People who develop Huntington’s disease (HD) are born with the genetic change that causes the disease. So why does it take decades, usually around 40 to 50 years, for the symptoms of the disease to appear? And why are certain brain cells more vulnerable to death than others? These have always been key questions in HD research. A new paper from the lab of Dr. Steven McCarroll gives us new insights into these questions, and it points a finger at the CAG repeats that are the genetic basis for HD.

Genetic stutter

At the genetic level, HD is caused by repeating C-A-G letters in the genetic code within the gene huntingtin, or HTT. However, we all have the HTT gene. In fact, we all have a stretch of CAGs that repeat within our HTT gene. It’s just that people who go on to develop HD have extra CAGs within their HTT gene – 36 or more. You can think of it like a genetic stutter.

In one of the biggest breakthroughs in HD research, scientists found that this genetic stutter actually gets bigger in some cells over time. This is a biological phenomenon called “somatic instability”, which is also sometimes referred to as “somatic expansion”. It’s the perpetual expansion of the CAG repeat in some types of “somatic” cells, or cells of the body. Researchers have found that the number of CAGs balloon in some cells, at times reaching up to 1,000 repeats!

However, some cells are more vulnerable than others to these effects of HD. Even though the CAG expansion that causes HD is found in every cell type in a person’s body, molecular signs of the disease are much more apparent in some types of cells compared to others.

All cells aren’t equal

Brain cells are most affected by HD. However, there are lots of different types of cells in the brain, and they’re not all affected in the same way. When people think of brain cells, they typically think of neurons – the tree-shaped cells responsible for directing our thoughts, feelings, and movements.

But there are other types of cells in the brain too. Glia are support cells that provide structure, nutrients, and maintain a healthy brain. Endothelial cells help form the blood-brain barrier, keeping harmful substances like viruses and some medications out of the brain. There are even different subtypes of neurons!

Medium spiny neurons, or MSNs, are a type of brain cell found in a region of the brain called the striatum that is almost exactly in the middle of our heads. MSNs help to control movement and coordination, and are particularly vulnerable to dying off as HD progresses. While we’ve known this for decades, no one really knew why. However, new experimental techniques, like those used by the McCarroll group, are getting us closer to the answer.

The beach vs. a sand grain

McCarroll’s team used a technique called “single nucleus RNA sequencing”. This let them look at the individual genetic signatures of every single cell in the brain samples they analyzed. It’s incredibly impressive! New single nucleus techniques, like those used here, are advancing what researchers know about HD because it transforms how they analyze samples.

About a decade ago, if you wanted to look at molecular changes in a tissue sample, you would chop it up and analyze it. Pretty crude in hindsight. This would give you a decent idea of the levels of molecules within an entire sample, but you wouldn’t be able to tell which cells were producing what molecules. This is kind of like taking a picture of the sand on a beach. You could probably tell if it was tan, or rocky, but that’s about it.

Single nuclei techniques allow researchers to zoom in and look at every single cell within a tissue sample. This would be like taking a sample of that beach and putting it under the microscope. So now instead of a uniform tan sample, you might see that some grains of sand are actually white fragments of shell, or blue pieces of sea glass; you get a much deeper understanding of the composition of that sample.

Expansions in single cells

When the researchers used single nucleus sequencing on brains of people who had HD, they found that CAG expansions were profound in MSNs, but not in other types of brain cells, like glia or other kinds of neurons. The authors suggest that we should perhaps reframe our thinking – rather than asking why MSNs are particularly vulnerable to cell death in HD, maybe we should be asking why somatic expansion is more prevalent in certain cell types, like MSNs.

From there, they could pull out the exact number of CAG repeats within each MSN for each brain sample. They could then map that against all the other genetic changes within each cell. Hopefully you’re starting to appreciate that this is a lot of data!

Mapping the number of CAG repeats with genetic changes, allowed them to calculate disruptions in those cells. Interestingly, they found that certain CAG repeat lengths were linked to the amount of genetic disruptions in the MSNs. So cells with CAG expansions between 36 and 150 didn’t seem to show signs of genetic disturbances. But once the repeats expanded beyond 150 CAGs, the changes they measured were huge. This suggests that something is going on inside the MSNs once the CAG length reaches 150 or more to disrupt the genetic signatures of the cell. But what?

Identity eroded

They dug deeper into the molecular changes that were happening inside the MSNs that had ultra-long CAG repeats of 150 or more. They were involved in the identity of the MSN itself – genes that make an MSN an MSN, and not another type of nerve cell.

As we covered, there are different subtypes of neurons in the brain. What gives them their unique identity is the genes and molecules that they produce. Some neurons produce molecules that inhibit the activity of other neurons, ensuring controlled and accurate movements. These are known as ‘inhibitory neurons’. Others produce molecules that accelerate and excite signaling between brain cells, which defines them as ‘excitatory neurons’. These definitions help researchers to classify neurons with identities.

As the CAG repeats stretched to 150 and beyond, the researchers found that MSNs began losing the genetic signatures of their cellular identity. Genes that should be off were on, and genes that should be on were off. The features that helped define them as MSNs were being eroded. Notably, in MSNs with ultra-long repeats, they found that the cells appeared to be turning on genes that cause cell death, perhaps providing a clue as to why this specific cell type is so vulnerable in HD.

