HDBuzz

We’re back for Day 2 of Huntington’s Disease (HD) Clinical Research Congress in Nashville, Tennessee! Daniel Claassen from HSG and Cristina Sampaio from CHDI kick off the meeting with an overview of what we’ll hear about in HD clinical research and discovery. 

They are highlighting the search for biomarkers, the buzz over recent results from uniQure, as well as the collaboration between HSG and CHDI that launched this new Congress. 

Keynote: Progress in Clinical Developments

First up was a keynote from Dr. Merit Cudkowicz from Harvard/MGH addressing her work running “platform trials” in ALS, which compare multiple treatments to a common control group. Her talk focussed on what the HD field can learn from ALS researchers, and vice versa. 

The ALS community has many parallels to HD – research has progressed to a better understanding of the disease, with ongoing trials, an engaged community, and global trial networks. However, the ALS field has multiple disease modifying treatments, and 300+ companies in the space. ALS researchers are particularly committed to open collaboration, and Dr. Cudkowicz heads up NEALS (Northeast ALS Consortium), which holds trainings for clinical researchers and promotes big data projects. Many companies in the ALS space share their control data in a common database that can benefit future trials. 

She described another consortium, ALLALS, a multi-institutional effort to organize the ALS clinical research landscape, which advocates with regulatory agencies and organizes studies to understand the earliest stages of disease, track progression, and identify new biomarkers. Dr. Cudkowicz talked about the evolution of ALS research and the major clinical trials leading to successful drugs that can extend people’s lives. The accelerated approval of tofersen was based on changes in NfL levels, the same biomarker that is tracked in many HD trials. 

Many current efforts (at least 6 experimental medications) target a gene called SOD1, which produces a toxic protein that damages nerves in ALS. There are additional genetic approaches underway, targeting other genes known to play a role in ALS. Unlike Huntington’s disease, the majority of ALS cases don’t have a known genetic cause. A variety of companies are taking other approaches to ALS biology to try and target pathways affected over the course of the disease. 

NEALS collaborators came together to design a “platform trial” called HEALEY. This is an ongoing way to evaluate drugs for safety and efficacy, using a common control group, so that fewer participants in clinical trials are given a placebo. Dr. Cudkowcz noted that this required tremendous partnership among ALS community members, donors, pharmaceutical companies, researchers, and the FDA. The platform has already supported testing of 7 drugs, and 3 more trials will begin soon. 

The trial’s structure allows for a 3:1 ratio of drug to placebo, where study participants are randomly assigned to a specific drug, and all of the placebo data is combined across trials. After the study period, participants can enter an open label extension portion of the study, where everyone receives drug. These platform trials have many benefits – they can be completed faster, at a lower cost, and with fewer participants assigned to placebo. It’s also a unique way to understand aspects of ALS that are tested across all drug arms, from behaviors to biomarkers. 

Companies have to apply to enter their drug into this platform trial. The consortium chooses promising therapeutics with diverse mechanisms of action. Around 1400 ALS patients have participated so far. Importantly, the researchers frequently step back and evaluate how well this structure is working, so that they can learn from their efforts and adapt the protocol to strengthen the statistics, streamline operations, and center the participant experience. The placebo data is pooled into a big database, along with biosamples that are made available to academic researchers studying biomarkers and progression of ALS. 

The HEALEY trial has been ongoing for 5 years; the team has spoken to 114 companies about it, and about half have applied to participate. They also have weekly open Zoom calls, and many types of opportunities for academics and companies to get involved. 

A recent paper examines the financial landscape in ALS and a common Catch-22: it’s hard to get funding for a clinical trial without demonstrating robust human data. The platform trial model is just one way to tackle the problem of helping companies gain momentum with good data. The HEALEY platform is also helping to match individual participants to early phase trials based on the biology of the person and the mechanism of the drug. They’re also accelerating the screening process by partnering with a “rapid response” team called an ACE (accelerated center of enrollment). 

Dr. Cudkowcz wrapped up with big thanks to all of the stakeholders that make this collaboration possible, from the philanthropists, to the researchers, regulators, and trial participants. Working toward successful clinical trials takes a village. 

HD Clinical Trial Updates

The next session was all about HD clinical trial updates from different companies working in this space. We’ll be hearing from uniQure, Novartis, and Skyhawk – 3 companies with exciting updates over the past year. All of the updates come from companies who are developing huntingtin lowering therapies – different types of drugs which aim to reduce levels of the harmful huntingtin protein. 

uniQure

First up we heard from Dr. Victor Sung (UAB) who will cover the big news from uniQure about AMT-130, the gene therapy delivered by brain surgery that they are developing for HD. uniQure recently announced positive top-line results from its Phase I/II trial of AMT-130 which suggests this drug is able to slow down the progression of HD – you can read a detailed overview here. 

Victor started by reviewing the details of the trial – delivery in six locations via brain surgery, how a harmless virus helps AMT-130 enter brain cells, and the design of the trial, which involved a group that received “sham” surgeries and did not get the drug. Those who received the sham surgery made up the control group, and were only part of the trial for 1 year because some groups felt it was unethical to intentionally give placebo to some people knowing they would progressively have worsening HD symptoms.  

There are groups that received low and high doses of AMT-130. Instead of a traditional placebo group, the team used data from the Enroll-HD study from people observed in early stage HD. Enroll-HD is the largest observational study for people with HD, currently tracking over 22,000 people in 23 countries across 157 sites across the globe. It follows people with HD as they live and age so that researchers can learn more about the natural progression of the disease. These external comparisons use specialized statistical methods to remove bias and match people in and out of the clinical trial. It’s also important to note that all of uniQure’s analyses were pre-specified – decided upon before the drug was ever given. 

When trial results are presented the first thing that is always shown are the traits of the participants – things like their CAG lengths, health measures, and symptoms at the beginning of the study. On average the groups should “match” pretty well in these characteristics. Victor reiterated the main results of the trial – people who received a high dose of AMT-130 progressed slower on measures of function (Total Functional Capacity, or TFC) as well as individual and combined scores on tests of thinking and movement (cUHDRS). This was less robust for the low dose. 

