EHDN 2026 Part 1: What’s next in the Huntington’s disease treatment pipeline?

With more than 1,300 people from around the world gathering in Kraków, Poland, for the 2026 European Huntington’s Disease Network (EHDN) Clinical Research Congress, there was plenty to talk about! From clinical trials already testing potential treatments to discoveries that might shape medicines of the future, the meeting showcased just how much Huntington’s disease (HD) research is happening across the globe. HDBuzz’s Dr Rachel Harding was there to hear the latest science firsthand and report back on the exciting developments, important discussions, and unanswered questions shaping the future of HD research.

What’s next for HD research?

While drugs already in clinical trials often grab the headlines, there’s a huge amount of work happening behind the scenes to develop and hone the next generation of treatments. Scientists are uncovering new ways that HD damages cells, identifying potential drug targets, and developing clever tools to test whether their ideas might work.

Many of these approaches are still being tested in cells or animals, so they’re a long way from becoming treatments for people with HD. But they offer a glimpse of what might be coming next.

Stopping the CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD from growing

HD is caused by an expanded stretch of C-A-G DNA letters in the huntingtin gene. Scientists have known for decades that these repeats can continue to grow in certain cells throughout a person’s lifetime, a process called somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. What’s become much clearer in recent years is just how important this process may be in driving HD.

Large genetic studies, known as genome-wide association studies (GWAS), have identified differences in DNA repair genes that influence when HD symptoms begin and how the disease progresses. These discoveries have put somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. firmly in the spotlight as a promising target for new treatments that aim to stop the CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD getting longer. 

Scientists have identified several proteins involved in DNA repair that influence this process. Although DNA repair normally protects our genetic material, some of the machinery can inadvertently make the expanded CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD even longer. At EHDN, researchers shared progress towards turning these discoveries into potential treatments.

MSH3: A promising target takes shape

MSH3 is one of the DNA repair proteins attracting considerable attention. Reducing its activity could help slow CAG expansion, potentially delaying some of the damage caused by HD.

Caroline Benn from LoQus23 Therapeuticstherapeutics treatments presented work on LQT-23, an experimental small molecule designed to target MSH3. In HD mice, LQT-23 reduced somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. in a dose-dependent manner. In other words, increasing the drug dose led to greater reductions in repeat expansion. The team is preparing to move towards clinical testing, with hopes of beginning studies in healthy volunteers in 2027. One attractive feature of LQT-23 is that it is being developed as an oral tablet taken once daily – potentially much easier to take than treatments that need to be delivered directly into the brain or spinal fluid. 

Jang-Ho Cha presented data from another company called Latus Bio, highlighting a different strategy for targeting the same protein. Their experimental treatment, LTS-201, uses a modified virus to deliver genetic instructions that reduce the amount of MSH3 made in brain cells. The idea is to provide long-lasting lowering of MSH3 following a single treatment. In HD mice, the approach reduced CAG expansion, while studies in non-human primates showed that the treatment could reach deep brain structures.

These are encouraging steps, but neither approach has yet shown that it can slow HD in people. The next challenge will be establishing whether targeting somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. safely produces meaningful benefit in people with HD. Both companies hope to launch clinical trials next year. 

Finding more weak spots in DNA repair

MSH3 isn’t the only protein involved in this process. Tom Massey presented research on PMS1, another DNA repair protein linked to somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.. His team showed that reducing PMS1 activity can slow CAG expansion in laboratory models. Interestingly, PMS1 appears to accelerate expansion rather than being the main underlying cause of it. This could make it an attractive drug target, particularly if its activity can be reduced without disrupting other important jobs it does in the cell.

Meanwhile, Claire Pimblett presented work on FAN1, a DNA repair protein that can protect against CAG expansion. Her research explored how different parts of FAN1 influence this protective effect, including how it works together with other DNA repair proteins.

Together, these studies are helping scientists understand the complicated molecular machinery controlling CAG expansion. Rather than having one possible target, researchers are uncovering several different ways to intervene.

How do we know if we’re stopping somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain.?

There’s a catch with treatments designed to slow CAG expansion: how can we tell whether they’re working? Somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain. happens gradually, and measuring changes directly can be difficult. Waiting years to see whether CAG repeats grow more slowly isn’t particularly practical during early drug development.

Verónica Inés Brito presented an inventive approach that could help solve this problem. Instead of measuring the CAG expansion itself, her team developed a method to detect DNA repair activity happening at the expanded huntingtin gene. The idea is that cells carrying expanded repeats undergo more repair activity. By measuring that activity, researchers may be able to detect changes much sooner. The method distinguished cells with expanded CAG repeats from those without and responded to MSH3 inhibitors, suggesting it could be useful for testing potential treatments that target repeat expansion. Encouragingly, the team also detected relevant signals in blood cells from people with HD.

