A new study led by researchers from University College London has helped uncover some of the earliest changes that happen in people with the gene for Huntington’s disease (HD), long before obvious symptoms begin. Very slight changes in brain scans and different metrics could be measured in young people with the HD gene who showed no changes in their thinking, behaviour, or movement. Measuring these very early changes paves the way for the HD community to begin thinking about testing medicines earlier in HD. Let’s get into it.

Finding out where it all begins

HD is a ‘CAG repeat expansion disease’. Everyone has a repetitive sequence of C-A-G DNA letters in their Huntingtin gene, but people who go on to develop HD have over 35 C-A-G repeats. The more C-A-Gs someone has in their Huntingtin gene, the earlier they are likely to experience symptoms.

HD is traditionally viewed as a disease which doesn’t impact folks with the HD gene expansion until they are in middle age. And it is certainly true that for the majority of people, they may not experience any obvious symptoms until well into adulthood.

However, folks have the genetic change which causes HD from birth, so scientists have long suspected that changes could be happening much earlier in the course of someone’s life if they have the HD gene expansion. We are also learning from recent clinical trial updates that some therapies might work better if we give them to people earlier, before their symptoms progress too far.

Seeing changes before they happen

But how would we know if drugs are working in young people with HD? If there aren’t obvious symptoms yet, then how would we know if we are slowing or halting the disease?

To try and solve these problems, many scientists have been working to study HD in people before they get symptoms. The idea is that if we can identify something that we can measure in younger folks with the HD gene expansion to predict their progression of the disease, then we might be able to show whether medicines are slowing or halting how HD is progressing by looking at that measure.

These measures are called “biomarkers” – biological metrics that we can track to see how HD is progressing in a person. The scientists in this study set out to try and pinpoint early changes in young people with the HD gene expansion in an effort to identify biomarkers for future drug trials.

HD community members made this study happen

Research like this can’t happen without the selfless volunteers who sign up for these studies, to whom we are all extremely grateful. Over 150 people participated in this study in total, roughly half of whom are people with the HD gene expansion, and the rest are people of similar ages without the HD gene expansion. These folks are part of the HD Young Adult Study (HD-YAS).

All of the people in the study with the HD gene expansion were categorised according to the HD Integrated staging system, or HD-ISS.. This staging system provides clear milestones for someone’s journey with HD. Stage 0 means that the HD gene is present, but there are no other changes. Stage 1 means that early changes in brain scans start to be observed. Stage 2 is when noticeable changes to movement and thinking also start to occur. Stage 3 is all of the above and when someone starts to have difficulty with daily tasks in their life.

When this study began, 81% of HD gene expansion carriers were at Stage 0, 17% were at Stage 1, and 2% were at Stage 2. So while they all had the HD gene expansion, most did not have noticeable signs or symptoms of HD. On average, these participants are about 20 years out from developing the movement symptoms associated with HD. This study took place over a very long timeframe of 4.5 years, during which about 20% of people with the HD gene expansion moved from Stage 0 to Stage 1, meaning that changes in brain scans could start to be measured.

From head to toe: comprehensive assessment of participants over 4.5 years

Participants in this study were assessed and tested in all sorts of different ways so that scientists could understand which factors might be changing over the course of the 4.5 years study, before the usual signs and symptoms of HD are obvious.

Clinical measures

The study included a large number of tests to look at thinking skills such as memory, attention span, and processing speed. They also assessed symptoms of mental health such as depression, anxiety, and sleep behaviours.

Over these 4.5 years, the researchers saw no significant differences to how thinking skills or mental health changed over the timeframe of the study between people with the HD gene expansion and people without. This tallies with previous studies from the HD-YAS group, where no differences were seen between young folks with the HD gene expansion and people of the same age without the HD gene when they looked at cognitive and psychiatric symptoms.

MRI brain scans

The research team also collected very detailed brain scans of folks in the study to see how different regions of the brain might be changing in size over time. They did this because some inner parts of the brain (called the striatum) get much smaller in HD and this is an early marker of HD in HD-ISS Stage 1. Shrinking of the striatum is thought to cause many of the symptoms of HD as disease progresses.