NfL is a biomarker that tends to increase as HD progresses; those participants who got AMT-130 had lower levels of NfL three years after receiving the surgery – one indication that brain health might be moving in a healthier direction. Dr. Sung acknowledged the participants in this trial, who are continuing over the course of *years* to undergo lumbar punctures on a monthly basis to study safety and biomarkers of HD. There haven’t been any major safety issues reported since December of 2022. 

Although there are caveats, like a small number of participants in the high dose group, these are positive data. This is the first time any drug in more than 100 trials seems to have changed the course of HD. 

Novartis

Up next was Dr. Beth Borowsky from Novartis, sharing an update on their plan to move votoplam (formerly PTC-518) forward. This drug was originally developed by PTC Therapeutics. After successful clinical trial results, Novartis licensed the drug to advance it to a Phase 3 trial and, hopefully, regulatory approval, which Novartis will be responsible for. 

Beth shared updates from the Phase 2 PIVOT-HD clinical trial of votoplam, an oral huntingtin-lowering drug taken as a pill. This trial tested low and high doses of the drug, compared to a placebo group. The overall results showed that votoplam lowered huntingtin, and decreased NfL levels, suggesting the drug could be helping signs and symptoms of HD. 

The side effects, or “treatment emergent adverse events” (TEAEs), were pretty balanced across groups, but nothing notable came up – though, as expected, folks starting the study later in the course of HD seemed to have more falls during the course of the study. 

This study was not designed to look at votoplam’s effect on symptoms, but nevertheless there were positive trends in the cUHDRS (a score that takes many movement and thinking tests into account). Like uniQure, Novartis/PTC looked at Enroll-HD data as an external control, and saw similar trends. 

One observation they made when looking at MRI data is that there were changes in the volume of the brain’s ventricles (fluid-filled spaces) and tissue in the striatum, the area most affected by HD. This is hard to interpret but Novartis suggests that this could be because of a change in how CSF flows throughout the nervous system. 

Just a reminder that this data is not new, and that moving forward Novartis is planning a Phase 3 trial that will test votoplam in a larger group of people with early HD. If positive results hold, they hope the drug could help people across a range of HD stages. 

Roche

Now we heard from Peter McColgan from Roche about their HD drug candidate called tominersen. Tominersen is another type of huntingtin lowering drug, but this time given by spinal injection. We heard earlier this year about Roche’s plans with tominersen in the clinic, specifically their choice to only continue with the higher dose of the drug.

Dr. McColgan reviewed the history of tominersen’s development at Roche, from the GENERATION-HD1 study that came to an end, to the ongoing GENERATION HD2 study being conducted in people with early HD. GENERATION-HD2 recruited 301 people with early HD, who received either a low dose of tominersen, a high dose, or a placebo. In April 2025, an independent data monitoring committee (IDMC) recommended that the study move forward with just the high dose. 

Dr. McColgan then talked about other huntingtin-lowering approaches in development at Roche, RG6662, a gene therapy originally developed by Spark Therapeutics that is delivered via brain surgery, and an ASO that lowers only expanded huntingtin, delivered via spinal injection. 

Selective lowering of mutant huntingtin requires detection of a tiny genetic difference between the healthy and expanded copies of the gene, known as a SNP (“snip”). SNPs are single genetic letter changes within genes that help make us all unique, but can also be targeted for these types of approaches. Roche’s new ASO targets a particular SNP, and they are trying to understand how common it is in the general population. 

Dr. McColgan is also reviewing Roche’s larger efforts in data sharing and digital data collection, done in partnership with families, other companies, nonprofits, and government entities. 

Skyhawk 

Next was Dr. Meghan Miller from Skyhawk Therapeutics, who are developing a molecule called SKY-0515, an oral huntingtin lowering drug. In addition to huntingtin, SKY-0515 may also reduce levels of PMS-1, a genetic modifier of HD that plays a role in the expansion of CAG repeats (somatic instability). While this would be an amazing “two for one” type of approach, we’ve not seen this data thus far. The drug works by sticking an extra piece of genetic material into the genetic message that makes the huntingtin protein – the insertion makes the resulting letter code look like nonsense, so the cell won’t turn it into protein. 

The first clinical study of SKY-0515 explored three doses of the drug in healthy volunteers, people who did not have HD. This allowed Skyhawk to look at the safety of the drug and the biology of its interaction with the human body. They saw no serious side effects, and the drug circulated through the body and was found at higher levels when higher doses were given. This “pharmacokinetic” or PK data is important for showing how the drug works in people. SKY-0515 also lowered levels of (healthy) huntingtin, and lowering was stronger with more drug. This is known as pharmacodynamic or PD data, showing that the drug is hitting the right target and having the expected action. 

In a third, “Part C” of the Phase 1 study, SKY-0515 is being tested in HD patients, first for 3 months at 2 doses, then participants have the opportunity to enter an open label extension for a year where everyone gets the drug. They are looking at safety, PD/PK, and some tests of symptoms. Similar to healthy individuals, people with HD had higher concentrations of the drug in their blood and spinal fluid at higher doses, and lower levels of huntingtin when treated with SKY-0515, also depending on dose. 

Dr. Miller is showing a decrease in levels of PMS1 as well, especially in the high dose group. This is our first look at this data! While the high dose reduces HTT by 62%, it also reduces PMS-1 by 26%. However we still don’t know if this is significant enough to change somatic expansion. There also does not seem to be an increase in the level of NfL after treatment, like we’ve seen with some other HTT lowering drugs. This is a good sign for safety and brain health. 

Skyhawk began a larger, Phase2/3 study called FALCON-HD, at 10 sites across Australia and New Zealand, and they hope to recruit about 120 participants to continue testing SKY-0515 at different doses for up to 1 year. Plans are underway to expand into other countries.  

