HDBuzz

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.

Picture a quiet neighborhood. Things used to run smoothly here. Kids played outside, front yards were mowed, and the neurons — the longtime residents — looked out for one another. But lately, fires are breaking out. And worst of all? The neighborhood’s most important firefighter, PKD1, has stopped showing up.

That metaphor details findings from a new study published in Cell Death and Disease. Researchers have found that a protein called protein kinase D1 (PKD1), long thought to be part of the brain’s emergency response system, is mysteriously missing in the brains of people with Huntington’s disease (HD). And when it’s gone, the damage gets a lot worse.

The Usual Suspects: Glutamate, Calcium, and Cell Death

Let’s rewind and talk about what usually sets the neighborhood ablaze. In the brains of people with HD, a specific group of neurons called medium spiny neurons (MSNs) are the most vulnerable. These cells are found in the center of the brain, in a region called the striatum. They are sensitive to a chemical called glutamate, one of the brain’s main message-sending molecules.

But when there’s too much glutamate activity, what scientists call excitotoxicity, the neurons get overwhelmed. Think electrical wires sparking, fires starting, no one around to stop them. This overactivity floods the cells with calcium, which in turn activates destructive enzymes like Calpain — basically a demolition crew that wasn’t invited.

Over time, the neighborhood falls into disrepair. A critical protein that MSNs need to stay alive, called DARPP-32, starts to vanish. This loss is a bad sign, like watching upstanding citizens move out of your neighborhood while bad actors move in.

Enter PKD1: The First Responder

For years, researchers believed PKD1 was one of the good guys, like a firefighter who runs toward the flames. In other types of brain injury, like stroke, PKD1 gets switched on and helps neurons survive. It does this in part by boosting another molecule that cleans up toxic waste known as oxidative stress.

In lab experiments run in HD mouse models, the scientists even engineered a version of PKD1 that’s always active, like a firefighter that never clocks out. That version, called PKD1-Ca, protected neurons from both excitotoxicity and oxidative stress. So far, so good.

Plot Twist: The Firefighter Goes Missing

But here’s where the mystery deepens. In brains affected by HD, both human and mouse models, PKD1 levels seemed to be decreasing. Not just in activity, but in the amount of protein. And that drop started early, especially in the striatum, a part of the brain most impacted by HD. These changes seem to be happening long before the cortex (the outer wrinkly part of the brain) was heavily affected.

In mice that model HD, the drop in PKD1 protein lined up with a drop in the levels of the mRNA message molecules which encodes the instructions to make PKD1. But in human brains? The instructions were still there, yet the protein was still missing. It’s like having the firehouse blueprints in hand, but no one’s building the station.

The disconnect between the amount of message and protein is still unclear. Maybe the PKD1 protein is being broken down too quickly. Maybe it’s getting misrouted. Or maybe there’s a larger system failure, like the emergency dispatch is offline and no one’s getting the call.

Researchers have found that a protein called protein kinase D1 (PKD1), long thought to be part of the brain’s emergency response system, is mysteriously missing in the brains of people with Huntington’s disease (HD). And when it’s gone, the damage gets a lot worse.

Support Crew Shifting Into Overdrive 

Here’s another wrinkle in the plot: researchers found PKD1 showing up in unexpected places, like reactive astrocytes. Astrocytes are a type of glial cell, the brain’s unsung support crew. They don’t send electrical signals like neurons, but they’re essential for keeping the brain running smoothly. Think of them as the neighborhood’s utility workers: regulating energy supply, cleaning up waste, and maintaining the environment so neurons can do their jobs.

Under normal conditions, astrocytes stay mostly behind the scenes. But in disease, they often shift into high gear, swelling in size, changing their behavior, and releasing signals that can either help or hurt. This state is called reactive gliosis, and it’s especially pronounced in HD brains.

The new twist is that researchers think PKD1, previously thought to live mostly in neurons, may be showing up in these reactive astrocytes, both in human HD brains and in parts of the mouse brain. The researchers aren’t quite sure how to interpret these findings. 

Are the astrocytes trying to rescue their neighborhood? Are they sending distress signals? Or is this just another sign that the brain’s usual systems are getting scrambled? Whatever the case, the discovery adds another layer to the mystery and suggests we may need to look beyond neurons to fully understand HD.

Putting It to the Test: What Happens Without PKD1?

To see if PKD1 was really making a difference, the scientists tested what happened when it was intentionally blocked. In a dish of rat neurons, they used a tool drug to shut PKD1 down. When those neurons were exposed to NMDA (a glutamate-like chemical that mimics excitotoxic stress), the results were disastrous: more neuron death, faster loss of the MSN-protecting protein DARPP-32, and full-blown cellular collapse.

