HDBuzz

New research is challenging how we think about treating brain diseases, like Huntington’s disease (HD). A study from the lab of Dr. Steven Goldman shows that transplanting healthy early-stage support cells from humans into the brains of adult mice that model HD improves movement, memory, and even survival. But that’s not all — these cells, called “glial progenitor cells”, seemed to influence neurons in the mouse brain to behave more like young, healthy ones. By targeting glia, rather than the neurons primarily affected by HD, this work opens the door to a bold new possibility for treating the disease.

The Brain’s Backstage Crew Steps Into the Spotlight

When we think about HD, we usually picture the effect the disease has on neurons. And for good reason: HD is a brutal genetic condition that primarily damages neurons, which are responsible for movement, learning, and memory. Historically, treatments in development have tried to target those neurons directly by trying to rescue them, replace them, or trying to silence the gene that’s wreaking havoc.

But what if the health of those same neurons could be improved by targeting other key players in the brain? In new work from the Goldman lab, scientists looked beyond neurons and focused instead on the brain’s supporting cast: glial cells. These “helper” cells, long thought to simply keep neurons fed and cushioned, are gaining notoriety as active architects of brain health. And when they’re replaced with healthy ones, they might be able to rebuild broken circuits and better support brain functions.

Huntington’s Disease 101: A Genetic Domino Effect

HD is caused by an expansion of a genetic sequence of CAG repeats in a gene called HTT. If just one copy of this faulty gene is inherited, that person will develop symptoms if they live long enough. The disease hits the striatum hard, an area of the brain in the center of the head responsible for movement and learning. In the striatum, HD leads to the death of medium spiny neurons (MSNs), the cell type that acts as the region’s main communication hubs.

As MSNs die off, so does a person’s ability to move smoothly, think clearly, and regulate their mood. Many past approaches trying to develop treatments for HD have largely focused on the neurons themselves. But neurons don’t live in a vacuum, and this new research shows that maybe we’ve been ignoring the soil while trying to rescue the tree.

The Aha Moment: Glia Aren’t Just Scenery

Earlier studies hinted at something big: when scientists transplanted healthy human glial progenitor cells into newborn HD mice, the disease slowed down. The mice behaved more like mice without the HD gene, their neurons fired less erratically, and their brain structures stayed more intact. That was enough to get scientists asking if this could work in adult mice too.

This new study aimed to find out. Researchers took human cells destined to become glia (called glial progenitor cells) and transplanted them into the striatum of young adult mice that model HD. These weren’t baby mice with developing brains, they were five-week-old mice already showing signs of decline.

But neurons don’t live in a vacuum, and this new research shows that maybe we’ve been ignoring the soil while trying to rescue the tree.

Rebuilding From the Inside Out

The results were impressive and encouraging.

The transplanted glia didn’t just survive, they appeared to thrive. They migrated throughout the striatum, integrated into the mouse brain, and replaced the host’s damaged glial cells. Crucially, they didn’t seem to develop the toxic protein clumps that plague HD cells.

Also striking were the effects on the mice themselves. In tests of movement, HD mice treated with these cells seemed to run around like their healthy peers. On tests of memory and anxiety-like behavior, they seemed to perform almost normally. And they lived about two weeks longer, which is significant for an animal model that usually dies by 18 weeks. While there’s no 1:1 comparison to what that could mean for people, or even that this approach will work for people, that’s a huge improvement in mouse time.

Glia as Gene Whisperers

Next the researchers dove into the neurons themselves to better understand the influence the non-HD glia could be having on them. They used a technique called single nucleus RNA sequencing (snRNA-seq), which shows what genes are turned on or off in individual cells. In untreated HD mice, the MSNs had dialed down levels of genes for communication, structure, and synapse-building.

But when those healthy glia were around, the neurons started singing a different tune.

Key genes flipped back on. Pathways that help neurons grow, connect, and function seemed to be revived. Even the way the DNA was packaged inside the cells appeared to shift toward a healthier state. It’s as if the glia were sending out repair signals, coaxing the neurons into reactivating their own genetic programs to regrow.

Brains Rewired, Literally

And the recovery wasn’t just molecular. The scientists also saw changes in brain structure.

Using a clever tracing method with a modified rabies virus, they imaged the neurons’ dendrites — the branch-like structures that receive signals from other neurons. In HD, these become shriveled over time, like a withered tree. But in the treated HD mice, the dendrites of MSN appeared to be restored, like a healthy tree with lots of branches. 

