Many people living with Huntington’s disease (HD) lose motivation to carry out some tasks. A new study shows that these apathetic behaviors are because of a change in the brain’s ability to weigh cost vs. reward. Pinpointing exactly why people with HD experience these changes can help develop treatments to improve quality of life.
Cost vs. reward
Apathy can be generally explained as a lack of interest, enthusiasm, or concern. But in psychology, it’s more than just feeling “lazy” or unmotivated—it’s a change in how the brain decides whether something is worth the effort.
Imagine your brain is like a shopper in a grocery store, deciding what to put in the cart. Each potential action in your day—like cooking dinner, going for a walk, or calling a friend—is an item on the shelf. Before choosing, the shopper (your brain) checks two things: the price tag (cost) and the value of the item (reward).
Cost can come in different forms. Some items may be on a high shelf or require heavy lifting, like a large bag of flour. The shopper must decide if the physical effort to grab it is worth it. Similarly, the brain evaluates if an action—like tidying the house—is worth the energy it takes. On the other hand, some items might not be available immediately and need to be pre-ordered, requiring patience, or costing time. The shopper must decide if waiting is worth it.
The shopper evaluates how much they want or need each item. Is it something delicious, useful, exciting, or just “meh”? If the cost (effort or time) outweighs the reward, the brain decides to leave it on the shelf.
Tipping the balance
In apathy, the mental shopper can become overly focused on costs, or less interested in the reward, often deciding that even valuable items aren’t worth it—or opting to skip the shopping trip altogether.
Although apathy is a symptom in many neurological disorders, the causes of apathy vary. In Parkinson’s disease, people with apathy feel less motivated by small rewards, thinking, “I just don’t care about that.” In another brain condition, frontotemporal dementia, the effort feels overwhelming: “I don’t want to do what it takes.” Even though both result in inaction, the brain’s reasoning behind the inaction is different. Understanding these differences can help scientists target treatments more effectively.
Apathy in HD
HD often affects thinking and decision-making, and apathy is a common symptom for many, though not everyone with HD experiences it. Apathy can have a big impact on daily life, making it harder for people to stay independent, work, or maintain relationships.
Researchers from the University of Otago in New Zealand and the University of Oxford in the UK were interested in figuring out whether the reduced activity seen in HD apathy is because people are more sensitive to the effort or time involved (“this feels too hard” or “I don’t want to wait”) or because rewards feel less motivating (“I don’t want it that bad”), or a combination of both. Understanding these differences could lead to better ways to support people with HD and improve their quality of life.
Measuring the make-up of apathy
Measuring something as complex as apathy isn’t easy, but researchers have developed creative ways to observe how people make decisions. They focus on how effort or time affects choices and how long it takes to make those choices.
In the Apple Gathering Task, participants play a computer game where they decide whether to squeeze a handgrip to gather virtual apples as a reward. This measures the “cost” of physical effort. In the Money Choice Task, they must choose between getting a small amount of money right away, or waiting for a larger amount later. This tests how they view time as a cost.
Of course, it’s not just about the decisions themselves, but also how the brain reaches them. In this study, the researchers used a technique called “Drift Diffusion Modeling” to analyze how quickly the brain gathers evidence for one choice over another. Think of it like a mental race between options. For example, someone sensitive to effort might be very quick to decide not to squeeze the handgrip, even if it’s for a lot of apples.
In these ways, the study examined whether in HD, people with apathy showed different patterns in their decision-making processes, shedding light on how their brains weigh costs and rewards.
Effort and time drive HD apathy
First, the researchers had to identify who was apathetic, which they did using clinical questionnaires. They also considered other HD symptoms like movement difficulties, cognitive issues, depression, and impulsivity, which can overlap with apathy, or influence the measurements in their experiments.
In the Apple Gathering Task, where participants had to squeeze a handgrip to earn virtual apples, people with HD who were apathetic were less likely to go for the apples as the effort levels went up, but not as the apple rewards got smaller. This gives a clue about the underlying cause of apathy in people with HD.
In the Money Choice Task, those with apathy were more likely to pick the immediate reward, finding it harder to wait for a bigger reward. Once again, this seemed to stem from a sensitivity to the delay, as if the cost of waiting was just too high.
As expected, the researchers found that compared to people without HD, it took longer for people with HD to weigh the options and come to a decision. However, the advanced analysis (drift diffusion modeling) revealed that people with HD with apathy were quicker to reject high-effort tasks and choose immediate rewards–the “do nothing” option won the mental race.
Overall, the study highlighted a “cost hypersensitivity” in apathetic individuals with HD, affecting both effort and time costs. This distinct brain mechanism may explain how apathy in HD differs from other conditions, and suggests that unique approaches to treatment are needed.
Research for managing everyday challenges
Apathy is not just a lack of motivation—it reflects a deeper change in how the brain processes and weighs the costs of actions, like effort or time, against potential rewards. This altered decision-making influences behavior, making certain tasks feel overwhelming or not worth it. Understanding the mechanism of apathy is crucial because simply trying to motivate someone without addressing the underlying cost sensitivity may not be successful.
By fine-tuning our understanding of psychological symptoms like apathy, we can pave the way for more targeted treatments. Future research will focus on connecting the physical brain changes in HD to these decision-making patterns, as well as therapeutic options, such as cognitive behavioral strategies that reduce perceived costs, medications that adjust brain signaling, or assistive technologies providing encouragement and feedback.
HD is a complex condition with many options to enhance quality of life. This study adds an important piece to the puzzle by exploring how restoring motivated behavior could bring us closer to improving the lives of those affected. Alongside research into disease-modifying therapies that address the root cause of disease, studies like this provide valuable tools to better manage the everyday challenges faced by people with HD.
