HDBuzz

Sleep is more than a nightly recharge, it is fundamental to brain health. A landmark 12-year study tracking people with the gene for Huntington’s disease (HD) suggests how specific sleep disturbances could be used to predict disease onset and related cognitive decline. Early sleep changes appear to emerge years before symptoms, while insomnia during the night seems to worsen near disease onset. These findings highlight sleep’s contribution to HD and suggest potential new paths for early detection and treatment.

Understanding Huntington’s Disease and Sleep: A Broken Clock in the Brain

HD is a genetic neurodegenerative condition causing progressive nerve cell damage, usually starting in midlife. It brings a mix of movement problems, cognitive decline, and emotional symptoms. Because HD’s genetic cause and typical timeline are known, it provides a rare “model system” to study early changes caused by brain diseases, including sleep disruptions.

Sleep is often overlooked as just passive rest. But imagine your brain’s sleep system as a finely tuned clock. In HD, this clock begins to break down long before symptoms appear. Scientists have known that sleep quality worsens in HD, but the exact timing, causes, and consequences have been elusive. This new study offers a rare, detailed glimpse into the brain’s broken clock and its potential connection to disease progression.

The Study: Following Sleep, Cognition, and Disease Over 12 Years (!)

Researchers followed 28 people with the HD gene but no symptoms (pre-manifest) and 21 people without the HD gene (controls) matched by age and sex. But this wasn’t a one-and-done study – they followed these people for 12 years! That’s a long time! Participants underwent rigorous sleep studies twice in a lab and wore wrist monitors at home for two weeks, providing detailed short- and long-term sleep data.

They also took tests measuring attention, memory, and executive function, and completed mood questionnaires. A blood test was used to measure neurofilament light (NfL), a protein released by damaged nerve cells that research strongly suggests tracks with HD progression. 

Crucially, after 12 years, 15 gene carriers had “phenoconverted”, meaning they developed clear HD symptoms. Comparing their sleep and cognitive trajectories to those who remained symptom-free gave powerful insights.

Sleep is often overlooked as just passive rest. But imagine your brain’s sleep system as a finely tuned clock. In HD, this clock begins to break down long before symptoms appear.

Key Findings: Sleep Disturbances Mirror and Predict Brain Decline

At the study’s start, there seemed to be no major differences in sleep or cognition between gene carriers and controls. But over time, particularly in those who went on to develop clinical signs and symptoms of HD, sleep problems appeared to emerge.

Sleep seemed to become highly fragmented, as if the clock was literally ticking off time, unable to settle into stable stages. Almost 90% of converting participants had “sleep maintenance insomnia”, meaning they were waking frequently after falling asleep and had disrupting restorative rest.

This insomnia seemed to be strongly linked to worse cognition, particularly attention, processing speed, and executive function, skills vital for planning and multitasking. It also seemed to track with higher depression scores and elevated NfL levels, suggesting a potential tie to ongoing nerve damage.

Interestingly, sleep stage instability, the “ticking” disruptions, seemed to start earlier, even before symptoms, and apparently could predict who would develop HD over the next decade with about 70% accuracy. In contrast, insomnia appeared closer to symptom onset but couldn’t be used to predict future conversion.

These findings suggest different sleep problems play distinct roles across the disease timeline, some as early warnings, others as markers of active disease progression.

What Does This Mean? Sleep as a Window and a Target for HD

This study suggests that sleep issues might not just be a symptom but possibly a contributor of brain decline in HD. If sleep maintenance insomnia participates in cognitive problems and nerve damage, treating it early might slow progression or improve quality of life.

Sleep changes, like instability and insomnia, could become valuable early biomarkers, helping identify who is at highest risk before symptoms appear. This opens exciting possibilities for monitoring and intervention.

Strengths and Limitations of the Study

The 12-year follow-up is an extraordinary commitment, offering rare long-term data in a genetically defined population. Combining lab-based sleep measurements with home readings strengthened confidence in the sleep findings.

Grouping participants by actual symptom onset instead of predicted timing improved accuracy in this study. Depth was added with the comprehensive cognitive, mood, and biomarker assessments.