In other words, the addition of new glia led to healthier neuron structure, which seemed to lead to better function. It seems the glia weren’t just band-aids, they were blueprints for rebuilding.

What’s Next? And What’s the Catch?

Of course, there are caveats. These glial transplants were done in young adult mice before full-blown symptoms. Whether the same effects can be achieved in much older human brains with HD is still unclear. Also, the mouse model used here progresses very quickly, at rates much faster than the human disease, so further studies in slower models are crucial.

And while the researchers uncovered some of the key pathways involved in the neuron-glia dialogue, we still don’t fully understand how glia orchestrate this repair. Are they releasing molecules? Forming special contacts? Changing the local environment? The answers could point the way to new drugs, or even glia-based transplantation therapies in humans.

It’s as if the glia were sending out repair signals, coaxing the neurons into reactivating their own genetic programs to regrow.

The Takeaway: A New Chapter in Brain Repair

This study offers more than just hope for a new HD treatment, it shifts our perspective on how we might treat this brain disease. And if future studies show that these results hold in older brains with more advanced disease, they could represent a sea change in when we might be able to treat HD.

Glial cells, once considered the backstage crew of the brain, are stepping into the spotlight as active healers, architects, and perhaps even directors of recovery. If they can rewire HD brains, might they be able to do the same in Alzheimer’s, Parkinson’s, or ALS?

We’re just beginning to understand the choreography between glia and neurons. But this research is a clear sign that to truly heal the brain, we need to stop looking at neurons in isolation and start thinking about the whole ensemble.

TL;DR: Glia Are the Brain’s Hidden Powerhouses

• Huntington’s disease damages neurons, but neurons don’t work in isolation, they are supported by glial cells.
• A new study transplanted healthy human glial progenitor cells into adult HD mice.
• The results seemed to show improved movement, memory, and lifespan.
• The glia also seemed to have an impressive effect on neurons, appearing to allow them to reactivate a healthy genetic program to grow and function like healthy neurons.
• This suggests glial cells could be a powerful new therapeutic tool, not just for HD, but potentially for other neurodegenerative diseases too.

Learn More

Original research article, “Human glial progenitors transplanted into Huntington disease mice normalize neuronal gene expression, dendritic structure, and behavior” (open access).

Do you remember playing “Simon Says” as a child? It was fun, silly, and surprisingly tricky. You had to listen carefully and only act when you heard “Simon says”. If you moved at the wrong time, you were out. It turns out that Simon Says isn’t just a playground game. It’s also a helpful way to understand what happens in the brains of people with early-stage Huntington’s disease (HD).

A recent study by Dr Marianne Vaugoyeau and her team of researchers from Marseille, France, investigated how HD affects attention and action impulsivity. Action impulsivity refers to the ability to stop ourselves from acting too quickly. This study showed that even before the more visible symptoms of HD appear, it may become harder for people with HD to manage their attentio, but not action impulsivity.

Everyday Life: Simon Says Moments

We’ve all had moments where our mind and body don’t quite sync up. Maybe you’ve started speaking before thinking, forgotten what you were about to say, or found your attention drifting in the middle of a task. It’s frustrating, and very human.

These everyday slips can occur more often and be more disruptive for people with early HD. They might interrupt a conversation even though they know they shouldn’t. Or they might buy an expensive fitness tracker on impulse, thinking it’ll be motivating,  you mostly use it to check the time.

These aren’t just moments of forgetfulness or distraction. They’re part of an invisible struggle in the brain, a tug-of-war between acting impulsively and trying to stay focused.

Why Does This Matter?

Understanding impulsive behaviour and attention issues in people with HD is important for several reasons:

• Early recognition: Subtle changes in attention and impulsivity could help doctors spot HD earlier and plan timely interventions.
• Better support: Families and caregivers might misread impulsive or inattentive behaviour as rudeness or laziness. Knowing it’s part of the condition can help reduce misunderstandings.
• New treatment possibilities: If we can target the brain systems involved in impulsivity and attention, we might improve quality of life, even in the early stages of HD.

The Adult Version of Simon Says

To explore these early changes, Dr Vaugoyeau and her team of researchers invited 20 people with early HDand 20 people without HD to take part in a computer task. 

