’t come online until after the age of 25.  

“Executive function” describes how people attend to information, problem solve, and stay on task. Bruce’s team studies different aspects of executive function and how it becomes impaired in HD. One project studies how CAG repeat length influences the progression of cognitive function. Another looks at how stress and inflammation influences cognitive abilities. A third will look at how social connectedness influences cognitive function. All of these projects involve assessing people with HD using different tests of thinking and problem solving, from working memory to symbol matching, among others. He and others have found a strong relationship between thinking abilities and coping abilities. 

One practical takeaway is that brain development happens on unique trajectories, but social support and treatment of individual symptoms can have a profound effect on a person’s ability to reason and consequently to cope with HD-related changes, especially for youth from HD families.

Next, we heard from Cristina Sampaio from CHDI who gave an overview of the inclusion and exclusion criteria in HD clinical trials, and how best to strive for balance and fairness. Inclusive trials ensure therapies reflect the diversity of the HD community and move faster to approval. 

Because HD is typically an adult onset disease, inclusion criteria focus on adults. Once a drug is successful, inclusion criteria are usually expanded after that to include more sensitive or resource intensive populations, including younger people and pediatric patients. Cristina explained the difference between cases that are considered juvenile, adult, or late onset HD. People who experience symptoms younger than 20 are considered to have juvenile HD, while those who develop symptoms over the age of 60 are considered to have late onset HD. 

Until recently, most HD clinical trials set inclusion criteria at age 18. This is because they were less complex, typically aimed at improving specific symptoms, like chorea. Because of that, the rate of progression was less relevant, so the lower limit was set to the legal age of consent. More recently, trials are aiming at disease modification and have updated the lower age limit to 25. This is because the rate of disease progression is highly relevant in this context. Because people with adult onset versus juvenile HD progress differently, these limits help to strengthen trial endpoints. 

Cristina made the point that there are many other inclusion criteria for clinical trials aside from age, such as disease stage. She also underscores that if there is a specific biological mechanism at play only in youth with juvenile onset, inclusion criteria would reflect the question the trial is trying to test. She reiterated that the minimum age is typically set to 25 years to exclude juvenile onset HD cases, because these early trials of disease-modifying genetic therapies are designed to test questions around the adult onset version of HD as safely and efficiently as possible. 

She’s also highlighted regulatory differences between the US, where the FDA approves drugs, and Europe, where the EMA approves drugs. The EMA requires a pediatric protocol for any trials that will include younger people, where the US FDA does not. So there are various practical, ethical, regulatory, and biological factors that guide how inclusion and exclusion criteria for clinical trials are selected. 

Ultimately the intent of clinical trials is to effectively and efficiently test if a drug will work in a population of people. Starting with a more uniform group of participants will speed answers around whether that drug will work. Any drug found to be effective in one group of people with HD can then be tested more broadly to see if it works in larger groups of affected individuals, including younger people, those with juvenile HD, and people who have progressed to later stages of the disease. 

The next speaker was Dr. Martha Nance from the Hennepin HealthCare HD Clinic in Minnesota. Her talk will reflect on treating people with juvenile HD, what care looks like today, and where science can help tomorrow. She reminded us that HD is a family disease, and turns to the story of researcher and family member Dr. Nancy Wexler who initiated work in Venezuela that led to the discovery of the HD gene, and how so many researchers in this room were trained by those who led that project. 

Martha has spent her career in Minnesota, where she studied the inheritance of HD through generations of families, building family trees known as “pedigrees.” She has learned a huge amount about the meaning and structure of families, and how human complexity gets shrunk into a circle or square on a diagram. She stresses that all of the researchers and clinicians in this room are part of the HD family, because we are all in some way affected by HD, and reminds us that it’s our responsibility to be prolific in passing knowledge down to our “professional progeny!” 

In the absence of a treatment, Martha emphasized that any HD professional or member of an HD clinical team has an opportunity to give their trainees firm ground to stand on and to make a difference in the lives of families. 

Next, Martha moved some of the work she’s done in kids with HD. She notes that there was evidence of somatic instability in very young patients with juvenile onset HD (JoHD), long before it became a therapeutic target. She believes that the field has not paid enough attention to JoHD in humans. 

Martha also reminded us that there is power in partnership among clinical researchers, who can pool their human data and their experience to better understand diverse aspects of HD and what is most common and meaningful to families. She highlighted that clinicians should talk to the parents about symptoms their kids are experiencing, not just assume they know what symptoms they may have because of what they’ve read in a book. 

Martha shared with the clinicians some of the practical things she has learned over the years: Do not say no to seeing kids with HD just because you may be an “adult neurologist”. Access schools and community resources. Expand your practice beyond medications. She emphasized how important it is to support and learn from parents, who have vast experience with JoHD and their child. And to celebrate day to day and help patients to have fun despite the tremendous challenges their families are facing. 

Martha highlighted Dr. Ignacio Muñoz-Sanjuán who heads up Factor-H and journalist/advocate Charles Sabine OBE, who organized a meeting of Venezuelan HD community members with the pope in 2017 – check out the 2020 documentary about it, “Dancing At the Vatican”. She’s also using her platform to highlight that kids with JoHD can have a profound impact, from advocacy to research. In an emotional ending, she encouraged us all to learn from the youth and professional progeny we claim to serve!

Abstract Poster Sessions

In the final session of the conference we heard short talks that were selected from the poster submissions. 