As we wave goodbye to 2024, the HDBuzz team reflects on a year marked by significant progress, challenges, and hope. From breakthroughs at the lab bench, advancements in drug development, and both road bumps and triumphs in clinical trials, we have gained new insights into the workings of Huntington’s disease (HD), and made great strides towards finding medicines which might slow or halt this disease. Alongside these developments, the HD community has witnessed the power of collaboration, advocacy, and innovation in driving research forward and improving care. This year-in-review highlights the key moments and milestones that shaped 2024 for HD research.
A new generation of voices at HDBuzz
HDBuzz has been a trusted source of unbiased, accessible information on HD research and clinical trials for over 14 years, helping HD families who are seeking answers and want to learn about the latest scientific advancements. This year, HDBuzz founders Ed Wild and Jeff Carroll passed the baton to a new generation of editors, led by Rachel Harding and Sarah Hernandez, to steer HDBuzz through this exciting new era of HD clinical trials and other research.
In addition to our new editorial team, we have welcomed many new voices to our writing team, from different geographies, backgrounds, scientific training, and career stage. Having multiple viewpoints represented across our writers ensures that HD families are getting content that spans what the HD field is thinking. This diverse team of writers includes our wonderful competition winners Zanna Voysey, Molly Gracey, Jenny Lange, and AJ Keefe.
Updates from world experts at HD-focussed conferences
The HDBuzz team has travelled far and wide to different conferences and meetings where the latest updates on HD research and progress in different clinical trials are presented by world experts in the HD field from both academia and industry. Many of the updates presented in these meetings are not yet formally published in peer reviewed journals, meaning we can bring you the most cutting-edge data and research on HD.
A hot topic in HD research in recent years is somatic instability, and 2024 proved a year where many breakthroughs in our understanding of this phenomenon were made. Somatic instability is the tendency of the CAG repeat sequence in the HD gene to expand further in certain cells of the body over time. A theory many HD researchers are exploring is that cells in the brain with more expansions might be more likely to get sick, thus somatic instability could be driving disease. Slowing down or even reversing CAG expansions by manipulating the way DNA is processed and maintained could be the key to unlocking this theory in the clinic.
2024 kicked off with some fascinating studies, investigating how the CAG number changes in different types of cells in brains from people with HD who have passed. Using these precious samples, the scientists could work out exactly which cells are affected by somatic instability, and how this tracks with which cells get sick and die in brains of people with HD over time. This granular level of insight is helping us unpick exactly what is going on in HD and is only made possible by the selfless decision of people with HD to donate their brains to research after they pass.
CAG expansion is not just a feature of HD, but actually a whole class of diseases called CAG-repeat disorders which include spinal bulbar muscular atrophy and some types of spinocerebellar ataxias, among other disorders. Given the parallels in the genetic underpinnings of these diseases, we learnt a lot about HD this year from ongoing research in ataxias.
Other research teams have been busy this year exploring the exact molecular consequences of somatic expansion in different models of HD. One team found that changes to the CAG number through somatic expansion can alter the way genetic messages are chopped up and reorganised, a process called splicing. Another group looked to see exactly how long a CAG number needs to be in mouse models of HD for cells in the brain to get sick.
Cellular insights
Beyond somatic instability, research teams around the world have been busy exploring other areas of HD biology. A number of teams have been looking at the blood brain barrier, a protective layer which keeps the brain safe but can also make it tricky to get drugs into the brain to treat diseases like HD. Advances in stem cell research mean that scientists can now make models of this barrier from cells in a dish.
As well as making these barrier structures in dishes, scientists can also make complex 3D organisations of human nerve cells called mini brains. Derived from stem cells, these structures hold great promise for helping us understand HD in living human brain-like organs, and potentially guide a path for cell-replacement therapies.
We learnt a lot about the cool-looking star-shaped nerve cells, called astrocytes this year too. These cells are important for brain health and seem to play a role in how cells are lost in the brains of people with HD. Again, this research was made possible because of brain donations.
In the pipeline
HD scientists are always looking for innovative ways to track how someone’s HD symptoms might be progressing. In 2024 we learnt of a team of scientists who were looking at huntingtin protein levels in tears. Whilst this might sound rather whacky, this approach is non-invasive, unlike taking spinal fluid or blood samples, and could help track HD progression or even how well huntingtin lowering drugs are working.
More surprising twists and turns for huntingtin lowering arose in a study looking at splice modulators, a class of drugs which change how the huntingtin message molecule is processed and cause levels of the protein to drop. It turns out that some splice modulators also target another protein called PMS1 which is involved in somatic expansion. Treating cells in a dish, some splice modulators seem to alter somatic expansion AND lower huntingtin. This could mean these drugs could have a two-for-one effect!
Edging closer to the clinic for HD are many CRISPR-based technologies. CRISPR is a clever tool which can precisely edit the DNA code. One of the key challenges at the moment is getting the CRISPR machinery into the right cells to make these changes. In 2024, a CRISPR therapy was approved for sickle cell disease. They got around the challenge of delivery by removing cells from bone marrow, editing them in a dish in a lab, and then adding them back later. Lots of researchers are looking to apply this technology to HD, including a team developing tools to interrupt the CAGs.
Updates from the clinic
Bumps in the road
Whilst we always hope for clinical trials to give us the positive outcomes we want, it doesn’t always work out that way unfortunately. Clinical trials are some of the most complicated, expensive, and risky experiments that scientists can do, and sadly 90% fail overall. Despite these disappointments, there is always a lot that the community can learn from any trial, whatever the outcome, with the large amount of data collected and different hypotheses tested. It also doesn’t necessarily mean the end of the road for the drugs in question.