In this study, ‘early HD’ refers to Stages 2 and 3 of the Huntington’s Disease Integrated Staging System (HD-ISS). For more information on HD-ISS categories, see our article about this system. In Stage 2, people with HD begin to experience symptoms. There may be changes in their movement, mind, and mood symptoms. The individuals affected can often still manage most daily tasks independently. In Stage 3, symptoms are more fully developed and have a bigger impact on daily life, meaning individuals usually need more support for everyday activities.

How to Play: Simon Says for Grown-Ups

The computer task was a bit like a grown-up version of Simon Says, and fittingly, it’s called the Simon task.

Here’s how it worked:

1. A green or red shape appeared on the screen. Participants then pressed a button on either their left or right hand, depending on the shape’s colour. Sounds easy? Not quite.
2. Sometimes the shape appeared on the correct side of the screen (e.g. shape on the left, press the left button). That’s like when Simon actually says what to do. No confusion, just follow the rule.
3. But other times the shape appeared on the opposite side of where you’d expect (e.g. shape on the left but press the right button). That’s similar to Simon being sneaky, your brain might want to follow the shape instead of the rule! 
4. The goal of this game? Ignore where the shape appears and focus only on its colour. It’s a fast-paced way to test how well people can stop, think, and act.

Thumbs on the Trigger (Sort Of)

During the Simon task, researchers placed tiny sensors on participants’ thumbs to measure muscle activity using electromyography (EMG). Sounds fancy, but it’s basically a way to eavesdrop on your muscles. EMG picks up the tiny electrical signals your muscles send out when they’re thinking about moving, sometimes even before you actually do anything. So even if a participant managed to stop themselves from pressing the button, the researchers could tell if their thumb had already whispered, “Let’s go!” This helped them figure out who was acting on impulse and who had better self-control, all by spying on a twitchy thumb!

What Did the Study Find?

People with early HD were able to do the Simon task, but they responded differently compared to those without HD:

1. People with early HD didn’t start moving their thumbs too quickly after the shape appeared on the screen. In other words, they weren’t acting on impulse.
2. Their brains took longer to figure out what to do. However, once they knew what to do, their physical movement was just as quick as people without HD.
3. They struggled to pay attention properly, like missing some of Simon’s instructions or getting distracted halfway through the task. Participant’s scores on attention-based surveys matched these findings.

Final Thoughts: More Than a Game

This study shows that even at the very earliest stages, HD begins to affect the way people respond, focus, and control their actions. But it doesn’t mean people with HD are acting impulsively all the time. Their brains just need more time to process what’s going on, and they may find it harder to stay focused. This research offers a hopeful message because it shows that even in early HD, the brain still retains control over actions and attention. Perhaps future treatments could focus on preserving these abilities, before more symptoms develop. It also gives people with HD and their families a clearer picture of what’s happening, making those frustrating moments feel less confusing.

After all, just like in Simon Says, the rules of attention can get tricky. But with the right tools and support, people with HD may stay in the game longer, and play it on their own terms.

TLDR:

• A “grown-up Simon Says” task helped researchers study attention and impulse control in early Huntington’s disease (HD).
• Electromyography (EMG) sensors detected tiny thumb muscle signals to see when movements were prepared, even if stopped.
• People with early HD showed slower processing and attention difficulties, but not increased impulsivity.
• Early changes in attention can help doctors spot HD sooner and guide better support and treatments in the future.

Learn More

Original research article, “Action impulsivity and attention deficits in patients at an early stage of Huntington disease” (paid access).

A recent study used miniature 3D brain models grown from stem cells to explore how the genetic change that causes Huntington’s disease (HD) might impact early brain development, before neurons even become neurons. What they found suggests that the tipping point that balances how cells mature may be off, and it could be because of changes in the cell’s energy powerhouse – the mitochondria. Let’s get into what they found, the major takeaways, and next steps.

Growing A ‘Mini-Brain’ In A Dish

You may have heard of ‘stem cells’ – cells that can be coaxed into becoming almost any cell type in the body, including neurons. Stem cells have been transformative for brain diseases like HD. They’re a powerful laboratory tool because they allow researchers to ask and answer questions in a controlled system of human origin, which is key for understanding the impact of HD in people. 

This powerful system was further advanced with the discovery of ‘induced pluripotent stem cells’, or iPSCs. iPSCs are produced through a method that adds molecules to turn adult cells, like skin cells, back into stem cells. Using this approach, new work is advancing what we know about HD.

One limitation of neurons grown from stem cells is that they’re typically grown on a two-dimensional plastic surface. Not very representative of the human brain! To overcome this challenge, researchers have developed a method to grow iPSCs in 3D, producing ‘mini-brains’ that resemble specific brain regions. 