Another presentation came from Mustafa Mehkary, writer at HDBuzz and a PhD student in Christopher Pearson’s lab. He described a sensitive approach for measuring CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD expansion using DNA found in cerebrospinal fluidCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. (CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.), the liquid surrounding the brain and spinal cord. This method allows testing of lots of samples at the same time, and the repeats seen in CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. tracked with those in the brain – super cool!

These tools are still being developed, but they could eventually make it much easier to test whether new treatments are hitting their intended targets. And that’s a big deal. Better ways to measure biology can help researchers make decisions about which potential medicines deserve to move forward.

Is there more to huntingtin than meets the eye?

While DNA repair attracted plenty of attention, researchers are also finding new ways to tackle huntingtin itself. HD is caused by a change in the huntingtin gene that leads to production of a harmful form of the huntingtin proteinhuntingtin protein The protein produced by the HD gene.. But the biology isn’t quite as simple as one gene making one protein. Scientists have discovered that the expanded huntingtin gene can also produce a shorter message molecule which encodes a huntingtin proteinhuntingtin protein The protein produced by the HD gene. fragment called HTT1a. This may contribute to the toxic effects of HD. 

Aikaterini Papadopoulou presented research exploring whether specifically reducing HTT1a could improve disease-related changes. Using an experimental RNA-targeting treatment in HD mice, the researchers reduced HTT1a levels and observed fewer huntingtin proteinhuntingtin protein The protein produced by the HD gene. clumps, along with some improvements in gene activity. Interestingly, some effects appeared more pronounced than when full-length huntingtin was targeted in this mouse model.

These findings raise important questions about which forms of huntingtin future medicines should target. However, the results presented were from mouse experiments, and more work is needed to understand how they might apply to people.

Looking beyond huntingtin

Another emerging theme was the search for proteins that influence HD without being directly involved in CAG expansion.

Mahmoud Pouladi presented work on MED15, a protein involved in regulating which genes are switched on and off. MED15 was also identified in GWAS as a gene that influences the age when HD symptoms begin, just like MSH3. Reducing MED15 in HD mouse models improved some signs and symptoms of HD. Curiously, some measures of huntingtin proteinhuntingtin protein The protein produced by the HD gene. accumulation increased even as other disease-related features improved.

This is a useful reminder that HD biology rarely follows a simple script. A change that looks concerning under one microscope might accompany improvements elsewhere, and researchers need to understand the full picture. Nevertheless, the findings suggest MED15 could be another potential treatment target if results continue to be promising. 

Helping cells take out the rubbish

One of the conference’s keynote lectures came from Nobel Prize-winning scientist Aaron Ciechanover, who helped uncover how cells identify and destroy unwanted proteins. Cells have a sophisticated recycling system called the ubiquitin-proteasome system. Proteins destined for destruction are tagged with a small molecule called ubiquitin, signalling that they should be broken down.

This machinery has inspired new types of medicines, including PROTACs and molecular glues, which can encourage cells to dispose of particular proteins. For HD, the attraction is obvious: what if we could persuade cells to selectively destroy harmful huntingtin?

These approaches are still emerging for HD, and the keynote wasn’t a report of a new HD treatment. But it highlighted how fundamental discoveries about the way cells work can open entirely new avenues for drug development.

Many paths towards the same goal

The breadth of research presented at EHDN gives us plenty of reasons for cautious optimism. From slowing CAG expansion to tackling harmful huntingtin and finding new ways to protect brain cells, scientists are exploring more approaches to treating HD than ever before.

Not all of these ideas will make it into the clinic, and there’s still a lot of work ahead. But each discovery brings new insights, and the diversity of approaches is encouraging. There’s no silver bullet for HD yet, but with researchers around the world tackling the disease from so many different angles, the pipeline looks increasingly promising.

Summary

• Scientists at EHDN 2026 shared a diverse range of potential HD treatments still being developed in the lab.
• Targeting DNA repair proteins like MSH3 and PMS1 could help slow CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD expansion, a key process that is thought to drive HD.
• Other genes identified in large human genetics studies, like MED15, are being explored in more depth may also represent new drug targets.
• New approaches to targeting harmful huntingtin and harnessing the cell’s recycling machinery offer additional possibilities for treatment.
• Better tools to measure disease-related changes could speed up drug development, but more research is needed before these approaches reach the clinic.