In people with the HD gene expansion but no symptoms, the researchers were able to measure decreases in the size of the striatum even though these individuals are two decades from when we would expect them to be diagnosed in the clinic and had no overt symptoms of disease. Some other measurements of brain volume were also more changed in people with the HD gene expansion.

When they broke down the data for people with the HD gene expansion into their respective stages, they could see a difference how quickly the striatum shrank between Stages 0 and 1, with a faster loss of brain cells in this region for people in the more progressed Stage 1. This finding aligns with our understanding that brain cells are lost at a faster rate as HD progresses.

NfL

NfL, or neurofilament light, is a biomarker that HDBuzz readers have heard a lot about recently, as it is commonly reported in HD clinical trial updates. NfL is seen as a biomarker of brain health, with increased levels generally indicating poorer brain health.

The researchers found that NfL levels in spinal fluid were shown to be much higher in people with the HD gene expansion than those without, and levels increased more rapidly for the HD gene group. Further, NfL levels also tracked with CAG number and age, with older folks with larger CAG numbers having the greatest changes to their NfL levels. Together, this further cements spinal fluid NfL as a very sensitive biomarker of HD progression, even at these very early stages of disease.

PENK

Proenkephalin, or PENK, is another marker which has been shown to track with the health of a type of brain cell called medium spiny neurons, the cells most impacted by HD. PENK differs from NfL as it decreases as this type of cell gets sick.

The researchers saw more rapid decreases in PENK in people with the HD gene expansion compared to people without the HD gene. Again, this was tied to CAG number and age, with older folks with longer CAGs having more drastic changes to their PENK levels.

Somatic expansion in blood

Somatic expansion is the phenomena by which the CAG number will increase in some cell types in the body over time. This idea is getting a lot of attention in HD research and you will have probably noticed that we are writing about it a lot as more and more studies are published.

Things really took off when genome-wide association studies pointed to somatic expansion as a potentially important factor for when symptoms of HD might begin. These studies look for genetic letter changes in our DNA code that are associated with earlier or later onset of symptoms than is predicted based on the CAG number alone. It turns out that many of these genetic letter changes are in genes which are involved in somatic expansion.

In this present study, the team looked at how much the CAG repeat number changed in cells from blood samples of participants. More expansions were found in blood cells of people with the HD gene expansion, with higher rates of expansion in folks with higher CAG numbers. The changes that are being measured here are tiny and it is rather incredible that the researchers can track this expansion from blood samples, where we know expansions are not very common, even in people with symptoms of HD.

Hearing these new results that detail the CAG repeat size increasing in blood samples may have you wondering if your CAG repeat number will get bigger over your life and if you should get re-tested for HD. In short, your repeat is very unlikely to change and you don’t need to get re-tested. The changes being detected in this study are super small – a win for sensitive experiments and a weight off your shoulders.

Other biomarkers

The researchers also looked at a host of other markers, completing an extremely thorough assessment of anything which might change more in people with the HD gene expansion compared to controls. This included the huntingtin protein itself which was barely detectable in most folks at this early stage, as well as markers of inflammation. Both huntingtin and these other markers of inflammation were no different to people without the HD gene expansion at similar ages.

How did these measures track with disease progression?

After making all of these measurements, the team next checked how they might track with disease, using the brain scan data as the mile markers for disease progression. Remember that shrinking of the striatum in brain scans is part of what defines Stage 1.

The researchers found that NfL and PENK levels at the beginning of the study could be used to predict how quickly cells are lost in the brain, even in people who are many years from experiencing symptoms. This is pretty amazing, given that these younger folks with the HD gene expansion had no detectable changes at all in cognition, memory, or their mood. The rate of somatic expansion in blood and how this changed over time also showed promise for predicting changes to brain structure and levels of NfL and PENK biomarkers.

This is the first time in humans that scientists have been able to link somatic expansion measured in blood with early brain changes, occurring approximately 20 years before movement symptoms begin. Scientists are very excited by this finding as it suggests that somatic expansion could be a key driver of brain cell loss in HD.

Why does this matter?