Importantly, even though they’re referred to as mini-brains, they can’t develop consciousness nor can they be grown into a full human brain. Scientists like working with them because they have been shown to recapture key aspects of human brain development and are especially useful for studying developmentally early biological changes. 

The HTT Gene – Important For Brain Development

In studying brain development, researchers discovered long ago that the huntingtin gene, Htt, plays an important role – mice that lack the Htt gene do not survive as embryos. Using genetic experiments, scientists figured out that this was because of brain development changes; mice that had Htt levels specifically lowered only in the brain failed to develop healthy brains. 

A recent study sought to clarify how brain development is altered by HD in cells of human origin using mini-brains. They used iPSCs with 70 CAG repeats, which usually leads to the onset of juvenile HD. This is important because individuals with juvenile HD show unique symptoms compared to adult-onset HD. These symptoms are associated with disorders where early brain development is affected, like seizures. 

Genetic Changes In HD Mini-Brains 

When the researchers grew mini-brains with and without the gene that causes HD, they noticed that those with the HD gene were smaller in size than those grown from cells without the CAG expansion. When they dug into this, it appeared to be due to defects before the neurons themselves were fully formed. Specifically, these changes were found in ‘neural progenitor cells’ – precursor cells that turn into nerve cells. 

Similar disruptions of neural progenitor cells have been reported in human foetuses with a CAG expansion. These findings suggest that changes due to the HD gene seem to have a role in the development of the brain. And because those changes are seen in progenitor cells that are precursors for neurons, the HD gene specifically seems to contribute to changes in early brain development, before neurons are actually formed.

The researchers went one step further, trying to understand what is causing this disruption. The study looked at different gene signatures between iPSCs, neural progenitor cells, and mini-brains at two different ‘ages’, with and without the gene for HD. They found that 47 genes levels were changed across all samples. The gene that was lowered the most in all HD samples was CHCHD2 which stands for ‘coiled-coil-helix-coiled-coil-helix domain containing 2’ – what a mouthful! You can see why scientists prefer CHCHD2. 

A recent study sought to clarify how brain development is altered by HD in cells of human origin using mini-brains.

The Powerhouse Of The Cell – HTT Changes How The Cells Use Energy

CHCHD2 plays a crucial role in the health of mitochondria, the powerhouse of the cell. Mitochondria generate most of the energy that a cell needs to function. Because mitochondria are so important for the cell, they frequently undergo rigorous ‘quality control’, where damaged mitochondria are degraded within the cell. Mitochondria can become damaged or ‘stressed’ under many different circumstances, for example when a cell needs a lot of energy, becomes sick, or is exposed to toxins.  

CHCHD2 is involved in how mitochondria respond to stress, and in HD neural progenitor cells and mini-brains, other genes involved in mitochondria stress responses were also found at unexpected levels. Essentially, the research team seemed to identify a stress response related to mitochondria caused by HD that’s present even at very early stages of development. Ultimately, this could be damaging for cells and impact the way the brain develops. 

Mitochondria form complex networks within the cell and are also very active. They can divide to generate more mitochondria during stress, or they can fuse to optimise energy production. To study these networks, the researchers used microscopes to look at the shape of the mitochondria. 

They found that mitochondria shape in HD mini-brains was different – some mitochondria were more fragmented, but others formed very large structures. While mitochondria can change their shape in a healthy cell too, it can also be a further indicator that these cells may be damaged or stressed. In older mini-brains, these changes in shape became worse, suggesting that defects in mitochondria increase over time and that the quality control system behind keeping mitochondria in check could be impaired by HD.   

Cells Need More Energy In HD

A big implication here is that the change in mitochondria networks and shape could have an impact on how mitochondria generate energy for the cell. To understand this better, the researchers investigated how the neural progenitor cells utilise energy. In cells with the CAG expansion, more energy was used under ‘resting conditions’. This means that mitochondria could have to provide more energy for the cell. HD mitochondria also showed changes in the way they produced energy for the cell. 

The team then examined whether these defects are specific for the less mature progenitor cells or if they’re also present in neurons. Interestingly, they found that mitochondria in HD neurons generated less energy for the cell but used more energy themselves. 

And all of these effects seem to hinge on CHCHD2, because when the scientists boosted its levels in the mini-brains, the changes in mitochondria shape and function were erased. This suggests that if these results are also seen in other models of HD, CHCHD2 could be a potential therapeutic target for improving mitochondria changes.