Limitations were that this was a small study of only 28 people, which got smaller at the 10- and 12-year follow ups. This is to be expected with such a long-term study, but this limits statistical power. It’s also important to remember that correlation does not prove causation, so sleep problems could be parallel effects of the disease rather than causes of changes to brain health. It’s also important to remember that this study focused on early stages, so findings might not apply to people with later stages of HD.

These findings suggest different sleep problems play distinct roles across the disease timeline, some as early warnings, others as markers of active disease progression.

Final Thoughts: Fixing the Broken Clock Could Change Everything

This study is a fantastic reminder that sleep is deeply woven into brain health and disease, for people with HD but also for everyone else. We all need a good night’s sleep for optimal brain function, but this is particularly true for those under stress, like caregivers and folks with diseases like HD. In HD, a broken sleep clock seems to precede and parallel nerve cell damage and cognitive decline.

When we recognize sleep as an active player in our brain health, not just a passive symptom of disease, it invites new research and therapeutic strategies. Could improving sleep quality delay HD symptoms or protect the brain? Might sleep measures become early warning signals for multiple neurodegenerative diseases?

The clock is ticking for people with HD. But understanding how it breaks, and how to fix it, could offer new hope in this devastating disease.

TL;DR – What You Need To Know

• A 12-year study tracked sleep, cognition, mood, and nerve damage biomarkers in people with the HD gene.
• Early sleep instability predicted who would develop HD symptoms years later.
• Sleep maintenance insomnia emerged near symptom onset and suggested a link to worse cognition and nerve injury.
• Sleep disruptions seemed to be closely tied to HD progression and might drive brain decline.
• Treating sleep problems could improve outcomes and slow disease progression.
• Sleep measures might serve as early biomarkers for HD and other neurodegenerative diseases.
• The study’s long follow-up and multi-method approach strengthen findings, but sample size was limited.

Learn More

Original research article, “Sleep abnormalities are associated with greater cognitive deficits and disease activity in Huntington’s disease: a 12-year polysomnographic study” (open access).

We learned on July 25, 2025 that Prilenia’s application to the European Medicines Agency’s (EMA) for pridopidine was not accepted for marketing authorization. While this is perhaps not surprising given the data around this drug in clinical trials thus far, it still comes as a great disappointment for the HD community. So what does this mean for the future of pridopidine? Let’s discuss. 

What is Pridopidine?

Pridopidine (previously called huntexil) is an experimental oral drug being developed primarily for Huntington’s disease (HD), and now also for ALS. It was originally thought to act by influencing dopamine signalling with the hope of improving movement symptoms for people with HD.

However, continued scientific research suggested that its effects seem to be mediated by activation of the sigma‑1 receptor (S1R), a protein found in nerve cells that helps manage cellular stress to maintain healthy cellular function. 

Pridopidine Clinical Trials

Multiple trials including HART, MermaiHD, and PRIDE‑HD found that while pridopidine was safe and well tolerated, it failed to meet its primary motor endpoints. Yet post‑hoc analyses, which is a way to examine data after the trial is run, suggested there might have been possible benefits in Total Functional Capacity (TFC) in some people with HD. TFC scores measure how well people can function at tasks like managing their households and finances, ability to work, drive, cook, and do other day-to-day activities. 

Pridopidine works through activation of the sigma‑1 receptor (S1R), a protein found in nerve cells that helps manage cellular stress to maintain healthy cellular function. 

That possibility of a benefit in TFC led to the Phase 3 PROOF‑HD trial focusing on function rather than motor symptoms. Post hoc analyses, like this one which pointed to TFC, are generally not sufficient for drug approval but can give insight into a subgroup of people or a dosage where the drug might be working. 

So while PROOF‑HD did not meet its pre‑specified primary endpoints in the overall population, exploratory subgroup analyses (especially excluding participants on dopamine‐altering medications) showed there may have been some favorable signals on function, cognition, and motor measures, though those results remain inconclusive.

Applying for EMA Marketing

Based on these potential favorable data in a subset of people with HD not on certain medications, Prilienia applied to the EMA for marketing approval in September of 2024. 

This application involved putting together a massive dossier of information that contained all the previous data around pridopidine. If it was approved, that would mean Prilenia would have the right to sell pridopidine in Europe for the treatment of HD. If it was rejected, that would send Prilenia back to the drawing board. 