Progress in Biomarker Research

The next session focussed on biomarkers for HD. Measureable shifts in huntingtin levels, NfL, and imaging, among other measurements, allow us to track disease and see how well therapies might be working. Emilia Gatto from INEBA kicked us off with an introduction to the progress being made in this field and reminding us how biomarkers are reshaping HD research. 

The first talk in this session was from Hilary Wilkinson at CHDI who is diving into a new biomarker lots of researchers are trying to establish – how might we measure somatic instability, the changes in CAG number over time, and the challenges of tracking this possible driver of HD. Hilary began by sharing the historical timeline of biomarker development for a completely different area of health research – heart disease – and how measurement of cholesterol as a biomarker became a main indicator of heart health. 

Similarly, Hilary proposed that measurement of CAG repeat instability could be a good biomarker because it is central to how HD begins and progresses, and is linked to other measures of health in people with HD. CAG repeat instability is a complex target, because the number of CAGs may change in individual brain cells, but this is much more subtle in blood. CHDI is working on measuring CAG repeat length using different technologies that produce different types of data. 

There are several technological and biological considerations when trying to measure CAG repeat instability, such as the precision and integrity of the assay, the location of the cells, and the amount of tissue used, among many other factors. The ability to quantitatively measure somatic instability will be essential as more researchers begin to develop therapeutics to stop the expansion of CAG repeats. Hilary notes that the nature of the drugs and the instability rates in different tissues will ultimately drive the development of these technologies. 

Next up is David Hawellek from Roche who discussed the use of huntingtin and NfL as biomarkers to influence decision-making in clinical trials. The audience loved his visual to explain how he used to think about academia as a magical world, versus his stark idea of industry, and how that thinking has evolved to one of partnership through innovation and exploration….

He details the journey of how the HD field was able to develop ways to detect huntingtin protein in the spinal fluid, a convergence of many ideas and resources between academic and industry researchers over the course of a decade, to where we now have accurate tests to measure expanded huntingtin protein.  

Assays to detect mHTT are complex and a lot of factors can influence how much huntingtin is detected in spinal fluid, including the size of the protein piece and how much the protein sticks to itself. Dr. Hawellek talked about different quantitative ways to measure mHTT, like through RNA tests, as well as sequencing assays that help determine whether a person has a particular genetic letter difference (a SNP) that might make them eligible to try an experimental therapy. 

In 2026-2027, Roche will be rolling out an assay called Elecsys for the measurement of NfL, a collaboration with CHDI. The HARMONISE: HD-NfL study led by Dr. Lauren Byrne will look at data from many studies of NfL to create a robust dataset that will help shape NfL as a biomarker. He cautioned that NfL levels are heavily influenced by a variety of health factors which should be taken into account during clinical trials, and acknowledges all of the industry, academic, and family members of the HD community who contribute to research on biomarkers. 

Our penultimate speaker in this session was Killian Hett from Vanderbilt. Killian’s research explores brain imaging as well as biomarkers in the spinal fluid and what they might reveal about HD progression. Dr. Hett uses MRI data to create beautiful visual maps of CSF flow. The way that fluid moves around the nervous system can have a profound influence on drug delivery. It is influenced by both the cardiac (heart) and respiratory (breathing) systems. Dr. Hett completed a large study of 145 participants who had scans in a specialized 3 Tesla MRI machine. They are studying the role of the choroid plexus, which regulates the contents and the circulation of CSF. 

His team uses mathematical modeling methods to detect the choroid plexus and other brain areas in MRI images, reconstruct it visually, and then draw conclusions about how it changes during aging and disease. They are also able to measure how quickly the CSF flows around the brain and spine, its maximum speed and volume, and again how this changes with aging and disease. In HD, there is a decrease in the volume of fluid, but increased speed. These findings will be important to consider for any research team that is aiming to deliver a treatment for HD into the spinal fluid. 

To wrap up this session, we heard from Jamie Adams from the University of Rochester and her research into digital measures in HD, highlighting how these tools can support better trial design, monitoring, and care. 

Dr. Adams started with some art and some history, showing an early stethoscope, simply a rolled tube of paper used to amplify the sounds of the heart through the chest, and a painting of an early knee surgery, in which the doctors notably have poor lighting and no protective or sanitary equipment. She used this as an example of how we have evolved to incorporate new tools and technologies into medicine throughout history. Digital health measures are now allowing us to monitor people with HD continuously and with less bias, in their day to day life. 

Digital health technology (DHTs) is any system that uses computing platforms, connectivity, and software to record and transmit large amounts of data about a person’s health. Wearable DHTs like smartwatches have been used in HD to understand how much movement people with HD have at home, what stage of disease they are at, and other aspects of their movement and behavior outside of a doctor’s office. 

In the Parkinson’s field, and also in HD studies of drugs to treat chorea, DHTs have been used to show that a medication effectively treats a person’s movement symptoms. They’ve even revealed insights about sleep and people’s patterns of movements around their own homes. 

There are different approaches to gathering this type of digital data. Some of it can be supervised, with a person coming to clinic. Semi-supervised approaches use tasks on tablets or smartphones for frequent collection at home, and passive data collects information continuously, like a smartwatch worn by a participant. 

Jamie Adams and Lori Quinn (Columbia) are co-leading the MEND-HD study, which will validate at-home measurements of gait and chorea, daily physical activity, and sleep quality using wrist and back sensors worn by participants at home. It’s fully remote – no clinic visits are necessary at all! 

Dr. Adams is also working with a company called Biosensics to test a remote monitoring solution called HDWear+ to monitor other aspects of gait and chorea in HD. They are also working on measuring HD speech using audio devices. 

Through these studies they hope to provide a roadmap for how to use these types of devices as meaningful endpoints in future clinical trials, and how to reduce burden for participants with HD. 

Clinical Research Insights

The final session of today was clinical research insights which will dive into the challenges and opportunities in trial design, clinical measures, and the HD-ISS staging system. 