Pridopidine is a drug with a complex history in the HD space. Now owned by the company Prilenia, it was originally designed to improve movement symptoms of HD and was later thought to possibly slow down the progression of the disease. Despite the negative results from the phase 3 PROOF-HD clinical trial, Prilenia are moving forward to try and get regulatory approval in Europe for the drug. We should know more about the regulator’s decision in 2025.
Another disappointment to many was the halting of development of dalzanemdor, previously called SAGE-718, by SAGE Therapeutics. Sage had hoped that dalzenemdor would work to improve thinking and memory problems experienced by people with HD. However, the drug had setbacks in clinical trials for other neurological diseases and unfortunately failed to show cognitive improvements in the DIMENSION trial where the drug was tested in people with HD.
In both instances, we know a lot of folks in the HD community who had participated in the trials felt as though the drugs had helped them, and that experience is completely valid. It could well be that folks in a certain age bracket, with a specific CAG number, or at a particular stage of HD respond better. However, the overall data in both cases did not prove the benefit of taking either drug to be significantly different from a sugar pill.
Moving in the right direction
Despite these setbacks, 2024 was abound with positive and hopeful news from other companies who have clinical trials underway. PTC Therapeutics who developed PTC-518, a pill which can be taken by mouth to lower levels of the huntingtin protein, shared an update with data to support good safety of their drug and even some suggestion that certain clinical scores seemed to be improving.
In quick succession, we then received another update on a huntingtin-lowering clinical trial, this time from Wave Life Sciences who have developed WVE-003 which is delivered by spinal tap. In this update, we learnt that their drug seemed to be generally safe, although flags were raised around their NfL data. Wave also reported that the drug appeared to be selectively targeting the expanded harmful form of huntingtin only, not the healthy version. Further, very preliminary data from MRI brain scans seemed to indicate that folks in the trial on the drug had less loss of brain tissue compared to those on placebo.
Another update came just a couple of weeks later from uniQure, about their huntingtin-lowering trials testing their gene therapy AMT-130, given as a single dose by brain surgery. Although we didn’t learn about target engagement in this update (i.e. is the drug actually lowering huntingtin), we did find out that the drug does seem to be largely safe in their updated surgery protocol and could potentially be slowing down symptom progression based on some clinical metrics.
Altogether, this was a bounty of positive news! Not to be an HDBuzz-kill but it is important to note that all of these trial updates are interim – not the final data, and the data are from relatively few people, so there is still a way to go to see how each drug shakes out in larger numbers of people with HD.
Although we did not get a blockbuster update this year from the GENERATION-HD2 trial testing tominersen, a huntingtin lowering drug given by spinal tap developed by Roche, we did learn recently that the trial has now completed recruitment. The scientists at Roche continue to pore over the data from the previous GENERATION-HD1 trial, gaining insights into what might work, and what won’t, to give tominersen the best shot in this next phase of its development.
New kids on the block
It’s been an exciting year with new companies in the HD drug discovery space getting started with clinical trials. Alnylam Pharmaceuticals kicked off their clinical trial investigating their huntingtin lowering drug ALN-HTT02, with the first participant receiving the drug in December this year. Skyhawk Therapeutics began their huntingtin lowering trial in Australia earlier this year and have already shared an update, demonstrating the promising safety profile and target engagement of their drug, SKY-0515.
Vico Therapeutics updated the community about their CAG-repeat targeting drug, VO659, that can lower huntingtin. Because it targets CAGs, this drug can lower proteins implicated in other CAG diseases, including spinocerebellar ataxias (SCA) 1 and 3. Their trial is testing the drug in folks from all 3 diseases – SCA1, SCA3, and HD. There are some concerns about safety that have been attributed to high dosing which Vico plan to alter in the next phase of their clinical studies. However, the drug does lower huntingtin and could prove to be a path for a new therapy for multiple rare diseases.
A sprinkling of approvals
2024 also saw a new drug approval for the HD community. Neurocrine Biosciences developed INGREZZA, which is used to treat the movement symptoms of HD. INGREZZA is the commercial name for Valbenazine, previously approved for treatment of HD. However, some people with HD have trouble swallowing tablets so Neurocrine made the drug in a sprinkle format to be shaken onto food, which was approved by the FDA.
Path to approval
As we edge closer and closer to finding drugs which might slow or halt HD, the field is thinking more about how these drugs might one day be approved and become accessible to the HD community more broadly. The different regulatory agencies which govern these processes are complex organisations, and their role and processes for drug approvals differ by geographical jurisdiction.
Towards the end of 2024, the HD family community met with the FDA to discuss the challenges they face and what they need from new medicines. Representatives from the FDA listened to the lived experiences of people with HD and family members, to better understand the urgency and needs of the community.
Conversations between companies developing medicines for HD and the FDA also moved forward in 2024. uniQure shared that following discussions with the FDA, that they are aligned on the key elements needed for a drug for HD to be approved. This exciting regulatory update matters beyond the uniQure clinical trials, as it maps a path forward for other potential disease-modifying drugs in the clinic, which are seeking to slow or halt symptoms of HD.
Learning from observational studies
In addition to the studies where different medicines or interventions are investigated, there are many different observational studies for HD. These collect biographical information, genetic data, and monitor disease progression over time with different clinical tests and biomarker studies. This helps to create a rich tapestry of data so that we might understand how HD impacts a wide range of people over the course of their life.
A very interesting study was published this year based on a wealth of genetic data that showed repeat expansion diseases, a class of diseases caused by DNA expansions that includes HD, are present at much higher incidence than previously thought. This study, and others, pushed back on the common narrative that HD is primarily a disease more common in people of White ancestry. In fact, HD impacts populations globally. Critical research in the US is investigating the racial disparity in accessing healthcare and healthcare outcomes for Black and Latinx individuals. Identifying these gaps is the first critical step in helping to combat these issues.