Worse yet, just removing PKD1, even without adding stress, seemed to be enough to start the damage. It turns out this protein may not just be helpful during a crisis, it could be critical for normal daily maintenance, like checking the smoke alarms and fixing faulty wiring.

The Comeback Kid: Turning PKD1 Back On

Here’s the good news. When the researchers turned PKD1 back on using their always-active version (PKD1-Ca), the effect was dramatic. In HD neurons grown in a dish, PKD1-Ca protected the cells. It preserved DARPP-32 levels and blocked cell death. It gave the neurons a fighting chance.

The researchers also tested it in mice that model HD, delivering PKD1-Ca straight into the striatum. It worked there too. Not only did it seem to preserve DARPP-32 in the treated area, but there were signs that it might have helped nearby neurons as well, like one house getting reinforced and then sending help to the neighbors.

PKD1 could be more than just background noise in HD. This study suggests it may play an important role in protecting vulnerable neurons, and that its early loss could make those cells more susceptible to damage.

What It All Means

So what’s the takeaway? PKD1 could be more than just background noise in HD. This study suggests it may play an important role in protecting vulnerable neurons, and that its early loss could make those cells more susceptible to damage. Restoring or enhancing PKD1 function might offer one potential strategy for intervention, but much more work is needed to understand how, when, and whether this could translate into a treatment.

There are still big, unanswered questions: Why does PKD1 disappear in the first place? Why do mouse and human brains show different patterns of loss? Can boosting PKD1 be done safely, and what role are other cells, like astrocytes, playing in this story? These are important directions for future research.

What this study does offer is a compelling new piece of the HD puzzle. It pushes the field to think differently about the molecular players involved — not just about those sparking the fires in the brain, but about the protectors that may be missing when the flames start to spread.

TL;DR — What You Really Need to Know

• Huntington’s disease causes specific neurons in the striatum to die, partly due to overstimulation by glutamate (called excitotoxicity).
• A protein called PKD1 is normally protective, like a firefighter putting out molecular fires.
• In both human HD brains and mouse models, PKD1 protein levels are significantly reduced, especially early in the disease.
• Blocking PKD1 made things worse; restoring PKD1 protected neurons and preserved key proteins like DARPP-32.
• Boosting PKD1 in mice showed promise, not just in treated areas but potentially in neighboring cells too.
• PKD1 could be a potential therapeutic target, and understanding why it disappears may help us uncover how the brain’s defenses break down in HD, and how we might reinforce them.

Learn More

Original research article, “Down-regulation of neuroprotective protein kinase D in Huntington´s disease” (open access).

Spark Therapeutics, recently integrated into Roche Pharmaceuticals, has been working on an HD gene therapy. It’s delivered via a one-time brain surgery and is designed to lower levels of the huntingtin protein. A (very) small safety study has recently begun, and so far, one brave individual has received this experimental therapy, known as RG6662 (or SPK-10001). Let’s discuss how company relationships fuel clinical progress, and what’s next in the development of the drug. 

The relationship between Spark and Roche

To capture your interest with a romance, let’s talk about how these companies found themselves holding hands. Spark began as a biotech company about a decade ago, based on academic research at the University of Pennsylvania. They developed the first ever gene therapy for an inherited disease (Luxterna) to treat a type of vision loss. Roche became particularly interested in this, as well as their work on a blood disorder called hemophilia, ultimately purchasing the company in 2019. 

While fully owned by Roche, Spark continued to grow, building a big scientific campus for discovery and manufacturing, and working on more gene therapies, including one for HD. In 2024-2025 the company went through a bunch of restructuring, and in May of 2025, Roche announced a new relationship status: Spark has been fully integrated. That means Roche now has full control of how Spark is managed, how it operates, and the future of the drugs they have developed. 

Taking an HD drug from its academic research origins, starting then growing a company, and partnering with an even larger one to enable clinical development – that’s a story arc we can commit to following! 

RG6662/SPK-10001

When a big company acquires a drug in development, they usually rename or renumber it according to their own system. We’ve mentioned SPK-10001 in our coverage of major HD conferences like the 2024 annual meeting of the Huntington Study Group and the 2025 CHDI HD Therapeutics Conference. Now (gasp) it’s taken Roche’s name: RG6662.

It is an experimental gene therapy, packaged inside of a harmless virus called an AAV. When it is injected directly into the brain, it can spread to many brain areas and deliver genetic instructions (creating a microRNA) to tell the cells to stop producing the huntingtin protein. RG6662 lowers both expanded huntingtin – the kind that arises from extra CAG repeats and can harm brain cells – and wild type huntingtin – the kind that is a healthy length. The goal is to lower huntingtin for a very long period of time with a single treatment, in hopes that this could slow or stop the worsening of HD symptoms. 