First up is Jeff Long from the University of Iowa. He has been investigating the relationship between antidopaminergic drug (ADMs) use and outcomes in HD. ADMs are a cornerstone of treating HD symptoms including unwanted movements, depression, and psychosis. They are critical for many people with HD who may be in danger of harming themselves or others. 

Jeff is a statistician and is digging into big datasets to understand whether ADMs cause faster change in clinical signs and symptoms of HD. For this question, he used the Enroll-HD database, looking at movement, thinking, and functioning metrics over 2 years. While this isn’t a drug trial, he can carefully select the data from people on and off ADMs, before and after they began taking these medications, to try to “simulate” a trial from human data after it has been collected. Then they use mathematical methods and AI to approach the statistics. 

After geeking out over the statistical methods he used, Jeff shared data suggesting that various thinking measurements worsen slightly when people take ADMs, but this doesn’t seem to be the case with movement-related symptoms. When he looked only at people taking antipsychotic medications, he saw similar results – people taking these drugs seemed to have worse cognitive symptoms, but overall movement symptoms don’t seem to be affected. Jeff also looked at different doses of these medications. Only people taking a high dose of ADMs had worsening of cognitive symptoms. 

He then showed data from a similar analysis he did using some of the data from Prilenia’s PROOF-HD trial, suggesting ADMs were associated with faster clinical change. This work was supported in part by Prilenia. There’s evidence that Prilenia’s drug pridopidine may have greater benefit in people who are not taking ADMs. It’s important to remember that ADMs remain a critical medication in our tool kit against HD, which Jeff himself notes.

Jeff makes a note of saying that he “can’t infer causation here” and we would really need a controlled clinical trial to understand if ADMs accelerate HD progression. So while there seems to be an association between ADM use and worsening of some HD symptoms, the results aren’t conclusive.  

During the Q&A, there was a comment around Jeff’s data suggesting ADMs increase disease severity – people who take these medications do so because they have cognitive issues, so it can be misleading to say that the medication could be causing cognitive issues. 

With a very tuned-in patient population, like we have in the HD community, the message that ADMs could make people worse can be particularly harmful.   

Our final talk for today is from Stan Lazic who is based at Prioris.ai. He has been investigating how some of the psychological symptoms of HD might contribute to HD-ISS staging, and what this means for research and care. HD-ISS stands for the Huntington’s disease integrated staging system – a unified way to track people in their journey with HD. 
To answer this question, Stan used data from the SHIELD-HD trial, originally started by Triplet Therapeutics and taken over by CHDI. While participation in these observational trials can be tedious for HD families, the data gets put to very good use by many researchers! 

Stan is also a statistician and went into detail about some of the specific patterns he pulled out from the data around the disease stages participants were in. He thinks these unique patterns may be related to symptoms of depression and anxiety. He also asked this same question for people who participated in the TRACK-HD and Enroll-HD studies, which increased the number of people he was able to analyze. 

Essentially participants in Enroll and other observational studies with a disorder related to anxiety and depression, and some other factors like arthritis and addiction, were more likely to “skip” an ISS stage of HD – in short, their disease course is less predictable. This information is important as existing scales evolve and improve, so that researchers can take into account many facets of HD to better define its progression. 

More updates to come

That concludes the talks for Day 2! Tonight we’ll be attending a poster session showcasing HD research from all over the globe. Join us tomorrow for Day 3, featuring translational science, hot topics, and issues relevant to HD youth.  

This month, HDBuzz is attending the first Huntington’s Disease (HD) Clinical Research Congress in Nashville, Tennessee. Gathered at this meeting are hundreds of scientists, doctors, and industry representatives who have come together to talk about HD clinical research and care. This conference has been organized by the Huntington Study Group (HSG) and CHDI Foundation, big players in the HD space in basic and clinical research.

Day 1 of this meeting is the HD Community Research Day, where speakers will be talking about topics relevant to families. Let’s get into it. 

Demystifying Clinical Trials Part 1: What Do I Need to Know?

The first session was an interview style panel intended to demystify clinical trials and explain elements of a study like protocols, endpoints, the experience of participation, and what questions to ask. Dr. Arik Johnson, Chief Mission Officer at HDSA, spoke with Dr. W. Alexander Dalrymple, a neurologist at UVA, Dr. Daniel Claassen, CEO of HSG, and Frances Saldana, an HD advocate and President Emeritus of HDCare. 

Dr. Claassen explained that the goal of a clinical trial is to test whether a new drug for HD actually works. Many people approach these studies wondering how they can access the therapy, but Dr. Claassen reminds us that a clinical trial is an experiment first and foremost. 

Dr. Dalrymple then defined what a clinical trial protocol is – essentially a detailed plan for how a trial will proceed. It contains the background on the science behind the drug (also called preclinical data), the types of tests that will be done to see whether symptoms worsen or stay the same, and the schedule of visits from screening through the end of the trial. Clinical trial protocols lay out a very detailed roadmap of everything that will happen in the trial, including a plan for timed “checkpoints” where the data will be examined to make sure testing remains safe to continue. 

Next, Dr. Claassen went on to explain clinical trial endpoints: measurements made to determine how HD is progressing. Examples are the kinds of tests you might have when you visit your HD provider, assessments of movement, mood, and thinking. Through an interactive Q&A, both participants and speakers have emphasized the importance of sharing with providers what HD symptoms are occurring, and which feel most important to capture. 

Dr. Claassen then spoke about a couple of different ways that clinical approval can be attained faster. For example, Orphan Drug Status from the FDA allows for a more streamlined process of regulatory review, when a drug is intended to treat a rare disorder, like HD. 

All of the panelists reiterated that a clinical trial is a major commitment, and having a good understanding of exactly what you’ll be going through is an important part of making choices about participation. 

Demystifying Clinical Research Part 2: The Clinical Research Process

Next, Lisa Hale, Director of Patient Engagement at Teva Pharmaceuticals, and UVA Neurologist Dr. Dalrymple shared more about possible partnerships between families and industry in the clinical research process. 