Armadillo model

To explain their hypothesis, the authors describe their data as an armadillo-shaped curve. For our non-American readers, an armadillo is a small, armored mammal with a hard shell made of bony plates, native to the southern United States and South America. (Picture for reference.) They’re low to the ground, with a curved body, and long flat tail.

With the armadillo body shape in mind, the CAG lengths of most MSNs seem to fall under the curved body part of the animal during the initial decades of life. Once the cells get to about 80 CAGs, the expansions begin happening more rapidly, on the order of years. These few cells with increasingly longer CAG lengths fall under the long flat tail part of the armadillo. At 150 this process speeds up even further in this model, taking only months to acquire hundreds of more CAG repeats. It’s only when CAGs reach a length of 150 or more that they start to see detrimental effects on the cells.

Armadillo schmarmadillo, what about people?

To describe their model of a slow acceleration in CAG expansion, the authors detail a hypothetical situation for someone who inherited 40 CAGs. They postulate that the first phase of expansion occurs slowly in MSNs, taking about 50 years to go from 40 to 60 CAGs. The next phase occurs a bit faster, taking about 12 years to expand from 68 to 80 CAGs. From there, the cell reaches a tipping point, where expansion occurs more rapidly. In just a few years a cell could go from 80 to 150 CAGs. After that, the expansion to hundreds of CAG repeats could occur in a matter of months. During this last phase, genetic identity of the MSNs is lost, and the cell begins turning on genetic programs leading to its death.

It’s critical to note that this is a hypothetical situation. None of the time values stated here are set in stone and are only being used to describe this model. This does not depict an exact situation of what’s happening to the MSNs in the brain of someone with 40 CAG repeats.

It’s also important to know that this doesn’t happen inside every MSN in someone’s brain all at the same time. This is an asynchronous process, meaning MSNs will acquire additional CAG repeats at different rates, producing a mosaic of CAG repeat lengths. Timing here will also be highly dependent on environmental factors, lifestyle choices, and genetic modifiers, all known to contribute to the age of symptom onset.

Advancing what we know

This work challenges long-standing theories of some of the ways we think about HD. When protein aggregates were first discovered in the late 1990s, most researchers thought that those sticky protein clumps were causing the signs and symptoms of HD. Over the decades, the thought in the field has broadened, where many researchers now feel various molecular components contribute to disease, including a component that’s contributed by the genetic material itself.

This new paper stands firmly in the second camp – that “HD pathogenesis is a DNA process”, caused by instability in the genetic code brought about because of a tipping point in the number of CAGs in the HTT gene in certain types of cells.

This is the first paper to deeply analyze these ultra-long CAG repeat lengths. Previous work could really only sequence the CAGs out to about 150 repeats. While we’ve known since 2003 that these ultra-long repeats exist, we just haven’t been able to read the DNA sequence. It’s actually technically quite challenging to get accurate sequences of very long stretches of repeating DNA letters!

The best time to treat HD

There’s been rigorous debate about the best time to treat HD. Of course it’s always easier to preserve something rather than trying to restore it. So general consensus has become that treating HD before symptoms appear would be the best time. But does that mean treating HD after symptoms appear wouldn’t have any benefit?

Encouragingly, this new work suggests that approaches targeting somatic instability may be successful even after symptom onset. That’s because CAG repeat expansion happens in neurons asynchronously. So even if some MSNs have acquired so many CAGs that they’re already turning on genetic programs leading to their death, other MSNs haven’t. Those are the ones that could be targeted to slow or stop HD progression.

What does this mean for HTT lowering?

The first potential disease-modifying approach out of the gate was HTT lowering. Afterall, we know the genetic cause of HD is expanded HTT, so it’s a very logical approach to lower expanded HTT levels for therapeutic gain.

There’s also lots of hope with other approaches, including targeting somatic instability. Lots of people are focusing on this area, and we’ll undoubtedly see these approaches coming to the clinic soon. But this doesn’t mean we should abandon HTT lowering approaches!

HTT lowering approaches had a rocky start, but we’ve recently received positive updates from several clinical trials suggesting that HTT lowering as an approach may be having clinical benefit. These studies are the first evidence we’ve ever had that something could be working to slow clinical signs of HD. So we definitely don’t want to stop now!

Zooming out for clarity

For the HD community, it’s important to remember that this type of deep molecular work is looking at cellular and molecular changes in a particular cell type. While the striatum is the most affected area of the brain by HD with MSNs certainly being the most vulnerable cell type, other areas of the brain and body are also affected by HD. Since this paper specifically looked at the striatum, we don’t yet know if these same types of mechanisms related to somatic instability are also at play in other areas of the brain and body.

It would be nice if science were black and white, but unfortunately it’s not. Somatic instability does seem to be a key in understanding HD, but it’s likely not the only driver of disease. There are likely various biological mechanisms contributing. Other work suggests that ultra-long CAG repeats aren’t causing death of cells in the cortex (the wrinkly outer bit of the brain). Since this part of the brain is also affected by HD, it suggests that somatic instability isn’t the only thing we should focus on. So diversifying therapeutic approaches, like with HTT lowering as well as targeting somatic instability, is our best bet.

And finally, we’d be remiss if we didn’t mention the people and families who made the selfless and generous decision to donate their brains to advance this research – thank you! These types of findings that challenge current thinking in the field are what drive research forward and take us in new scientific directions, helping to define truth in this disease and discover new treatments. That all relies on the strong partnership we have between the researchers and the HD family community.

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.