Historically, many observational studies have focussed on obvious symptoms of HD, such as uncontrollable muscle movements and difficulty with swallowing. Scientists are now beginning to investigate less obvious effects of HD such as social struggles. There is an increasing awareness of how much these less well-recognised signs of HD can impact an individual and their quality of life.
Another study looked to see which drugs people with HD are already taking and how these tally with the way disease progresses. They found that taking the commonly prescribed beta blockers was associated with delayed onset and slower progression of HD symptoms. This super cool finding was made possible by all of the wonderful folks who participate in Enroll-HD, a testament to the power of the huge dataset contributed by so many HD family members, that helps scientists pull out these cool findings.
Taking action now
The end of 2024 has edged us closer to finding drugs that might slow or halt disease symptoms. Some of these breakthroughs seem tantalisingly close but as we cheer on the HD scientists and clinicians driving these developments forward, there are lots of actions we can take in the meantime.
One thing which became very apparent this year was the amazing acceleration of HD science through the selfless donation folks made of giving their brains to research after they have passed. So many of the stories we have featured this year have showcased breakthroughs that can only be made with these precious samples. If we want to know more about the effects of HD in the human brain so that we can advance treatments, we need to study the human brain. And thanks to generous donors, we now have more studies than ever conducting such experiments.
Supporting HDBuzz
The model that funds and supports HDBuzz shifted in 2024. In addition to support from various wonderful foundations, we began accepting donations directly from our readers to ensure the sustainability and growth of HDBuzz. This decision was made with great care and consideration to ensure the continuation of HDBuzz. Despite these changes, HDBuzz has never accepted funding from pharmaceutical companies so that we can maintain impartiality on the research updates and clinical trial news we cover.
Donations support website maintenance and updates, translation of our articles into various languages, travel to conferences so that we can report on the latest research, travel to meetings to present and directly interface with the HD community, and for the time our writers and editors spend reading, writing, developing content, putting together presentations, and presenting to the HD community. Our content will never be behind a paywall and will always be available to all, but if you would like to support us, we are grateful for every penny. We’re eager to put all donations to good use and have exciting things in store for our readers in 2025!
Looking ahead to 2025
2025 is going to be a big year! Not just for HDBuzz, but for HD research as a whole. Several major clinical trials are ending soon that will generate conclusive data. In short order, we will have definitive answers about certain drugs that could modify the course of HD! So put on your party hat, throw some glitter in the air, and get ready to ring in 2025 with HDBuzz at your side.
Proteins are like molecular dancers, with the cell acting as their dance floor. Proteins pair up with various partners to perform elaborate dances. Depending on who they partner with, they can carry out different functions in the cell, just like
someone might prefer to do the waltz with one partner, but the salsa with another. Identifying key dance partners in health and disease can help us advance treatments for diseases like Huntington’s.
Pairing up for the molecular waltz
Scientists often focus on a protein’s dance partners when investigating a protein’s function. Knowing which proteins are pairing up sheds light on how that protein works and what it does inside the cell. Cells are like an extraordinarily crowded dance floor, with billions of interacting proteins, constantly interacting with and swapping partners in an elaborate rhythm.
Identifying protein interactions is critical to our understanding of disease. Diseases can alter who a protein likes to interact with, which can affect the functions that it carries out in the cell. If our once tango-loving protein refuses to dance with a certain partner, they may no longer like to do the tango. That could be an issue if that’s their signature dance.
Huntingtin on the dance floor
In the case of Huntington’s disease (HD), researchers are working to map the dance partners of the protein Huntingtin. A spelling mistake in the Huntingtin protein causes HD. Knowing the interaction partners of Huntingtin with and without the spelling mistake can help uncover cellular processes altered by HD. Scientists can use this knowledge of protein interactions to improve our understanding of disease mechanisms and, eventually, develop potential treatments to test in clinical trials.
In a recent publication, a team led by Dr. Cheryl Arrowsmith at the University of Toronto devised an experiment to see all the different dance partners that Huntingtin has, not just other proteins. This work showed that huntingtin also binds to a molecule called RNA.
RNA: A new Huntingtin dance partner
RNA, a cousin of DNA, is best known for its role in producing proteins. While DNA primarily serves as a genetic blueprint for building proteins, RNA has a much broader range of activities. The most studied type of RNA is messenger RNA, also called mRNA, which codes for protein.
However, up to 90% of RNA molecules don’t code for proteins and are not mRNA. Instead, they interact with proteins, coordinating important cellular processes. In this way, these so-called “non-coding” RNAs act like protein dancers themselves or are at least protein choreographers, helping proteins dance together. While most proteins don’t partner with RNA, the new work from Dr. Arrowsmith’s group suggests that Huntingtin appears to be one of the few that do. This raised the possibility that the spelling mistake in Huntingtin that causes HD could disrupt these interactions.
Scientists had a couple of reasons to suspect that Huntingtin might partner with RNA. For example, when they used powerful microscopes to closely examine the exact shape and physical structure of Huntingtin, they noticed a spot on the protein that could, in theory, fit an RNA molecule right into it.
In addition, previous experiments by Dr. Arrowsmith’s lab showed that RNA molecules strongly partnered with Huntingtin in certain experiments where they were trying to study Huntingtin’s protein interactions. In fact, so much RNA partnered with Huntingtin that they needed to perform additional steps to get rid of the RNA (because they were interested in proteins at the time). However, this led them to wonder, what ARE those RNA molecules that partner with Huntingtin and could they play a role in HD?
The dance between Huntingtin and RNA
Before diving into more complex techniques, the researchers conducted a simpler experiment. They mixed RNA into a kind of “science jello” and subjected it to an electrical current. Because RNA molecules have a negative charge, they migrate toward positive charges positioned on the opposite side of the jello. Scientists compared the speed that the RNA moved through the jello with, and without, Huntingtin mixed in.