Lisa began by explaining the difference between an observational trial, one that simply gathers information by measuring aspects of HD, versus a clinical trial, which tests whether an intervention like a drug or device is safe and effective. She highlighted the importance of diversity in clinical research, and some of the reasons that people take part in research – hope, access, and the desire to make a difference. 

Following this, Lisa laid out the timeline for clinical research, from discovery and development in a lab, through preclinical research on animal models, to the three phases of human testing, followed by approval. All along the later stages there is input from regulatory agencies that ultimately are responsible for whether a drug is approved for use by patients or not. 

A Phase 1 trial is about safety, Phase 2 side effects and how the drug works inside the body, and Phase 3 is a larger study to look at effectiveness in a larger population. The lesser discussed Phase 4 trials can take place following the approval of a drug, to make sure that the drug remains safe and effective, when it is given in the real-world context of prescriptions in clinic. 

Lisa reminded the audience that the reality is that about 9 out of 10 medications being tested in clinical trials don’t get approved. About half don’t work as hoped, about 3 in 10 have unmanageable side effects, and about 1 in 10 are difficult to take to the finish line for other reasons, sometimes financial.  

Dr. Dalrymple talked about the importance of a “control group,” or “placebo group,” a set of participants who do not receive a drug, so that they can be compared to those who do. He explains that participants are usually assigned randomly to get the drug or not, even in a rare disease like HD. In some cases all participants may receive the experimental treatment, and a separate observational group (like Enroll-HD participants) is used as the control. 

9 out of 10 medications being tested in clinical trials don’t get approved

The speakers wrapped up with big thanks to all clinical trial participants for their bravery and selflessness – it’s a big decision, and a big commitment! 

Informed Consent: Beyond the Fine Print and Into the Experience

Next we heard from McKenzie Luxmore and Danielle Buchanan from HSG, who talked about the process of consenting to a trial. They wanted to explain to the audience what these consent forms are and why they are so long and convoluted! 

Informed consent forms used in observational and interventional research participation explain the purpose of the study, what it entails, risks, known side effects, confidentiality, and contacts for questions. McKenzie broke down all the different types of terms that can go into a trial’s title, including phase, blinding, randomization, multicenter, placebo control, and longitudinal or cross sectional. Our glossary can help if you need a refresher! 

Next, she talked about what the forms tell a potential participant about a trial; the purpose, background, who is being tested, activities and visits, how long the trial is, what options the person has if they don’t participate, and what happens if someone is hurt during a trial, among other items! McKenzie reminded the audience that signing an informed consent form means that you have read the forms, understand them to the best of your ability, and have had the chance to ask questions, and agree to participate in the trial. 

Danielle encouraged folks to take time in the consent process, by requesting a copy of the form beforehand, carefully reading and discussing with loved ones, and asking the study team any questions. Then it can be signed, and it’s good to hold onto a copy for reference. She recommended that people focus on the schedule of events, and how comfortable they feel with the procedures and the risks. After signing, it’s a good idea to keep on hand the research team’s contacts, and any info about medications that are not allowed during the study. 

People with lived experience of Huntington’s disease are the real experts

These documents can be very long and complex! While a lot of the legal language must remain, sometimes companies assemble committees of family members for input on how to make the process smoother and more understandable. The speakers reminded everyone that they should expect the research team to help them understand anything they sign, and that it’s important to advocate for oneself when agreeing to participate in a trial! 

The FDA and You: Making Your Voice Heard

The next speaker was Phyllis Foxforth, Senior Manager of Advocacy at HDSA, who emphasized that people with lived experience of Huntington’s disease are the real experts, and will speak about how they can partner with clinicians and researchers to drive improvements in access and care. 

Phyllis believes that HD community members have an opportunity and a responsibility to tell medical product developers and regulators what is challenging about HD and what is most important to them. Regulators like the FDA have different types of engagement programs to get community feedback. 

The HDSA recently organized a Voice of the Patient survey and a Patient Focused Drug Development meeting with the FDA in order to engage with regulators about what’s important to people with HD. 

A Day in the Life: Research Visits from Start to Finish

The afternoon session focussed on what’s happening now and next in HD research. First, in a brief session, Danielle Buchanan, a clinical project manager at HSG, and Dr. Katherine McDonell, Assistant Professor of Neurology at Vanderbilt University Medical Center, explained what happens during a research visit for a clinical trial.

Visits are typically made up of different types of study measures, including surveys and thinking tasks, tablet and computer tasks, sample collection like blood, saliva, or CSF, movement tasks, brain MRI, and EEG. The speakers stressed that the research team, from coordinators to clinicians, is there to help folks navigate all the steps of the trial, as well as to support family members and study partners. 

Huntington’s Research Today and Tomorrow: A 5-Year Outlook

Next we will heard from Victor Sung from UAB, who will tell us all about his 5 year outlook on what’s coming in the HD clinical trial pipeline. Victor runs a large HD clinic at the University of Alabama. He notes that following the recent uniQure news his clinic has received more than 50 calls a day from people wanting to learn more. He’s excited about what’s next after this landmark study. 

Victor laid the groundwork for his talk by explaining that there are multiple approaches to HD research, including lowering the amount of huntingtin protein in brain cells, and preventing the expansion of CAG repeats. His takeaway was “the more the merrier!” The field welcomes all the players in the game who are looking for ways to slow down HD and to address the symptoms. He believes that one day there will be an “HD cocktail” of multiple options in different phases of progression. 

This is a historic moment because it’s the first time a drug for HD has moved the needle on disease progression

Dr. Sung spent some time getting into the uniQure announcement which we covered in late September. The most important graph shows that people who received AMT-130 progressed more slowly 3 years after the initial surgery, based on how much their scores on thinking and movement tests changed over time. 

This is a historic moment because it’s the first time a drug for HD has moved the needle on disease progression, but the data is nuanced. AMT-130 is not an approved or available treatment, there are more regulatory steps to go, and there are many future conversations to be had about access.  Victor noted that there are many more drugs on the way that are exploring other drivers of HD and applauded HD research participants for rising to meet the great challenge of testing experimental therapies. 