Essentially, the research team seemed to identify a stress response related to mitochondria caused by HD that’s present even at very early stages of development. Ultimately, this could be damaging for cells and impact the way the brain develops. 

Takeaways And Next Steps

Overall, the results in the paper suggest that the HD gene may stress mitochondria, cause inefficient repair, and change the way they produce energy for cells, even in early brain development. 

An important caveat to this work is that most of the results were from cells where both copies of the Htt gene had the CAG expansion. This is very rare in people with HD and future work is needed to see if the results hold in models with just one copy of the HD gene.

One of the reasons this work is important is because mitochondria health and function in neural progenitor cells helps regulate the pace of development – orchestrating balance between which cells remain progenitors and which cells mature into neurons. Cells that commit to staying a progenitor or becoming a neuron on an altered timeline may be more sensitive to cellular stress in the future, contributing to their death in HD. 

This perhaps suggests that findings from this paper could help define the tipping point of developmental changes in the brain caused by HD. While more work is needed to see how these results hold beyond cells grown in a dish, this study highlights that mitochondria and energy production could be an early therapeutic target to consider. 

TL;DR – What You Really Need To Know

• Scientists used 3D “mini-brains” from stem cells to model early brain development changes in HD.
• HD mini-brains were smaller and showed defects before neurons fully formed.
• Changes were found in neural progenitor cells, the brain’s early builders.
• A key energy-related gene, CHCHD2, was reduced in HD models, disrupting mitochondria (the cell’s powerhouse!).
• HD cells burned more energy at rest and had oddly shaped, stressed mitochondria.
• Boosting CHCHD2 reversed the problems, pointing to a possible new treatment target.

Learn More

Original research article, “Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure” (open access).

A recent publication discusses a non-invasive way of measuring levels of expanded HTT protein in the brain, using an imaging tool called a PET tracer. The results were variable, but there’s still a lot to learn from the study as development of HTT tracers continues!

Measuring Levels Of Huntingtin In The Brain

One of the hallmarks of Huntington’s disease (HD) is the buildup of sticky protein clumps in brain cells. Known as “aggregates,” they contain bits of expanded HTT protein and other debris. Huntingtin aggregates tend to increase over time and there’s a lot of evidence to suggest that they contribute to damage in the HD brain. 

We have known for many years that these structures exist because scientists have studied brain tissue from animals and from people after they have passed. More recently, sensitive tests have been developed to measure levels of expanded HTT in living people using samples of CSF, the fluid that surrounds the brain and spinal cord. 

These methods have transformed our ability to test genetic therapies aimed at lowering HTT, but they are imperfect. It’s not clear exactly how well levels of expanded HTT from CSF reflect levels inside of brain cells. Wouldn’t it be great if there were a way to visualize in real time, without needles or the need to store and test samples, the amount of protein in there? 

That way, researchers could monitor how well a HTT-lowering drug was working, understand better how protein buildup corresponds with symptoms, and figure out who might be a good candidate for a clinical trial in the earliest stages of HD.  

Brain Imaging As A Way To Measure Expanded HTT?

Having a way to see features of the brain non-invasively is the idea behind PET tracers to image expanded HTT. A big HD research foundation, known as CHDI, has been working on this for several years, and they recently published a human study in collaboration with a clinical team in Leuven, Belgium. 

Positron emission tomography, also known as a PET scan, involves a radioactive molecule called a PET ligand. In this HD study, the ligand was designed to stick to clumps of the expanded HTT protein. The radioactive part of the ligand emits tiny particles that lead to a reaction producing bursts of energy (photons). A PET scanner detects these photons and calculates where they came from, and then a computer image shows all the places where the ligand is stuck.

Participants in a PET study received the tracer, then gave it time to reach the brain. Then they laid in a scanner that took images showing where expanded HTT is located and how much of it is present. Afterwards, the body cleared the tracer away. 

Over the past several years, CHDI had designed and selected an expanded HTT tracer, tested it in tissue, in living mice and monkeys, and most recently in a few healthy people to make sure it could be used safely. The recent study, called iMagemHTT, tested the tracer in 12 people with HD (who have expanded HTT in their brains) and 12 people without HD (who do not). They broke these groups down into younger and older individuals as well. 

Unfortunately, the tracer stuck to a lot of stuff that wasn’t expanded HTT, in some people more than others. This led to a lot of variability between individuals, both with and without HD.