After Prilenia submitted their application to the EMA, they announced a partnership with Ferrer, a Spanish pharmaceutical company. Their partnership was intended to further develop and commercialize pridopidine.  

So where do we stand?

July 2025 Update

In their most recent update, Prilenia and Ferrer shared that the EMA refused authorization for pridopidine’s marketing authorization application for HD. This means pridopidine will not be sold for the treatment of HD in Europe. 

Despite what will undoubtedly come as a disappointment for many in the HD community, Prilenia and Ferrer emphasized their continued commitment to advancing pridopidine for the HD and ALS communities. In their statement, they said their plan is to initiate a “potentially registrational global HD study” in the near term. 

So it appears that while Prilenia and Ferrer have been dealt a setback, they don’t have plans to discontinue advancing pridopidine for HD. Like you, we’ll have to wait to hear more from these companies about their specific plans. 

Looking Forward

The failure of advancement for any HD drug is a massive disappointment. However, the data around pridopidine suggested this was the likely outcome, at least for now. While we did our best to temper expectations within the community, we understand that many HD families were still holding onto hope. That hope is never misplaced; it’s what drives the entire research effort forward.

At HDBuzz, our job is to share not just the excitement, but also the realities based on the best available science. We don’t take lightly the responsibility of being your trusted source, and we’ll continue to bring you the clearest, most objective updates possible — no hype, no false hope, just real science.

In their most recent update, Prilenia and Ferrer shared that the EMA refused authorization for pridopidine’s marketing authorization application for HD. This means pridopidine will not be sold for the treatment of HD in Europe.

Even with setbacks like this one, 2025 has already been a remarkable year for HD research with positive updates from uniQure and PTC Therapeutics, a trial from Skyhawk Therapeutics advancing, and the first doses being given in Phase 1 trials by Spark Therapeutics and Alnylam. And there’s still more news expected to come! 

Promising trials, innovative approaches, and new insights are on the horizon, all pushed forward by you, the HD community. So don’t give up hope, because the path to progress is rarely straight, but it is still moving forward. And we’ll be here to walk it with you, every step of the way.

TL;DR

The European Medicines Agency (EMA) has rejected Prilenia’s application to approve pridopidine for treating Huntington’s disease (HD) in Europe.

Although safe and well-tolerated, pridopidine failed to meet primary endpoints in several trials, including the Phase 3 PROOF-HD study, though some exploratory subgroup data showed modest signals.

Despite the setback, Prilenia and Ferrer remain committed to developing pridopidine.

Learn more

Original press release (open access).

An international collaboration between world leaders in Huntington’s disease (HD) that spans both academia and pharmaceutical companies is giving us new insight into how HD progresses. This study has given researchers a detailed timeline of how brain connectivity changes in HD. Using an advanced technique called MIND, researchers traced how brain communication networks shift over decades, from a chaotic overdrive to widespread breakdown. They found that these shifts aren’t random, they’re shaped by disease stage-specific changes that unfold in a dynamic, evolving way. Picture the brain as an orchestra, desperately trying to keep the music going, only to fall out of sync as the HD progresses.

Act I: The Brain’s Opening Crescendo – Hyperconnectivity

In the earliest stages of HD, years, even decades before symptoms arise, the brain isn’t going quiet. In fact, it’s playing louder. A new study used a large collection of data from the observational studies TRACK-HD, TrackOn-HD, and the HD Young Adult Study (YAS). These studies aren’t testing a drug, but are rather designed to follow people with HD as they naturally live and age. They have followed hundreds of people without and with HD for many years, spanning people aged 18 to 65 in all stages of HD. This is a huge dataset!

A major finding of this study is that hyperconnectivity, a state where brain regions are over-communicating, is one of the first detectable features of HD. It can emerge more than 20 years before motor symptoms begin, sometimes even in childhood.

You might expect that a brain with HD would steadily lose function over time. But that’s not what this research showed. Instead, the early HD brain looks like an orchestra where multiple sections begin to play too loudly, as if trying to compensate for someone in their section who was a no show. This might be the brain’s attempt to maintain performance despite early, subtle losses in some neurons.