Perspectives on Research: A Participant Panel Discussion

In this next section of the day, participants took the mic. A panel of folks from the HD community shared what it was like for them to join trials, why they decided to participate in HD research and how the experience could be improved. 

The panelists shared about the family and community members who inspired them, their genetic testing journeys, and their desire to do something to feel motivated and to benefit the next generation of people with HD. 

Challenges they highlighted include participating in research while holding down jobs and caring for family members or children, and navigating the logistics of observational research visits, especially out-of-pocket expenses and reimbursement. 

The panelists note that the care teams at resources at various clinics can make a huge difference as far as the experience goes, and that logistics and procedures get easier the more you participate. 

Ask the HD Experts Anything!

The final session to wrap up the Community Research Day is one of our favourites – “Ask the Experts.” This Q&A with HD clinicians and scientists allows audience members to ask anything they want about HD research, drug discovery and clinical trials. 

HDBuzz also runs these type of sessions with many of our partner organisations so look out for our next one if you have any questions. You can also contact us any time with your queries or comments. 

More updates to come

That was it for Day 1 – thanks for reading! Tune back in for our coverage of Days 2 and 3. 

A team of scientists have discovered small molecules that block the DNA repair protein MSH3, thought to be a key driver of repeat expansion in Huntington’s disease (HD). Although still at an early stage, this work opens the door to a new kind of therapeutic strategy: slowing down HD before symptoms begin. Let’s get into what they found. 

Unstable C-A-Gs

HD is caused by an extra-long stretch of DNA C-A-G letter repeats in the huntingtin gene. The longer the repeat, the earlier symptoms tend to begin. But it’s not just the inherited repeat length, also called a CAG number, that matters. These DNA repeats can grow even longer during a person’s lifetime in some cells in the body by a process called somatic instability. Many researchers are working to understand how expanding DNA repeats contribute to disease. A leading hypothesis is that faster repeat expansion may lead to faster disease progression.

This idea is supported by findings from large-scale genetic studies in people with HD, which have identified additional genes, beyond the huntingtin gene, that influence when symptoms begin. Many of these so-called modifier genes are involved in a biological process called DNA repair that keeps unwanted DNA changes in check. Of particular interest to HD researchers are the DNA repair modifiers involved in the pathways thought to drive and control somatic instability. 

A new drug target: MutSβ and MSH3

One of these DNA repair modifier genes encodes the protein MSH3. MSH3 is an attractive possible drug target because it plays a central role in recognising DNA errors that lead to CAG repeat expansions. Importantly, blocking it from working is thought to be unlikely to raise cancer risk, unlike some of the other modifiers found so far.

MSH3 teams up with another protein, MSH2, to form a complex called MutSβ (pronounced mute S beta). The MutSβ molecular machine uses energy in the form of ATP, a type of cellular “fuel”, to scan DNA for mistakes. 

Although MutSβ normally helps cells by spotting and fixing certain kinds of DNA errors, in the case of HD it can actually make things worse. The MutSβ machine can mistakenly act at CAG repeats in the huntingtin gene and rather than protecting DNA, causing repeats to get longer over time through somatic instability. 

So, while MutSβ is generally “helpful” for DNA repair, in the special context of CAG repeats its activity can backfire. The scientists reasoned that if small molecules could block how MutSβ uses the ATP fuel, they might be able to stop this molecular machine from working. This might then help reduce CAG repeat expansions, which could delay when signs and symptoms of HD begin.

A needle in a haystack

The research team developed a sensitive test to measure how well MutSβ was working in a test tube and then screened an enormous library of almost one million different chemical compounds to see which might stop it working. 

In this first round of screening, they identified thousands of candidate molecules, but most turned out to be false positives or weak inhibitors.

The team improved their screening methods to weed out artifacts. This included things like “sticky” molecules that get stuck on lots of different proteins, not just MutSβ. After these filtering steps, just 11 promising compounds remained.

With this shortlist, the team looked at exactly how they stuck to MSH3, compared to other related proteins. They found several compounds only stuck to MSH3 and not closely related proteins like MSH2 or MSH6, reducing the risk of possible cancer-related side effects.

Seeing the molecules at work

The researchers didn’t just stop at finding hits. They used special microscopes and other tools in the lab to see exactly how the small molecules stuck to MSH3 in atom-by-atom resolution. 

These structural snapshots confirmed that the compounds act in the expected way, by blocking the ATP fuel from being used by MutSβ. By “seeing” exactly how the compounds work, the scientist can now make informed decisions about how they can make them even better in the future. 

Why this matters for HD

These results are an early but exciting step toward drugs that could slow or prevent CAG repeat expansions, potentially delaying HD onset. 

The identified molecules are a long way from being ready for the clinic. Their properties would have to be substantially improved to ensure they worked inside cells and eventually in people, rather than just in a test tube. 

But thanks to the data shared by this team, scientists in this group and drug hunters from around the world can make rational decisions about how best to do this as quickly and as efficiently as possible. 

The road ahead

This study shows that MSH3 can indeed be drugged, and it provides the first molecular blueprints for exactly how to do it. 

There’s still a lot to do to improve the drug-like properties of these compounds and make sure they don’t have any unwanted side effects. Even then, we don’t yet know for sure if blocking MSH3 with this type of therapeutic will actually reduce somatic instability in cells or animal models of HD, or most importantly, whether this will slow or halt the signs and symptoms of HD in people.

The good news is that there are a lot of different teams working in this space to try and solve these problems. This includes the biotech company, Loqus23 ,and the pharma company Pfizer, as well as lots of academic teams of scientists. 

Together, their efforts are steadily advancing the search for therapies that target a possible genetic driver of HD progression.