The Challenges Of PET Imaging

The main goal of this study was to test the expanded HTT PET ligand in a larger group of people to look at its “dynamics” in the brain. This means making observations about how well it sticks to expanded HTT, how fast the body clears it away, how consistent it is between different people, and whether it can actually be used to measure levels of the expanded HTT protein in people with HD, compared to control participants who should have no expanded HTT. 

One challenge with PET imaging is that often the ligand will stick to things it’s not supposed to. When this one sticks to something that is not HTT, it lights up the brain in unexpected places and creates a “noisy” picture. Even in people without HD, who have no expanded HTT in their brains, there will be some tracer that grabs onto other proteins and shows up on the screen. Researchers who specialize in brain scans can apply all sorts of complex math afterwards to analyze the images, balance out individual and group differences, and help to see the real “signal” through the “noise.”  

There are many, many factors that can influence variability in measurements – things like age and individual brain differences, but even things like the time of day, or whether a person has eaten beforehand! For this reason, the team did multiple scans on the same person, sometimes in the same day, sometimes a week apart.   

What The Scanners Saw

In this HD study, the expanded HTT tracer entered the brain and was cleared away at rates typical for PET scans, and importantly, it did this similarly in people with and without HD. That tells us that HD doesn’t affect the ability of a person’s cells to take up the tracer or to break it down, which could skew the results. 

As for the meat of this experiment, visualizing expanded HTT itself: unfortunately, the tracer stuck to a lot of stuff that wasn’t expanded HTT, in some people more than others. This led to a lot of variability between individuals, both with and without HD. Applying one common type of analysis, this meant it was actually pretty hard to identify brains with expanded HTT and those without. 

However, another statistical method compares a person’s own cerebellum (the back, bottom part of the brain controlling posture and coordination) with the parts most affected by HD, and then compares between groups. When they analyzed the image data in this way, the expanded HTT ligand did bind more in people with HD compared to people without. This is what we would expect, given that people without HD don’t even have expanded HTT in their brains. 

Another observation they made was that if a person had 2 scans in one day, those two scans might look quite different from one another! When they had the scans a week apart, the results were less variable. This was surprising, but it’s important information that could be used later to determine the frequency and timing of PET scans for a future study. 

There are newer PET ligands actively being tested in tissue and animals that may stick better to the expanded HTT protein and less to other structures and debris. 

Why So Variable? 

After years of testing in tissues and animals, it’s a bit disappointing that this tracer didn’t produce a blazingly strong signal that would allow us to visualize expanded HTT in people with high accuracy. In fact, the authors conclude that this PET ligand isn’t the right one to move forward with for a clinical study or diagnostics in humans. But they can learn from the process, and there are new, better compounds in development that are likely to produce a much clearer picture.  

The authors speculate about the potential reasons for the discrepancy between promising data in animals and variable data in humans. Man-made models of HD don’t capture all of the features of disease in humans, and animal and human brain cells don’t always take up and break down substances in the same way. 

Additionally, the mouse models they tested have super-long CAGs and more clumps than people, and the monkeys were injected with genetic material that leads to extra expanded HTT protein – that could be why the tracer worked more clearly in animals. The tracer could also be sticking, not just to HTT, but to other types of protein clumps that build up during normal aging in people.       

Next Steps

Even though this particular ligand didn’t provide a clear picture of expanded HTT aggregates in the brain, the researchers can quickly apply these learnings to future studies. There are newer PET ligands actively being tested in tissue and animals that may stick better to the expanded HTT protein and less to other structures and debris. 

Future studies might include multiple scans spaced farther apart at the same time of the morning or afternoon, since that seemed to decrease the variability. They could also be designed to include more people, to increase the chance of drawing solid conclusions.

Ultimately, HD scientists are not giving up on the potential to use PET imaging to measure levels of HTT protein in a safe and non-invasive way. It would represent an important addition to the toolbox of methods for tracking HD and measuring the success of clinical trials. The approach simply needs a bit more tweaking, and meanwhile there are numerous research groups working to overcome these barriers with additional techniques. We’ll be sure to provide updates as they come! 