They found that, in the presence of Huntingtin, RNA moved through the jello more slowly, suggesting that RNA was in fact partnering with Huntingtin. Importantly, this slowing effect was not observed when DNA was mixed with Huntingtin, suggesting that Huntingtin has a specificity for RNA. This is important because DNA and RNA are chemically quite similar, but functionally very different. This experiment showed that Huntingtin is specifically interested in dancing with RNA, not DNA.
Encouraged by this result, the scientists decided to dig deeper by analyzing all the RNA that partnered with Huntingtin in living cells grown in a dish. As expected, they found that Huntingtin parternerd with many different RNA molecules. They next narrowed their investigation by focusing on some of those RNA partners to learn more.
A NEAT dance sequence
While reviewing Huntingtin’s RNA partners, the researchers noticed some interesting patterns. Many of these RNA molecules were involved in activities that are critical for cell survival. Because these activities are so crucial, they are not the kinds of RNA you would want Huntingtin snubbing on the dance floor!
Huntingtin also prefers to partner with a specific type of RNA containing lots of guanine, a building block of RNA. To confirm this, the scientists made an artificial “lab-made” RNA strand with lots of guanines and, sure enough, Huntingtin sidled right up to it.
The researchers decided to shine the spotlight on one RNA that consistently partnered with Huntingtin and contained lots of guanine: NEAT1. NEAT1 is an RNA that plays a key role in forming something called paraspeckles – tiny structures inside the nucleus of cells that control RNA production. You can think of paraspeckles like the VIP lounge on the molecular dance floor. NEAT1 is the RNA choreographer specifically for the VIP lounge, dancing with partners there and regulating the dances of others. Huntingtin will join the VIP area, but has no problem dancing in other areas of the cell. The researchers found that when Huntingtin joins the VIP lounge paraspeckles, it likes to partner with NEAT1.
Next, the team wanted to know if levels of NEAT1 were changed by the spelling mistake in Huntingtin that causes HD. Although they found levels of NEAT1 were lower in brain cells grown in a dish and mouse brain tissue containing the Huntingtin spelling mistake, the results from human brain tissue were less clear. During the early stages of HD, NEAT1 levels were lower, but NEAT1 levels were higher in later stages of the disease. The scientists suggested this could be caused by the loss of brain cells as the disease progresses. Regardless, these results suggest that NEAT1 levels are changed in Huntington’s disease.
The VIP lounge
To see if there is a direct connection between NEAT1 and Huntingtin, the scientists tested whether changes in Huntingtin levels could affect NEAT1 levels or the paraspeckles that NEAT1 organizes. Afterall, if you know your favorite dance partner will be a no-show, you might not show up either! The researchers found that when Huntingtin levels were lowered, NEAT1 levels rapidly decreased afterward, suggesting that Huntingtin stabilizes NEAT1. So NEAT1 really only wants to be around if Huntingtin is around too. Because NEAT1 is crucial to forming paraspeckles, reducing Huntingtin also led to smaller and fewer paraspeckles in the nucleus. So without Huntingtin, NEAT1 doesn’t even bother organizing the VIP lounge. That’s a serious commitment to your dance partner!
Next, the researchers asked if the spelling error that causes HD effects NEAT1’s role in organizing paraspeckles. They found that brain cells grown in a dish that have HD-causing Huntingtin had fewer paraspeckles, and those that remained were smaller. This suggests that both the loss of Huntingtin and the presence of HD-causing Huntingtin disrupt paraspeckle formation, possibly by destabilizing NEAT1.
These findings are significant because they show that Huntingtin interacts with NEAT1, an RNA crucial for paraspeckle formation, and this interaction is disrupted in HD – potentially causing serious problems in the brain. However, there are still some important unanswered questions. For one, most of these experiments were done in cells grown in a dish, so we don’t know if the same interactions occur in the human brain. Additionally, the consequences of reduced NEAT1 and paraspeckle formation in the brain remain unclear. Previous studies in mice suggest that NEAT1 is not essential for brain development or brain cell survival. Still, the consequences of disrupting NEAT1 or paraspeckles in humans, or during human disease, are unknown.
Zooming out on the dance floor
While most of this work focuses on NEAT1 and paraspeckles, let’s not lose sight of the big picture: Huntingtin interacts with RNA! NEAT1 was just one of up to 571 RNAs the researchers found that may interact with Huntingtin, many of which were involved in important activities like producing energy. Future studies are needed to examine how Huntingtin might affect these other RNAs just as this study analysed NEAT1. For example, if Huntingtin is important for NEAT1 stability, could Huntingtin stabilize other important RNAs?
Let’s think therapeutics – where does this research get us? First of all, this study will certainly motivate additional research into Huntingtin’s RNA connection. And, if an interaction between any specific RNA and Huntingtin were found to be harmful or beneficial, then small molecules that influence that partnership could be designed. In the elaborate choreography of cellular processes, finding the right molecular dance partners is like playing the perfect song – it can set the stage for a harmonious performance or prevent a misstep that disrupts the entire routine.
Research led by Dr. Peg Nopoulos from the University of Iowa used the Enroll-HD database to answer a key question: “How does beta-blocker use influence motor-diagnosis onset and progression rates in premanifest and early motor-manifest Huntington’s disease (HD)?”. They found beta-blocker use was associated with positive effects!
Subtle changes because of HD
While HD primarily affects the brain, people with HD have subtle changes to their nervous system that can also affect heart rate and blood pressure. The scientists who worked on this paper had previously shown that these subtle nervous system changes happen early in life, which could cause their effects to build over time.