However, just like an orchestra playing too loudly and out of sync, this early overactivity isn’t necessarily healthy. It was linked to changes in neurofilament light (NfL) levels, a marker that tracks with brain health and nerve cell breakdown and can be measured in blood or brain fluid. So while the early hyperconnectivity might reflect compensation, it’s also a sign of stress, suggesting the brain might be straining to keep the music going.

Act II: The Middle Movement – When the Conductor Walks Out

As HD progresses toward the late pre-manifest stage, a sharp transition appears to occur. That initial hyperactivity doesn’t seem to last. The overactive brain networks begin to falter, and the orchestra loses its timing. This is the point in the concert where the conductor might walk offstage, leaving the musicians to drift out of sync.

The study found that in this mid-stage of HD, a new mechanism kicks in: trans-neuronal spread. This is the idea that the disease-causing HD protein might propagate from one brain region to another along neural connections, almost like a bad note spreading from section to section. The brain’s communication network becomes a route for the disease to move and intensify.

Interestingly, researchers identified specific “epicenter” regions of the brain that seemed to play a role in this trans-neuronal spread only in this mid-stage. It’s as if the disease chooses a few critical players in the orchestra to sabotage the rest. But this is a limited window; the epicenter-driven spread fades as the disease continues, reinforcing the idea that HD progresses in distinct stages.

Using an advanced technique called MIND, researchers traced how brain communication networks shift over decades, from a chaotic overdrive to widespread breakdown.

Act III: The Finale in Dissonance – Hypoconnectivity and Breakdown

By the time someone reaches the stage of HD where symptoms are outwardly visible, the music has largely fallen apart. The orchestra is no longer too loud, instead it’s eerily quiet. The study revealed widespread hypoconnectivity, a dramatic reduction in communication across the brain’s major networks. This was observed in 48 out of 68 brain regions, suggesting a systemic breakdown.

The instruments, or more precisely, the brain’s long-range brain cell connections, appeared to no longer be functioning. Think of the violins missing half their strings, the wind section gasping for air, the percussion fading into silence. This breakdown strongly correlates with high levels of NfL, indicating extensive damage to the brain’s wiring.

Yet even here, a few sections persist. The occipital cortex, responsible for visual processing, showed some pockets of increased activity. Unlike the rest of the brain, these changes didn’t correlate with NfL, raising the possibility of resilience or compensation. Maybe a few musicians are still trying to play, even after the rest of the orchestra has gone silent.

Behind the Music: The Cellular Players and Their Shifting Roles

So what drives this shifting performance? The study points to a fascinating interplay between different biological mechanisms that dominate at different stages. Early on, the disruptions are primarily driven by toxic processes within individual neurons. It’s like certain musicians playing the wrong notes, regardless of what the conductor says.

These early-stage disruptions were closely linked to neurotransmitter systems, the brain’s chemical messengers. The study suggested changes in specific systems particularly involved in the brain’s initial hyperconnectivity. These neurotransmitters play crucial roles in learning, memory, mood, and adaptation, suggesting that the brain’s most flexible systems may be first to respond, and first to fail.

As the disease progressed, these players also changed. Neurotransmitters that regulate pain, mood, and reward seemed to be affected in early pre-HD. And in late pre-HD, systems around mood regulation and impulse control seemed to be affected. These findings match with what we know about some of the earliest changes people with HD start to experience.  

In the mid- and late stages, the dominant mechanisms seemed to shift toward genetic disruptions and mitochondrial dysfunction, more systemic issues that impair cellular function across the board. The music becomes not just off, but increasingly impossible to play.

What makes this study so valuable is the large collection of data used from 3 observational studies (TRACK-HD, TrackOn-HD, and HD-YAS), providing a layered and time-sensitive understanding.

A Stage-Specific Symphony of Decline

What makes this study so valuable is the large collection of data used from 3 observational studies (TRACK-HD, TrackOn-HD, and HD-YAS), providing a layered and time-sensitive understanding. So while clinic visits for these observational studies can be laborious, each blood draw, clinical assessment, and research visit provides incredibly valuable information that scientists are putting to good use to better understand HD. It’s time very well spent!