There are a ton of HD researchers at universities and in biotechnology and pharmaceutical companies who are working to develop treatments to try to slow down, halt, or even reverse somatic expansion. Many scientists were already convinced that this was a pretty good idea based on the genome wide association study data showing that instability might be associated with how early or late someone might experience HD symptoms. This study advances the field because we now have a sensitive biomarker in measuring blood CAG levels that can be used to detect changes before symptoms appear. This opens the door for clinical trials to begin in pre-symptomatic people living with the HD gene expansion.

Professor Sarah Tabrizi, who led this study, said: “Our study underpins the importance of somatic expansion driving the earliest neuropathological changes of the disease in living humans carrying the HD genetic expansion. I want to thank the participants in our young adult study as their dedication and commitment over the last 5 years mean we are truly nearing prevention clinical trials in Huntington’s disease.”

We would like to join Sarah and her team by thanking everyone who participated in this study. This research would not have been possible without you. The HDBuzz team is excited to see where this research points to next and looks forward to reporting on that soon.

It’s exciting to think about the treatments currently in trials that aim to halt or slow Huntington’s disease. But can we dream big and start thinking beyond that now? Could we one day not only stop Huntington’s disease but actually repair the damage it causes by growing and replacing the brain cells that have been lost?

Can we replace what is lost?

When we think about finding a cure for Huntington’s disease (HD), the first idea that often comes to mind is stopping or correcting the CAG expansion in the huntingtin (HTT) gene—the genetic mutation that we know causes this devastating condition.

Over the decades, we’ve learned a lot about the genetic root of HD, but this raises an important question: Even if we could fix the gene, what about the nerve cells in the brain already lost and the damage caused by the disease’s progression?

Replacing brain cells that have been lost offers an exciting possibility to restore lost brain function and, perhaps, reverse the devastating effects of the condition. By harnessing advancements in cell replacement, researchers are opening new doors for potential treatments.

The brain’s building blocks

To understand this possibility, it’s helpful to look at how the brain works. The brain is composed of many different types of cells, including neurons and glial cells. Neurons are the stars of the show—responsible for transmitting signals and forming the networks that control everything we think, feel, and do.

Most types of cells are “dividing cells”. For example, if a skin or liver cell is damaged, a nearby cell will divide in two to replace the damaged cell. But neurons are “non-dividing cells”. This means that if you lose a neuron to aging or disease, a nearby neuron won’t divide to replace it.

However, this isn’t the case for all cell types in the brain! The brain is also made up of a cell type called “glia”. Glia are support cells that provide structure, nutrients for neurons, and help to maintain a healthy brain environment. Importantly, glial cells can divide and replenish their numbers. Scientists are increasingly focusing on glial cells because we might be able to use them to regenerate neurons.

Remove, reprogram, replace

Thanks to decades of groundbreaking research, there’s now hope that even the brain’s inability to replace lost neurons could be overcome. One approach involves reprogramming cells outside the body. This means taking a specific type of cell—often bone marrow cells or other accessible cell types—out of the body, reprogramming them using genetic tools, and implanting them back into the desired area of the brain to complete their transformation into replacement neurons.

Leading researchers in this field, called regenerative medicine, like Dr. Malin Parmar, are translating scientific discoveries into clinical applications. Her trailblazing work focuses on developing techniques to generate dopamine-producing neurons, an approach currently being explored as a treatment for Parkinson’s disease.

These advancements are not only laying the groundwork for treating other neurodegenerative disorders, but also highlight the potential for tailored, cell-based therapies that could one day regenerate the neurons lost in HD. By demonstrating the feasibility of reprogramming and transplanting functional neurons into the brain, her research brings us closer to transforming these experimental approaches into clinical realities.

Although implanting new neurons into the brain comes with significant challenges—such as ensuring the new cells survive, integrate into existing networks, and function properly—clinical trials in this area for other diseases have already begun, demonstrating both feasibility and promise. The hope is that these advancements could help repair the damage caused by diseases, like Huntington’s, and restore lost brain function.