They thought that medications used to treat these subtle changes, like those recommended for minor heart problems and small elevations in blood pressure, could potentially have global benefits for the nervous system, perhaps having a larger influence on HD symptoms overall.
LOLs for a calmer heart
The researchers were specifically interested in a class of medications called beta-blockers. You’ve likely heard of many of these medications – propranolol, metoprolol, and atenolol are 3 commonly prescribed beta-blockers. A trick for identifying them is that they end in the suffix -lol.
Beta-blockers are a routinely prescribed pill for managing various conditions, like high blood pressure, irregular heart rhythms, and anxiety. They work by blocking the effects of adrenaline and other stress hormones on the heart and blood vessels, helping to slow heart rate and reduce overall cardiovascular strain.
Beta-blockers have been widely used in clinical practice for over 50 years, with the first drug in this class, propranolol, approved by regulatory agencies in the 1960s. Since then, they have become a mainstay treatment for a range of cardiovascular conditions due to their proven safety and effectiveness.
Over decades of use, beta-blockers have demonstrated a strong safety profile, with side effects that are well understood and manageable in most patients, making them one of the most trusted types of drugs in medicine.
Enroll in action
To answer questions about the effect of beta-blockers on the onset and progression of HD, the researchers turned to the Enroll-HD database. Enroll-HD is the largest global observational study focused on HD, involving people from around the world. Over 20,000 people are currently part of Enroll-HD! No drug is given during the study; it’s designed to simply watch people with HD as they live and age and see how that differs from people without HD.
During clinical visits for Enroll-HD, participants are asked questions by their neurologists, including current medication use. This information is then de-identified so no one can match clinical information to a specific person, and researchers across the globe are given access to that data. This allows leaders in HD research from around the world to dig into this data and ask and answer questions that will get us closer to a treatment.
Delay and decrease
Dr. Nopoulos’ group used the Enroll-HD dataset to analyze the use of beta-blockers in people with the gene for HD who were not yet experiencing symptoms (premanifest HD) and those with early motor symptoms. The most common reasons people took these meds was because of high blood pressure, anxiety, depression, and heart problems like irregular heart rhythm or coronary artery disease.
For people in the premanifest HD group who were taking beta-blockers, the chance of being diagnosed with disease onset was decreased by 19% to 38%, depending on the specific medication. That’s quite a bit! (The 38% decrease was seen for those taking propranolol.)
People with early motor symptoms who were taking beta-blockers showed improvements in several tests used to measure progression of HD symptoms, compared to people not taking beta-blockers. The beta-blocker users had slower progression in motor symptoms, slower decline in their ability to carry out day-to-day tasks, and a slower decline in thinking and memory tests.
However, when they got into the nitty gritty of the data for the early motor group, the type of medication seemed to matter. In looking at the 3 most common beta-blockers that were used in Enroll-HD – metoprolol, propranolol, and bisoprolol – only some of the meds influenced some of the tests. Only metoprolol affected motor symptoms, and only bisoprolol affected the ability to carry out day-to-day tasks and thinking and memory.
Process or prescription?
These results beg the question – is it the medication that’s having the benefit or treatment of the underlying condition? To answer that question, the group also looked at another medication commonly prescribed for cardiovascular issues – ACE inhibitors.
While ACE inhibitors are frequently prescribed for similar health issues for which beta-blockers are given, ACE inhibitors did not have the same positive effect in this study. ACE inhibitors showed no positive association with HD onset and symptom progression. This suggests that there’s something specific about beta-blockers, and not just treating these heart-related issues, that is having this beneficial effect.
Limitations
The largest limitation of this study, which is noted by the authors, is that they’re looking at correlation, not causation. They can’t say for sure if the positive changes in onset and progression are caused by beta-blockers. They can only say these positive changes are associated with beta-blockers.
Studies like Enroll-HD allow researchers to dig through lots of data and are very helpful for pulling out this type of association. But clinical trials are needed to draw firm conclusions about the effects drugs are having. However, once scientists know about positive associations, they can then do specific experiments to get at exactly what is driving the association, which can lead to the development of other drugs, and future clinical trials.
The data is also limited in that the Enroll-HD database has limitations for collecting data from disease progression biomarkers, like neurofilament light (NfL). NfL is a molecule that’s released from damaged and dying brain cells. We know that NfL levels rise as HD progresses. However, we don’t know if NfL levels change with beta-blocker use. The second iteration of Enroll, which is currently being rolled out, is designed to expand in ways that will improve collection of biomarkers, including NfL.
The fine print
In studies like this that can only generate associations, there’s always some fine print. While we can’t say for sure if beta-blockers are the cause of these improvements, we can call out a few of the confounding variables to try and understand what else could be at play here.
We know that beta-blockers are frequently prescribed for anxiety. We also know that unchecked anxiety can impact motor symptoms in people with HD and have major effects on one’s ability to carry out day-to-day tasks. It’s possible that beta-blockers used to suppress anxiety had a positive effect simply because they reduced overall worry and unease, leading to improved daily life.
We know that HD causes vascular changes, particularly in the brain. We also know that treating low level hypertension with beta-blockers could have long-term benefits for vascular effects. So it’s possible that managing vascular changes early could be leading to some of the positive changes noted in this study.
We also know, for sure, that living a healthy lifestyle is correlated with later disease onset and slower progression. It’s likely that people going to the doctor for medical problems that would be treated by beta-blockers are more health forward, so they may exercise more frequently or eat healthier foods too. So it’s possible that at least some of the positive benefits noted in this study could be because those taking beta-blockers are, overall, more health conscious people.