Going public

Now that we’ve binged the first few seasons, let’s get up to date on the storyline. The Spark-Roche connection has birthed a new gene therapy trial of RG6662/SPK-10001. A June 12^th letter directed specifically to HD families and shared by advocacy organizations, stated that the first patient had been dosed in a small clinical trial. If it feels like this baby came out of the blue, rest assured that there have been massive efforts behind the scenes to take this new HD drug from bench to bedside. 

Notably, Spark representatives have presented updates on the pre-clinical science at the biggest recent HD conferences. Last November we touched on their efforts in primates to test the drug’s safety and confirm its ability to spread to different areas of the brain, lowering huntingtin for up to a year. In February they shared data from mouse and primate studies that looked more closely at dosing, delivery, and biomarkers like NfL. They have also talked about their work to optimize the surgical procedure, and their plans for the upcoming trial. 

The trial itself

The study will have multiple parts and it will move forward over several years. Spark and Roche announced initiation of the first part of the study (Part A), which will now pass fully into Roche’s hands. It will run in the USA and is planned to involve participants with early HD aged 25-65, with a CAG repeat length of 40 or more, who are mostly independent in their activities and care, and have a loved one who can be their study companion. In Part A, 8 participants will receive RG6662, as an injection into the caudate and putamen – the parts of the brain most vulnerable in HD.

Part A takes it slow, checking very carefully for safety. If all seems to be going well for the first recipient of RG6662 (they will be monitored for at least a few months), then Roche will proceed with the next participant. There may also be a “dose escalation” to test whether a higher amount of drug might be better. “Our team will learn from each participant’s experience, and we will adjust the study based on learnings,” Roche and Spark shared in the joint announcement.  

Part B of the study will include a placebo arm, so some of the participants will receive a “sham” brain surgery with no drug delivered. Then Part C would allow those who were assigned a placebo to receive RG662 later on, and Part D will involve long-term follow-up of all of the participants to look at safety and effectiveness over a much longer period of time. 

Looking to the future

We’ll have our eyes peeled for more news around the progress of this trial, of course – and we’re excited that another gene therapy has reached the clinic. What’s also notable here is the public display of affection partnership and engagement. Not all companies make joint community-facing announcements about the initiation of a study. Both Spark and Roche have a history of partnering with advocacy organizations early in drug development, and Roche’s learnings from the GENERATION HD1 and GENERATION HD2 trials will surely inform their strategy in HD moving forward. They have partnered with the Huntington Study Group, an organization with many years of experience running HD trials, to carry out the study. 

All in all, years of data and exploration in animals as well as many touchpoints with the HD community allowed Spark and Roche to move ahead with the design of a clinical trial in people. It’s particularly encouraging when companies use their knowledge, partnerships, and community connections not only to make scientific decisions around dosing and delivery, but also to integrate safety and support measures that meet the needs of people with HD and their companions. We’ll be sure to keep you in the loop as more sparks fly. 

TL;DR

• Spark Therapeutics, now fully integrated into Roche, has launched a small safety trial of a one-time gene therapy for HD called RG6662 (formerly SPK-10001).
• Delivered via brain surgery, the therapy uses an AAV vector to lower both mutant and normal huntingtin protein levels.
• The first participant has received the treatment, marking a major milestone after years of research.
• The multi-phase trial, starting in the U.S. with early-stage HD patients, will gradually assess safety and dosing before expanding.
• Spark and Roche’s collaboration emphasizes transparency and patient engagement, building on past HD trial experiences to guide their approach.

Community letter

The latest instalment in a series of big studies to understand the genetics of Huntington disease (HD) just hit the shelves. These studies have focused on how small changes in the genetic letters of a person with HD can impact when they develop symptoms of the disease. The previous instalments in this series have been particularly important for opening up new ways to understand HD and to develop new treatments. So let’s have a look at how this study was done, and what this newest volume tells us that is different from the previous ones.

The genome is a book, but we all have spelling changes

The genome of every person is made up of 4 letters – C, A, G, and T. They’re combined in different ways to make every gene in our body, like how the 26 letters of alphabet can spell out all sorts of different words on each page of a book. 

But we each have spelling changes on individual pages of our personal book (our genome) that differ from other people. You can think of these spelling changes as differences of a few letters that spell a similar word, like gray and grey. Sometimes a T is replaced by a G, or C is replaced by a A, just to give two examples. These changes can be shared with many other people – what we call common variants – or they might only be found in few other people around the world – which we call rare variants.