Conversions in the brain

Another exciting approach to generate replacement neurons is converting cells already present in the brain into neurons, all without the need for removing any cells and transplanting new ones. This is where glial cells, the brain’s “support team,” come into the spotlight. Glial cells share a similar developmental origin with neurons (we could even call them cellular cousins!), making them a natural and compatible choice for reprogramming.

The process involves “convincing” glial cells to activate specific genetic programs that guide them into becoming neurons. Think of it as flipping a switch in the cell’s genetic instruction manual, activating previously dormant neuron-making instructions.

Scientists like Drs. Magdalena Goetz and Benedikt Berninger (and many more) have identified certain molecules, called transcription factors, that act like master regulators to unlock specific genetic pathways. These transcription factors guide the glial cells through a carefully choreographed transformation, allowing them to acquire the structure and function of neurons.

This approach is particularly exciting because it sidesteps some of the challenges associated with cell transplantation, like immune rejection or difficulty integrating new cells into existing brain networks. By working directly within the brain’s existing cellular environment, reprogramming glial cells offers a promising, less invasive alternative for regenerating neurons lost in neurodegenerative diseases like HD.

But, how do you turn one cell type into another?

If you think about it, every cell in your body has the same DNA. When you were just an 8 cell blastocyst, those cells divided with the same DNA until you got to the person you are today. So the genetic code throughout every cell of your body is identical.

But why do certain cells look so different? Why do some become muscle cells that assemble into fibers to form your muscles, while others become cells that beat in your heart, and still others form the intricate networks of neurons in your brain? The answer lies in which parts of their DNA they “read” and use.

You can think of the genetic code as a massive instruction manual containing all the directions needed to create any cell type in your body. Every cell has access to this manual, but they only read the sections relevant to their specific role.
For example, a neuron reads the instructions necessary for developing and maintaining its complex tree-like structure that allows them to communicate with other cells. Meanwhile, other parts of the genetic code remain unopened, like chapters that aren’t needed for a neuron’s job.

Cellular cousins

Neurons and glial cells come from the same family tree, so glial cells already have access to the genetic blueprints for becoming neurons—they just need the right push to open those chapters of the book. Scientists are exploring how to provide that push, using tools like antisense oligonucleotides (ASOs), short hairpin RNA (shRNA), or viral vectors—the same kinds of technologies being investigated for HD treatments.

While this approach is still in its early stages, researchers have shown in animal studies that it’s possible to generate new neurons in the brain from glial cells. These studies offer hope, though translating these findings to humans remains a challenge.

Heading to the clinic

This research is still far from being prescribed by your doctor, but it is marching its way to the clinic. Some clinical studies have already tested transplanting engineered cells back into patients for conditions like spinal cord injuries, HIV/AIDS, and immune diseases.

This type of approach requires the use of medication to suppress the immune system to prevent rejection of the transplanted cells. If we could reprogram glial cells within the brain itself, we might be able to sidestep some of these challenges and create a treatment that’s both more effective and less invasive.

In fact, there are drug companies that are taking both of these approaches, working to develop cell replacement therapies for HD right now. Sana Biotechnology is a company working to transplant new brain cells to replace those that are lost in HD. NeuExcell Therapeutics is a company working in the HD space to convert glial cells already in the brain to new neurons.

In the fight against HD, stopping the disease would be a game changer—but imagining a future where we can also repair the brain is an exciting and inspiring possibility. The ability to regenerate neurons could transform not only how we treat HD but could also unlock the potential of the brain to heal itself.

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.

In 2024, these meetings included the CHDI Huntington’s Disease Therapeutics Conference in Palm Springs, the Hereditary Disease Foundation Milton Wexler Biennial Symposium in Boston, and the Huntington Study Group Meeting in Cincinnati. All of these meetings had stellar line-ups of over 100 talks, panels, and discussions about the hottest topics in HD research. We are excited to bring you more updates early in 2025 at the next CHDI meeting.

Basic research

Somatic instability

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.

Many members of the HD community are helping to drive this science forward by participating in clinical trials, observational studies, and surveys. None of the progress we have made over the last year would have been possible without you – the HD community. There are also practical steps we can all take to keep our brains as healthy as possible, preparing our future healthcare plans and needs, and making choices about family planning.

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.