Prescription for change
The major take home from this new study is that the use of beta-blockers is associated with delayed motor diagnosis in people with premanifest HD and delayed disease progression in people with early motor symptoms. However the most effective beta-blocker is unclear since the exact drug that showed benefit varied by experiment. And notably, dose was not examined since it varies wildly based on medication and indication for which it is prescribed.
If this study has you wondering if you or a loved one should start taking a beta-blocker for HD, please reach out to your primary care physician or neurologist. While beta-blockers are generally safe, there are contraindications for these medications, such as low blood pressure, COPD, and circulatory problems.
One thing that we learned unequivocally from this study is that the people participating in Enroll-HD are changing the face of HD research. With their help, scientists are uncovering critical information to generate ideas that will lead to future clinical trials. The strength of the HD community and their participation in these large observational studies is the real prescription for change.
Vico Therapeutics recently presented at several conferences to share an interim update on their Phase 1/2a clinical trial testing their drug called VO659, which targets the repeating C-A-Gs in people with Huntington’s disease (HD). These data suggest that VO659 may be able to reduce levels of the toxic HD protein in the small group of participants tested so far and gives insights into safety. But how does VO659 work and how is Vico’s approach different to that of other companies? Let’s get into it.
Too many C-A-G repeats are the cause of HD
In everyone’s genetic code, there are 2 copies of a gene called Huntingtin, often shortened to HTT. Near the start of the HTT gene code, there are repeating C-A-G DNA letters. In folks who don’t have HD, both gene copies will have less than 35 C-A-G’s repeating in a row.
However, people with HD will have more than 35 C-A-G repeats, typically in just one of the copies of their HTT gene. This expansion of the C-A-G’s in the DNA is the genetic cause of HD.
Our DNA is like a recipe book for the molecules that make up the cells of our bodies. Our cell’s machinery carefully copies down each recipe into a message molecule which can then be used as a template to make the protein molecule it encodes.
The HTT gene is the DNA recipe that encodes the HTT protein molecule. So if the DNA encodes a C-A-G expansion, we will also see this expansion in the copy of the message molecule and in the protein.
VO659 – a drug to target repeats
VO659 is a type of drug called an antisense oligonucleotide or ASO, developed by the Dutch company, Vico Therapeutics. VO659 is delivered by spinal injection so that it can spread through the nervous system and into the brain.
ASO’s are designed to specifically bind onto certain types of genetic message molecules, which results in them being sent to the cell’s trash can. Without the message molecule, the protein molecule they encode cannot be made, so the level of this protein will decrease.
VO659 is designed to target long strings of repeating C-A-Gs in genetic message molecules, like the one found in the expanded HTT message in people with HD. This means that treatment with VO659 should specifically decrease the levels of the expanded HTT in the cell.
Expanding C-A-G repeats cause disease beyond HD
HD is not the only disease caused by expansion of C-A-Gs, there are in fact a total of 10 diseases which have similar genetics. In addition to HD, these include other rare diseases such spinocerebellar ataxias 1 and 3, often called SCA1 and SCA3.
Like HD, SCA1 and SCA3 are also caused by genetic mutations which increase the number of C-A-Gs over a specific threshold and result in neurological disease. These C-A-G increases occur in genes called Ataxin-1 and Ataxin-3 for SCA1 and SCA3 respectively. The expanded proteins encoded by C-A-G expanded Ataxin-1 and Ataxin-3 are thought to be toxic and a key driver of SCA1 and SCA3 disease.
As VO659 is designed to target long C-A-Gs, this means that it could be a useful drug to help reduce the toxic proteins made by any C-A-G expansion disease, including HD, SCA1, and SCA3.
Preferential lowering of the toxic copy
Runs of repeating C-A-Gs are found in many different genetic message molecules. Indeed, the regular healthy HTT gene typically has ~18 C-A-Gs. So how does VO659 work to target disease message molecules?
Data previously presented by Vico at the 2023 CHDI Therapeutics Meeting, reported on by HDBuzz, showed that the drug prefers very long C-A-G’s so it mainly seems to target disease message molecules, like the expanded HTT message. This is a preference though, as the regular HTT message is still targeted by VO659, just to a lesser extent.
This is a completely different approach from other ASOs being tested in the clinic to treat HD. Some target total HTT (unexpanded and C-A-G expanded) such as tominersen developed by Roche, while others target only the disease-form of HTT, such as WVE-003 from Wave Therapeutics. Unlike Vico who are targeting the C-A-Gs that are present on both the expanded and unexpanded copies of HTT, [Wave’s approach uses a unique genetic signature] (https://en.hdbuzz.net/371 that’s only present on the expanded copy.
Basket trials can help us find new drugs for rare diseases more quickly
Given the promise that VO659 has for HD and other C-A-G repeat diseases like SCA1 and SCA3, the scientists at Vico Therapeutics designed a “basket trial” to test it out. A basket trial is where people with different diseases which have a similar kind of molecular alteration are grouped together into one trial.
The basket trial approach can help to more quickly assess the safety of a drug, as well as how well it works, in more people. HD is considered a rare disease with ~1 in 4000 people affected. SCA1 and SCA3 are even more uncommon, both with ~1 in 100,000 people affected.
With so few people, it can be very challenging to recruit enough participants for a trial exclusively for just one of these diseases. By grouping people with different types of C-A-G repeat diseases, it can help scientists more quickly and efficiently test a drug in the clinic which might work for all of them.
In this case, Vico enrolled people with SCA1, SCA3, or HD, all of whom have an increased C-A-G repeat in their Ataxin-1, Ataxin-3, or HTT genes, respectively, into their Phase 1/2a clinical trial.
Designing a trial to test VO659 in people with C-A-G repeat diseases
To be enrolled in the trial, participants must be 25-60 years old and have a genetic diagnosis of SCA1, SCA3, or HD. These tests report back a C-A-G number and to qualify for the trial, people with SCA1 need 41+, SCA3 need 61+, and HD need 36+.