Summary 

• CAG DNA repeats expand in some cells over the lifetime of someone with HD through a process called somatic instability.
• The DNA repair protein MSH3, part of the MutSβ complex, is a driver of repeat expansion and an attractive drug target.
• Scientists screened nearly one million compounds and identified a handful that specifically block MSH3 from working. 
• These molecules are early-stage tools, but provide the first blueprints for drugging MSH3 to potentially treat HD. 

Learn more

“Orthosteric inhibition of MutSβ ATPase function: First disclosure of MSH3-bound small molecule inhibitors”, (paid access). 

A new study has shed light on the role of the regular huntingtin protein in the brain. For years, researchers have known that the faulty expanded huntingtin protein drives Huntington’s disease (HD), but this new study shows why the regular version matters for brain health. By lowering regular huntingtin (HTT) in brain cells, scientists discovered hidden changes inside nerve cells that might help explain why some past HD drug trials may have run into trouble. Far from being discouraging, these findings give researchers a clearer roadmap for designing future therapies that are safer and more precise. Let’s take a closer look.

The Role of Huntingtin in Huntington’s Disease 

HD is caused by a change in a single gene called HTT. People with HD have a DNA “stutter,” a repeated stretch of the letters C-A-G, that is much longer than usual. Since everyone inherits two copies of each gene, one from their biological mom and one from their biological dad, people with HD typically carry one expanded HTT gene and one regular copy. This means that their cells produce two versions of the huntingtin protein: a faulty, expanded form that drives the disease and a regular form that supports brain health.

The Promise and Challenge of Huntingtin-Lowering

Most of the treatments currently being tested for HD in clinical trials aim to lower huntingtin protein (HTT) levels. The goal is to reduce the toxic expanded huntingtin protein, but many of these approaches also reduce the regular version. 

In recent years, potential HTT-lowering therapies have faced challenges in clinical trials, with some not working as expected or raising safety concerns. There are many reasons why this may have happened, but one possible explanation is that reducing too much of the regular HTT protein could be harmful. 

This has led scientists to ask an important question: what happens if too much regular HTT protein is lost? By understanding this, researchers can design safer trials and develop drugs that target the expanded form while sparing the healthy one.

In this new study, the researchers began to answer this by lowering expanded huntingtin in a type of brain cell, the nerve cell that transmits signals, and uncovered hidden changes that may explain why some past drug trials ran into trouble. Far from being discouraging, these findings offer a clearer roadmap for designing HD therapies that are safer and more precise.

Why Study the Hippocampus

Most research on regular HTT has looked at the developing brain, where regular HTT is essential, or at the striatum, the region that helps control movement and is most affected in HD. But most drugs circulate throughout the whole brain, not just one area. To better understand how lowering regular HTT affects overall brain health, scientists in this study turned to the hippocampus, a region of the brain that plays a central role in learning and memory.

How the Study Was Done

The researchers began by lowering regular HTT in nerve cells from a mouse hippocampus which were grown in a dish. To do this, they used a tool called siRNA, which works like a genetic “off switch” by telling cells to stop making a chosen protein. This allowed them to reduce regular HTT in a precise and controlled way.

After treatment, the researchers used special markers to label different parts of the nerve cells and then looked at them with microscopes. These microscopes can zoom in so closely that scientists can see all the intricate details of the nerve cells, including the synapses where nerve cells connect and communicate, and chromatin, the DNA-and-protein bundles that package up all our genetic material and help control whether genes are switched on or off. The team tracked how the structure of nerve cells changed as regular HTT levels dropped.

The researchers also created a mouse model to replicate the experiment and confirm the results. This step is important because findings in simple systems, such as cells grown in a dish, do not always translate to the complexity of a whole brain and body. In these mice, regular HTT was specifically removed from the hippocampus using a harmless virus that delivered a molecular switch that tells certain genes to turn off. In this case, the switch was designed to shut down the gene that makes regular HTT.

The Wiring Looks Pretty Normal

When the researchers looked at the wiring between nerve cells in these mice, they found that these structures remained mostly unchanged with less regular HTT around. That means reducing regular HTT levels did not immediately seem to disrupt how nerve cells connect to each other.

The Nucleus Reveals the Answer

The big changes were hidden deeper inside the cell. When the researchers looked at the nucleus, the control center where DNA is stored, they saw clear effects. After regular HTT was reduced, the nuclei grew larger compared to the nuclei of untreated cells.

Even more importantly, DNA in these nerve cells became less tightly packaged, making it harder for the cell to manage which genes were active.

The researchers also looked at proteins and chemical tags that help control whether genes are switched on or off. When regular HTT was lowered, their levels shifted from their usual balance. Together, these changes suggested the nucleus was less stable, even though the wiring of the nerve cells looked fine.

What This Means for the HD Community

At first, the idea that reducing regular huntingtin can affect the stability of nerve cells in the striatum might sound worrying. But in fact, these insights are good news for the HD community. For the first time, researchers know one of the possible reasons why some huntingtin-lowering drugs may have faced problems in earlier trials. Knowing this means the next generation of drugs can hopefully be designed to avoid those pitfalls. Instead of trial and error, scientists now have a roadmap showing what they should try to target and what to protect.

Importantly, this study lowered regular HTT by much more than what current drugs being tested are designed to do. In cells, levels dropped by about 86%. In comparison, clinical trials usually aim for a 30–50% reduction of regular HTT. The changes seen in this study potentially reflect what happens when the amount of HTT is lowered too far, giving researchers a clearer sense of the safe range to target.

This research also shows that not all changes are obvious at the surface. While the wiring between nerve cells looked normal, the nucleus revealed the hidden stresses that might come from lowering regular HTT. That insight gives scientists a powerful tool to check whether new drugs are safe before they move to larger trials.

A Step Closer to Safe and Effective Therapies

For families, the message is hopeful: every study, even those that uncover challenges, helps sharpen the path towards effective treatments. By understanding how regular HTT supports brain health, researchers can better design drugs that lower the harmful expanded HTT while minimizing effects on regular HTT.