TL;DR — What You Really Need to Know

• A new PET tracer was tested to non-invasively measure expanded huntingtin (HTT) protein in the brain, which could help track disease progression and treatment effects in Huntington’s disease (HD).
• The tracer was safe and behaved similarly in people with and without HD, meaning HD doesn’t interfere with how the body takes up or clears the tracer.
  However, the tracer showed a lot of “noise”, meaning it stuck to things other than HTT, making it hard to clearly distinguish HD brains from non-HD brains in the scans.
• Some analysis methods did reveal more tracer binding in HD-affected brain regions, but overall, the results were too inconsistent to use this tracer in clinical trials or diagnosis.
• Surprisingly, scans taken just hours apart looked quite different, while those spaced a week apart were more consistent, highlighting the need to fine-tune scan timing in future studies.
• Despite the challenges, researchers gained valuable insights, and new, more specific tracers are already in development, keeping hope alive for PET imaging as a future HD biomarker tool.

Learn more

Original research article, “PET imaging with [¹¹C]CHDI-00485180-R, designed as radioligand for aggregated mutant huntingtin, in people with Huntington’s disease” (open access).

Welcome to your June roundup of the latest and greatest Huntington’s disease (HD) research, served up fresh and easy to digest! This month, we’ve got gene therapies revving up, brain wiring revealing surprising detours, and molecular firefighters missing in action. From emotional rollercoasters inside the brain to decoding irritability storms, June’s science brings us closer to understanding HD’s many twists and turns. Buckle up for a fun ride through the newest discoveries lighting the way toward better treatments and brighter hope.

The 2025 HDBuzz Prize for Young Science Writers Is Open!

The 2025 HDBuzz Prize for Young Science Writers officially opened this month! This year the competition is supported by the Hereditary Disease Foundation (HDF). We’re inviting early-career researchers, such as PhD students, postdocs, early stage investigators, and clinicians, who are actively involved in Huntington’s disease (HD) research to write an entry in accessible, engaging language. Beyond enhancing communication skills and bolstering CVs, winners will see their work published and syndicated globally, and receive a prize of US $200.

To enter, applicants should write a ~200‑word pitch explaining their proposed topic and its importance to HD families. Selected pitches will be invited to submit full articles. The deadline for pitches is July 1, 2025, at 5 pm ET. Winning submissions will be announced in autumn 2025, published in multiple languages, and help diversify the perspectives featured on HDBuzz. If interested, get cracking!

Full Steam Ahead: uniQure’s On Track With Hope for Accelerated Approval of Huntington’s Disease Drug

On June 2, 2025, uniQure shared that they’re aligned with the FDA about moving forward with their HTT-lowering gene therapy, AMT‑130. If the next round of results from their ongoing trial continues to meet endpoints and show positive results, an additional clinical trial wouldn’t be needed for a shot at accelerated approval. 

They’ve hashed out manufacturing plans (so they can make enough for folks should things work), agreed on statistical analysis plans around the cUHDRS and NfL biomarkers, and decided to compare AMT‑130 patients to the massive Enroll‑HD dataset instead of a traditional placebo group. All of this keeps uniQure on track to potentially submit an FDA Biologics Licensing Application (BLA) in Q1 2026 — fingers crossed! 

Looking ahead, uniQure is set to show off 3‑year follow-up data by the end of September 2025, and then regroup with the FDA in Q4 2025 to set sights on that BLA filing. If all goes to plan, this could mean the first-ever gene therapy approved for Huntington’s disease. But, full disclosure: the whistle hasn’t blown yet. Everything hinges on uniQure having strong data through Q3 2025. Here’s hoping that data delivers the signal we all want!

If all goes to plan, this could mean the first-ever gene therapy approved for Huntington’s disease. But, full disclosure: the whistle hasn’t blown yet. Everything hinges on uniQure having strong data through Q3 2025.

One Disease, Many Paths: How Brain Wiring Shapes Huntington’s Symptoms

HD doesn’t follow just one path. It rewires the brain in different ways depending on the symptoms. A new brain imaging study found that people with more movement and thinking issues reroute activity through backup circuits, like the brain’s version of side streets after a highway closes. But folks with mood and behavior symptoms lose connections more broadly, especially between emotional hubs.

These findings help explain why HD looks different from person to person, and why care should be tailored to each brain’s unique “traffic pattern.” It’s a step toward more personalized treatment, guided by how the brain is wired, not just what symptoms show up.

Inside the Brain’s Theme Park: How Huntington’s Disease Disrupts the Emotion Coaster

In Brainland, the theme park inside your head, the “Emotion Coaster” takes you through loops of joy, sadness, and anger. But for folks with pre‑manifest HD, the ride starts sputtering early on, especially when spotting anger, sadness, and fear on people’s faces. It’s like the coaster’s brakes get stuck, making it tougher to read emotional cues. This can be jarring when the rest of the park (memory, movement) seems fine.