For many years, a group of talented scientists called the Genetic Modifiers of HD Consortium, or GeM-HD for short, have been looking at the impact of common variants – common genetic spelling changes – on how people develop HD. What this means is that they found common genetic spelling changes in people with HD and then looked to see if their symptoms of HD differed based on the spelling changes. 

To date, the GeM-HD consortium has studied thousands of people with HD and hundreds of thousands of spelling changes in every single person. That’s a lot of data to analyze! So new volumes in the series are only published about once every 5 years. 

The latest volume

This new study from the GeM-HD Consortium is the third. It comes after two big studies that the Consortium published in 2015 and 2019. 

The first study, published in 2015, was a true bestseller. It revealed that spelling changes in people who develop HD earlier or later happen on very specific pages (genes) of the human genome. Many of these pages (genes) with spelling changes that make HD appear earlier or later seem to be connected with how the CAG repeat that causes HD becomes longer or shorter. 

The discoveries by the Consortium in the first volume set off a major change in how scientists think HD develops – focused on how the CAG repeat gets longer or shorter in the body, a process called somatic instability. It also changed how drug companies think about developing new medications to treat HD.

The GeM-HD sequel, which hit the shelves in 2019, told us even more: that there are multiple spelling changes on specific pages (genes) that can impact HD in opposite ways. For example, one spelling change might make HD develop faster, but a different spelling change further down the page might make HD develop slower. 

The GeM-HD consortium has studied thousands of people with HD and hundreds of thousands of spelling changes in every single person. That’s a lot of data to analyze!

But this second volume ended with a cliffhanger mystery: do the spelling changes in people who develop HD earlier or later also change the length of the CAG repeat in people? Up to that point, it was mostly guessing, based on the pages where the spelling changes were found. That’s what this third instalment is about.

The plot twist

To explore whether the spelling changes that impact symptoms of HD also alter the length of the CAG repeat, the Consortium scientists took a clever approach: they compared the previously studied spelling changes on those pages (genes) with the number of letters for the CAG repeat on the HD page (gene), each on different pages of the book. 

Surprisingly, and perhaps confusingly, the answer is not always yes, and sometimes no. The Consortium scientists found that sometimes a spelling change can make symptoms of HD worse but have no impact on the length of the CAG repeat at all. The opposite can also occur – sometimes there are spelling changes that change the CAG repeat but don’t change the symptoms of HD. 

Does this mean that new drugs being designed to stop changes in the CAG repeat will not work? It’s not clear, since the Consortium scientists were only looking at changes in CAG repeats in the blood, which may have little to do with what’s happening the brain. That’s a story for another volume. But the third volume ends with one clear glimmer of hope.

A hero for the next story?

One of the pages (genes) where the spelling changes do what scientists hoped they would is MSH3. You might have already heard of MSH3 as a new drug target for HD, a strategy based on work from other skilled HD scientists, including teams in the UK and US. 

On the page (gene) for MSH3, the GeM-HD Consortium scientists found that spelling changes impact the CAG repeat in blood in a way that matches what drug hunters are now trying to imitate. This means that there is good evidence from the genetics of people with HD that the therapeutic approach of targeting MSH3 may work. However, we still don’t know exactly how all the spelling changes in MSH3 and other genes are impacting HD in the brain.

Perhaps we will find out more in the next volume from these scientists! But fans of the series may not want to wait another five years. 

Science made possible thanks to HD families

These pioneering studies of genetic spelling changes and how they impact HD could not have happened without the participation of thousands of people with HD and their families who donated their blood and DNA for research. Every person with HD who donated their blood and DNA to research helped to make these discoveries possible.

TL;DR

• GeM-HD scientists have released their third major study exploring how small genetic variations (spelling changes in DNA) influence when symptoms of HD begin.
• Earlier studies revealed some changes are linked to how the CAG repeat in the HTT gene changes, a key factor in HD. This new study asked whether those same genetic changes also directly affect the CAG repeat’s length.
• The answer? It’s complicated. Some variants influence symptoms without changing the CAG repeat, and others change the repeat without affecting symptoms. So, while CAG repeat instability matters, it’s not the whole story.
• One key finding supports the current drug-development strategy: changes in the gene MSH3 both affect the CAG repeat and align with symptom changes, reinforcing MSH3 as a promising drug target.
• This work, made possible by thousands of HD families donating DNA, continues to shape how we understand and treat HD, and hints at more discoveries to come in future “volumes.”

Learn more

Original research article, Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects (open access).