Science is a step-by-step process. What we know today is built from the lessons of yesterday, and this study adds an important piece to the HD puzzle. With each discovery, the picture becomes clearer, and the future of safe and effective therapies comes into sharper focus.

Summary

• Huntington’s disease is caused by expanded huntingtin (HTT), but regular HTT is essential.
• Reducing regular HTT in hippocampal nerve cells left synapses intact but disrupted the nucleus, with looser DNA and weaker gene “off switches.”
• These results help explain one of the possible reasons why some huntingtin-lowering drug trials didn’t work as we had hoped
• Most importantly, they show the path forward: new drugs should take into consideration how much of the expanded HTT and regular HTT are reduced and find a balance that supports healthy brain function.

Learn more

“Huntingtin reduction results in altered nuclear structure and heterochromatic instability.” (Open access).

Meet this 2025 HDBuzz Writing Competition Winner

Gravity Guignard is in her final year of an Honours Bachelor of Science at Trinity College, University of Toronto, specializing in Fundamental Genetics. She conducts research in Dr. Derek van der Kooy’s laboratory, where she studies the development of neural stem cells.

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

Think about the last time you were stressed. What did you do to feel better? For many of us, it’s talking through our frustrations. Getting rid of things that stress out our cells also requires good communication. The central communicators? Chaperone proteins. Chaperone proteins are just like the chaperones at a school dance. They direct misbehaving proteins to where they need to go and keep them from causing more chaos in the cell. Proteins can be misbehaving in cells for many different reasons, but in diseases like HD, the expanded huntingtin protein is thought to misbehave because it isn’t folded properly and clumps together. 

A study identified the co-chaperone SGTA as an expanded huntingtin interactor in HD model cells and mice. Co-chaperones are like the hall monitors that report to chaperones. SGTA is potentially a promising therapeutic target because it is not essential for cellular processes and increases survival of patients of other protein misfolding diseases. Let’s get into this study and what they found. 

Finding the Troublemakers

In HD, expanded huntingtin clumps together into groups of misfolded proteins called aggregates. Chaperones target misfolded proteins to minimize the chaos in the cell. Expanded huntingtin aggregates are like magnets for chaperones. Despite this, chaperones fail to control the chaos caused by expanded huntingtin aggregates.

This is a key problem with using chaperones as a therapeutic target, but there are other issues too. Like the chaperones at a school dance, catching the chaos is not their only job, they also have to setup the dance. Chaperones help make new proteins, direct traffic in cells by sending specialized proteins to specific locations, and clean up by targeting old and damaged proteins to the cell’s trash can. Boosting the amount of a chaperone with a therapy doesn’t seem to help in HD. Having too many chaperones can be too much of a good thing and instead of productively removing the problem, we’ve introduced more chaos. 

Getting Caught by the Hall Monitors

Here’s the good news. There’s a subset of helper proteins called co-chaperones that work with chaperones. The role of co-chaperones is to serve as the first response. Like hall monitors, they find the sneaky misfolded proteins and stop them from causing more problems. The sneaky protein is reprimanded by the co-chaperone and delivered to the chaperone. The chaperone is ultimately who decides what to do with the protein, but the co-chaperone often helps the chaperone find the protein, hence the name co-chaperone.

A study has identified the co-chaperone SGTA to be of particular interest as a new star hall monitor. Kubota and colleagues found that SGTA associates with the huntingtin aggregates in HD model cells and mice. They also found that SGTA associates with a large proportion of the huntingtin in cells models of HD that we would expect to be in the aggregated stage. Even though aggregates act like magnets for cochaperones like SGTA, the co-chaperone needs to be in range of the aggregate. The authors propose SGTA is acting on the aggregate and even identify the region of SGTA molecule that sticks to the huntingtin clumps. Now we’ve identified a hall monitor capable of reprimanding huntingtin before it takes it to the chaperone.

Strengthening the Frontlines

The big question now that we know SGTA interacts with huntingtin clumps is whether we can use it as a target for developing new medicines for HD. Researchers increased the amount of SGTA in HD model cells to see if it would reduce huntingtin clumps or cause more chaos. They found that increasing SGTA made expanded huntingtin less aggregated and more soluble. This suggests that SGTA isn’t just getting stuck on the huntingtin magnet but is intentionally acting on sneaky huntingtin.

Boosting SGTA to change huntingtin solubility is a major finding. Huntingtin aggregates are big insoluble protein clumps, and SGTA overexpression shifts expanded huntingtin toward a more soluble state. SGTA seems to specifically target small immature aggregates rather than large mature ones. Because of this preference, SGTA may help determine whether immature or mature aggregates should be targeted to treat HD.

What’s Next

This study shows the importance of trusting the hall monitors of the cell. Researchers found not only that SGTA binds to expanded huntingtin, but also that when you increase the amount of SGTA in the cell, the properties of expanded huntingtin change to a less aggregated state. This suggests that SGTA is acting on expanded huntingtin to decrease its aggregation.

Where do we go from here? Increasing our cellular hall monitors shows promise as a therapeutic target, but there is still lots of work to be done. What is SGTA doing to decrease aggregation? Why is increasing the amount of it effective? Is it working with a chaperone or acting all on its own? These are vital questions for future research.

Summary

• Chaperones target misbehaving proteins to prevent further chaos to the cell.
• In HD, expanded huntingtin misbehaves into aggregates that are not effectively managed by chaperones.
• Early studies find the co-chaperone SGTA to interact with expanded huntingtin.
• Increasing the amount of SGTA reduces the aggregation of expanded huntingtin.
• Co-chaperones may serve as an underutilized therapeutic target for managing HD.

Learn More

Original research article, “SGTA associates with intracellular aggregates in neurodegenerative diseases” (open access).

Meet this 2025 HDBuzz Writing Competition Winner

Chloe is a PhD candidate in the lab of Dr. Emily Sontag in the department of Biological Sciences at Marquette University. Her dissertation work focuses on how quality control proteins interact with the huntingtin protein associated with HD when mutated. She hope this work can contribute to future therapeutics.

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