A group at Harvard and MGH used MRI scans to map this coaster’s traffic patterns and found the brain zones that power emotion radar aren’t lighting up the way they should. When the coaster loses steam, social misreads can snowball, causing worked-up conversations, awkward moments, or missed cues. But here’s the silver lining: noticing this early wobble could let caregivers give a heads up, like the ability to add emotional training wheels before the big rides go haywire. Early detection could mean smoother rides ahead.

When a Short Fuse Becomes a Storm: Understanding Irritability in Huntington’s Disease

Living with HD can feel like walking around with a tiny temper volcano inside. In a new study, researchers spoke with people both before and after HD symptoms show up to explore what irritability really feels like. It’s not just a mood swing — it erupts suddenly, over little things, and leaves both the person with HD and their loved ones in a storm of frustration, confusion, and emotional exhaustion.

But there’s hope behind the clouds. The team broke down what triggers these “irritability storms” (hunger, fatigue, chaos, stress) and how people cope, through things like taking a break, leaning on friends, tweaking routines, or even using medication to ease the pressure. A major takeaway is that irritability is a real symptom of HD, not just grumpiness, and recognizing it means we can offer targeted support to help manage it with more grace and understanding.

The latest volume of HD genetics research reveals new gems but also mysteries

Researchers have just dropped the newest edition of HD genetics studies, and it’s unearthed hidden treasures (and a few puzzles). They’ve uncovered fresh genetic “spelling quirks”, from rare interruption variants that change how the notorious CAG repeat behaves, to tiny DNA flags that shift symptom timing by over a decade. Plus, they’ve spotlighted epigenetic tweaks in gene regulation, which act like traffic lights malfunctioning and causing genetic chaos in brain cell development.

But that’s not all. These findings raise big, yet awesome questions: Which of these quirks are the true game-changers, and which are just background noise? It’s a bit like discovering secret side quests in an open-world game — you know there’s cool stuff to unlock, but you need the right strategy to access the boss fights. In short, genetics has tossed us fresh gems…and a few cliffhangers, too.

Spark Therapeutics (now part of Roche) just kicked off a new gene therapy trial for HD and the first patient has been dosed with their one-and-done treatment, RG6662 (aka SPK‑10001).

Spark ignited: first HD patient dosed in new Roche gene therapy trial

Spark Therapeutics (now part of Roche) just kicked off a new gene therapy trial for HD and the first patient has been dosed with their one-and-done treatment, RG6662 (aka SPK‑10001). This AAV-delivered therapy is designed to permanently dial down levels of both expanded and unexpanded huntingtin protein via brain surgery, aiming for a lasting therapeutic effect. It’s been a saga: from academic discovery, to biotech startup, to Roche’s acquisition, now culminating in this exciting first-in-human milestone.

The Phase 1 “Part A” trial in the U.S. will start slowly and safely, dosing up to eight people with early-stage HD aged 25–65, with careful monitoring and potential dose adjustments. Subsequent phases include placebo-controlled arms while ensuring everyone eventually gets the real therapy, followed by long-term safety and effectiveness checks. Spark and Roche are partnering closely with HD advocacy groups and the Huntington Study Group, showing serious community engagement and transparency — a spark ignited indeed!

Trouble on the Block: When the Neighborhood Loses Its Best Firefighter

Imagine your brain is a neighborhood, and neurons are the residents. Normally, when things go awry, like a fire breaking out, PKD1, the brain’s “molecular firefighter,” rushes in to save the day. But in HD, PKD1 is missing in action, leaving neurons vulnerable to damage. Without PKD1, neurons can’t handle the stress from overactive signals and toxic buildup, potentially contributing to their decline.

Researchers have discovered that PKD1 levels drop early in HD, particularly in the striatum, even though the genetic instructions to produce it are still present. This suggests that the body knows it needs the firefighter but isn’t producing it properly. Understanding why PKD1 goes missing could help scientists find ways to bolster the brain’s defenses and protect neurons from the damaging effects of HD.

That’s a wrap on June’s HD research highlights! Each study adds a new piece to the puzzle, helping us better understand the brain’s challenges around HD. With gene therapies advancing and fresh insights into symptoms and brain changes, the future looks brighter than ever. Stay curious, stay hopeful, and we’ll keep bringing you the science that matters.