Participants of the trial also need to be in the early stages of SCA1, SCA3, or HD. For people with SCA1 and SCA3, this was defined as mild to moderate disease with a Scale for Assessment Rating of Ataxia (SARA) score of 3-18. For people with HD this is defined as Stage I disease with a Total Functional Capacity (TFC) Score of 11-13 and a Unified Huntington’s Disease Rating Scale (UHDRS) Diagnostic Confidence Level (DCL) of 4. All of these acronyms stand for different clinical metrics which can help doctors measure how far along in disease someone is.
The data presented so far are from a total of 23 people enrolled into the trial; 6 with HD, 3 with SCA1, and 14 with SCA3. The trial seeks to test 3 different doses of VO659 (10, 20, and 40 mg) to work out which dose is safe and also effective at targeting the disease-causing message molecules. All of the people with HD in the trial are receiving the top 40 mg dose of the drug.
Everyone in the trial is receiving four doses of the drug given once every 4 weeks. However the trial is continuing for 23 weeks after dosing has ended, allowing measurements to be made of folks who have taken the drug, to see how well it may be working and how safe it is after dosing has stopped.
Interim update results – what do we know about VO659 so far?
This interim update was shared via a press release and also through presentations at the recent EHDN and ENROLL-HD 2024 meeting in Strasbourg in September, and at the International Congress of Ataxia Research (ICAR) in London in November. Let’s get into the new data…
Safety
In a Phase 1/2a trial, one of the most important things to be determined about a new drug is how safe it is in people. The recent press release from Vico states that the drug is generally safe and tolerated which seems like good news. However, when data from the interim update were presented at the recent EHDN and ICAR meetings, we learned that this wasn’t the full picture.
Of the 6 people with HD who were given the drug, 4 people experienced radiculitis, a painful condition related to nerve damage. All individuals who experienced this serious side effect, termed a serious adverse event (SAE) in clinical trial speak, received at least three doses of the highest amount of the drug tested (40 mg).
This is a side effect observed in studies investigating other ASO therapies. Vico plan to mitigate this issue moving forward by lowering the amount of drug given to people in the trial. Fortunately, 3 of the 4 people experiencing this side effect are showing signs of recovering.
All other side effects were minor, including headaches, dizziness, and nausea, and were in line with what was expected for this type of clinical trial.
NfL
Neurofilament light, also called NfL, is a biomarker of brain health. Measured in the spinal fluid, if NfL levels go up, it is generally an indicator that brain health is declining. (So, for NfL levels, up is bad and down is good.)
The data presented at ICAR and EHDN suggest that NfL might go up a bit after dosing in some people, which could be reasonably expected after a lumbar puncture. Looking at all the data collected so far for folks who have reached their 4th dose, the good news is that in nearly everyone who received the drug so far, the levels didn’t go up significantly in the long run.
In more recent data from the ICAR presentation, it actually looks like there might be a 2.5% decrease in 5 people with HD who received the 40 mg dose after 120 days, 5 weeks after their last dose. This is encouraging, but we should be cautious with data from such a small number of people.
HTT lowering
Vico looked at how the levels of the expanded HTT protein changed in people with HD who received the drug. As this expanded form of HTT is only made in people with HD, they had samples from just 6 people to look at. Two people in this group of the trial have very early HD so the levels of expanded HTT in their spinal fluid were actually too low to measure with confidence.
In the press release and presentation at EHDN, a 28% reduction in expanded HTT levels was seen for folks with HD receiving 40mg of the drug after their 4th dose. This shows that the drug is working as expected and lowering HTT levels.
In more recent data presented at ICAR, HTT levels were shown to be reduced by 38% in 3 people. This data was collected at 120 days, 5 weeks after these folks received their last dose. This seems to suggest that the effect of the drug is long lasting, and expanded HTT levels remain low even after dosing with the drug has stopped.
What about people with SCAs?
Data have been shared for folks in the trial with SCA3, to see how their expanded Ataxin-3 levels changed in both spinal fluid and blood samples. No change was seen in spinal fluid but it does look like the levels seem to go down in blood samples in some people.
There doesn’t seem to be a dose-dependent effect in these changes i.e., more lowering in people who got more drug. However, it’s very early days with very few people, so we might need to wait for more data from more people to know for sure.
What’s next for VO659?
More data
This Phase 1/2a study is ongoing and there is a lot more data to be collected. Until we have those final and complete datasets, we won’t quite know the outlook of this therapeutic approach for the different diseases being investigated.
Dosing strategy
Something we knew from the preclinical data (aka data gathered in the lab from cells in a dish or animals that model HD) shared by Vico is that this drug really seems to hang around and keep working for a long time after it is administered. The fancy science term for this is that the drug has a long half life. This can have potential issues if too much drug accumulates in specific tissues in the body over time, but can also have the benefit of meaning that you don’t need to dose people quite so often.
The radiculitis in 4 folks who received the highest dose of the drug could well be linked to the fact that the drug sticks around for a long time but we don’t yet know the exact cause. Moving forward, Vico have stated that they are planning to dose people with VO659 much less frequently, between 1-3 times a year, in future studies of this drug.
Another trial?
Vico believes that VO659 appears to be a promising treatment for people with SCA3 and HD. They are already in discussions with regulators on a plan for a phase 2 trial of this drug in people with HD.
At the end of the day, these early stage clinical trials are designed to test safety and tolerability of new drugs, which is exactly what Vico are working out with this trial. While there do seem to be a few potential safety issues with the highest dose of VO659 being tested, Vico are following up on those and evolving their strategy to address the issues they’ve seen. We’ll be sure to keep you updated as VO659 advances.