Dr. Blair Leavitt from Incisive Genetics presented on the company’s HTT lowering gene therapy, which is allele-selective meaning it only targets the expanded HTT gene. Their technology uses CRISPR to make cuts that lead to lower levels of HTT. Blair reminds us that CRISPR is a tool involving a CAS9 enzyme, think of this like the molecular scissors that can cut DNA, alongside a guide RNA that targets the gene of interest (in this case, HTT). 

Gene editing was first accomplished in sickle cell anemia, and Incisive is working with similar tools. Incisive’s IG-HD01 leverages CRISPR technology as well as lipid nanoparticles (LNPs) which uses the body’s cholesterol system for delivery. You can think of LNPs as micro Trojan horses – they contain the therapeutic drugs against HD and the LNP gets them to where we want them to be. 

Incisive has done a variety of experiments to show that their methods lead to efficient delivery of gene editing technology, in cells as well as in different tissues in animal models. Blair is showing this with beautiful fluorescent images. They have also examined different aspects of safety and toxicity. 

Blair introduced Incisive’s therapeutic “pipeline” laying out methods, biological targets, and plans for trying to move their drugs into the clinic. He is focusing today on IG-HD01, their “lead candidate” (furthest developed drug) for HD. He believes that targeting the DNA, the source of the expanded HD-causing protein, should be the most efficient way to intervene in the toxic pathways leading to HD symptoms. 

IG-HD01 is an allele-selective gene editor, meaning that in each cell it reaches, it chops out a portion of the copy of huntingtin containing the CAG repeat expansion, while leaving the healthy copy intact. Of note, this means that Incisive’s technology targets DNA, not the mRNA copy message. Blair touched on some of the elements of research that are more often presented to investors – considerations around intellectual property and plans for manufacturing. These factors are important as young companies seek investments in early stage clinical studies! He also highlighted that they’re moving forward with development plans and hope to start a clinical trial in 2027. 

Next was Dr. Christopher Mezias from the Critical Path Institute, who discussed frameworks for regulatory science and biomarker validation. Standardizing biomarker assays and benchmarks is key to accelerating approval of HD therapies. The HD-RSC (Regulatory Science Consortium) is a partnership between the Critical Path Institute, an organization that brings people together in various disease spaces, and other organizations, like HD nonprofits, companies, and the FDA. 

Chris recapped the definition of a biomarker, something we can measure to track disease and determine how treatments are working, and reminds us that many approaches to tracking HD are necessary at different stages of the disease. There are different ways to get a new biomarker to be accepted by a regulatory agency like the FDA as an endpoint in a clinical trial. These are formal processes that have to be approached in collaboration with researchers, companies, and affected communities. 

Chris touched on the many categories of biomarkers and the complexity of how they are used to focus on disease progression, treatments, and response. CHDI and C-Path recently held a workshop to discuss how best to use imaging as a biomarker for HD progression. C-Path uses a framework to make decisions about what aspects of collaboration, data, and drug development to prioritize. It incorporates perspectives from many “stakeholders” including family members, patient facing orgs, regulators, scientists, clinicians, and companies. 

Chris highlighted the complexity of approaching regulators like the FDA with a new biomarker to use in clinical trials, which requires providing evidence on its usefulness, in what context it will be used, and what it adds to the field. One of C-Path’s goals is to make sure that measurements made across many locations using diverse technology (like different MRI machines) will be consistent enough across the board to use in a clinical trial. When there’s a lot of variation, that requires a closer look.  

The final talk of the conference was from Dr. Jang-Ho Cha of Latus Bio, who presented data on targeting MSH3 to prevent CAG repeat expansion, thought to be one of HD’s root causes. Latus was founded by Dr. Bev Davidson, a world leader in gene therapy and HD research. They work on one-and-done gene therapy treatments for serious brain diseases, and lots of their leadership have a background in the HD field. 

As a neurologist, Jang-Ho reminds the crowd that medicine in neurology is driven by 3 rules – “location, location, location”. In other words, for a gene therapy to work, it has to hit the right part of the brain and it has to be distributed in an efficient way. Latus targets the brain areas most affected by the diseases they study, which for HD is the deep brain structures known as the striatum. 

Latus has engineered specialized, harmless viruses (AAVs) to deliver genetic drugs to brain cells – they are specifically focused on ways to do this in the right location and at low doses. Historically it has been very difficult to get these viruses to areas deep inside the brain. Jang-Ho is showing fluorescent images demonstrating that their virus can enter and spread from the deep brain areas that drive changes in movement and motivation in HD, and outward to the areas involved in cognition and executive function. 

So they’ve got this very effective “envelope” that can be delivered to the right place, and inside it they put a piece of man-made genetic code that can target a DNA repair gene called MSH3. In people, tiny changes in MSH3 can dictate how early or late HD symptoms appear. In different models, knocking out MSH3 has slowed the expansion of CAG repeats and led to improvements in cell health and behavior. 

Latus has data to show that their MSH3-targeting virus can reduce the expansion of CAG repeats in HD mouse models – the higher the dose, the more it reduces somatic instability. 

Next steps for their company involve preparing to submit an IND (investigational new drug) application with the FDA, the first step that tells regulators about plans to move towards clinical trials in humans. 

Thanks for following along!

That’s all for us from the HD Clinical Research Congress! We hope you enjoyed the coverage and we’ll see you next year!