From this work, we’re learning that HD is not a simple, straight-line descent, it’s a multi-act drama with distinct biological players, turning points, and feedback loops. The research suggests that each stage of HD is defined by different mechanisms, from neurotransmitter disruption to cellular communication spread to full-scale network collapse.

It also shows that these changes are trackable over time, with brain imaging and blood-based biomarkers like NfL helping pinpoint when things go wrong. That means future treatments might not just focus on slowing decline, but on targeting the right process at the right time, catching the brain when it’s still trying to play, even if off-key.

TL;DR: The Big Takeaways

• Early HD isn’t quiet, it’s loud. Hyperconnectivity (over activation) appears decades before symptoms, likely as a mix of compensation and early damage.
• The brain acts like an orchestra, first overplaying to seemingly compensate, then falling apart as coordination fails.
• Disease progression is stage-specific. Early on, issues within cells seem to dominate; later, disease spread and systemic breakdown appear to take over.
• Different neurotransmitters seem to play key roles at each stage, with what appears to be distinct impacts on brain connectivity.
• NfL levels track with connectivity loss, making it a useful marker for identifying when the music begins to falter.
• This model opens the door to earlier, more precise interventions, targeting specific processes before full-blown symptoms appear.

Learn More

Original research article, “Cell-specific mechanisms drive connectivity across the time course of Huntington’s disease” (open access).

While the genetic change that causes Huntington’s disease (HD) leads to several problems for cells, researchers believe they could stem from one core issue: the length of the genetic change increasing over time, like a snowball gaining mass as it rolls downhill. This genetic phenomenon, known as somatic instability or somatic expansion, seems to be a key driver of disease progression. In a recent study, scientists developed a new variant of CRISPR, a powerful gene editing tool, to interrupt this genetic expansion, potentially paving the way to new therapeutic opportunities. 

A Genetic Snowball

HD is caused by a change in a gene called HTT, specifically where the genetic letters C-A-G are repeated several times. In people with HD, this CAG section is longer than normal, jump-starting a deadly chain reaction inside brain cells. Unlike most mutations, which remain the same throughout life, the CAG repeats in HTT grow longer with age, like a snowball picking up speed as it barrels downhill. 

At birth, most people with HD have around 40 to 50 CAG repeats in their HTT gene. Over time, that number grows exponentially inside cells, sometimes surpassing 500 repeats by the time symptoms develop! If the initial repeat is above a critical threshold (36 repeats), the expansion turns into a kind of genetic snowball over time and begins growing out of control.

However, HD is not alone; it belongs to a broader category of diseases called trinucleotide repeat disorders – a fancy term for 3 (tri) genetic letters (nucleotide) that repeat (repeat – ok that one was obvious…). These disorders all share a similar problem with snowballing mutations. One such example is Friedrich’s Ataxia, which is driven by a growing CTG repeat that also worsens over time. 

The observation that several brain diseases are caused by a growing trinucleotide repeat raises a key question: Why are growing trinucleotide sequences so toxic to brain cells? Normally, genes like HTT are used to produce messenger RNA, also called mRNA, a temporary copy of DNA that is used to make proteins, the machines of the cell. However, long trinucleotide repeats cause the RNA to twist into super-tangled and stable knots, clogging the cell’s protein-making machinery. As these tangled RNAs grow longer and more abundant, they increasingly disrupt protein production, eventually contributing to cell death.

Interrupting the Instability

What if there were a way to break this snowball effect before it spirals out of control? Scientists at Harvard University, led by Dr. David Liu, hypothesized that they could interrupt the repeating CAG sequence by simply replacing one of the CAGs with a similar, but harmless, CAA sequence. 

By interrupting the repeating CAGs, even with a similar CAA sequence, the underlying pathway that leads to the CAGs growing with age might get blocked! In other words, inserting a CAA sequence is like placing a patch of rocks on the hill, causing the snowball to smash into them and break its momentum! 

Liu and his team were inspired by previous research showing that CAA interruptions seem to delay disease onset. Typically, the number of CAG repeats strongly predicts when someone will develop HD, but genetic studies identified people with long repeats but delayed ages of onset. 

