HDBuzz

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!

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).