Examined more closely, these genetic outliers were discovered to contain short CAA interruptions within their CAG stretch. Remarkably, these simple interruptions were linked to a 12-year delay in disease onset! Motivated by these observations, Liu and his team wondered if they could intentionally insert CAA sequences into cells with the gene for HD, and if this could recreate the protective effect. 

Unlike most mutations, which remain the same throughout life, the CAG repeats in HTT grow longer with age, like a snowball picking up speed as it barrels downhill. 

CRISPR Cracks the Snowball

Precision genetic changes, like swapping a CAG to CAA, are simple in theory, but extremely challenging in practice. Liu and his team turned to CRISPR, a gene-editing tool that acts like molecular scissors to alter specific DNA sequences. They developed a special type of CRISPR, called base editing, that looks for CAG repeats and swaps some of them out for CAAs. 

Using human cells growing in petri dishes, they found that their CRISPR base editing strategy successfully modified the HTT CAG repeat in about 80% of cells, with no signs of toxicity. Even more promising, they found these simple CAA interruptions seemed to stop the CAG repeat expansions after 30 days. They even noticed the CRISPR-edited cells appeared to grow faster and look healthier!  

Because this type of CRISPR targets all CAG repeats (not just the one in HTT) and introduces CAA interruptions into them as well, they needed to confirm that other genes were not disrupted by accident. In total, they found about 250 other genes changed by CRISPR, likely because they contained similar CAG repeats. However, only about 50 of them are active in brain cells, and just one appeared to be significantly disrupted. While this finding doesn’t rule out risk, it does suggest that unintended edits are unlikely to cause serious issues. Regardless, minimizing accidental edits will be a top priority moving forward!

Interrupting CAGs with CRISPR

Now comes the big challenge: Can the team get the CRISPR machinery into cells in a living brain and successfully edit CAG sequences? Liu’s team used a mouse model of HD that carries 110 CAG repeats in its HTT gene, and this repeat grows rapidly as the mice age (repeat instability). To deliver CRISPR to the brain, the team packaged up CRISPR into a harmless virus, which acts like a gene delivery service, injecting the genetic editing tools directly into cells. 

Four weeks after injecting the CRISPR-loaded viruses into the mice, the researchers found that about 30% of the cells seemed to have picked up the gene editing tool. Of the 30% of cells containing CRISPR, around 75% appeared to have at least one CAA interruption in their HTT gene. That means about 1 in 5 brain cells successfully received the protective genetic change – not perfect, but a promising start! After 12 more weeks, the researchers examined the length of CAG repeats and found that expansion seemed to not only stop, but some CAG repeats may have even shortened! 

To investigate if their approach worked beyond HD, the researchers repeated their experiments in cell and mouse models of Friedreich’s Ataxia, another repeat expansion disorder. Excitingly, they observed similar results: up to 55% of brain cells seemed to contain repeat interruptions, and the repeats appeared stable over time, showing no signs of expansion with age. 

Collectively, these findings seem to show that the snowballing repeat expansion in HTT can be stopped, and this approach might even apply to other repeat disorders.

Will CRISPR Break the Ice?

Collectively, these findings seem to show that the snowballing repeat expansion in HTT can be stopped, and this approach might even apply to other repeat disorders. However, there are a couple of reasons for caution. This study focused on whether CRISPR could insert CAA interruptions and halt repeat growth, but it did not assess whether this intervention improves symptoms or delays disease. Knowing the impact of this type of therapeutic approach on HD signs and symptoms is essential for determining if it should move forward.

Additionally, reducing unintended changes to genes other than HTT will be critical before moving to human trials. Another issue is delivery – human brains are much bigger than mouse brains, and getting CRISPR into enough brain cells to make a difference will be particularly challenging. 

Regardless of these current limitations, these results are a major step forward. With advances in gene editing accuracy and more effective delivery methods, CRISPR is likely to become a powerful tool in the fight against HD and other trinucleotide repeat diseases. 

TL;DR: The Big Takeaways

• The problem: HD is caused by a mutation in the HTT gene, where CAG repeats grow over time, a process called somatic expansion. This “genetic snowball” seems to worsen brain cell function and drive disease progression.
• The insight: Even a small interruption in the repeating sequence, like swapping a CAG for a similar and harmless CAA, may be able to slow or stop expansion and delay symptom onset.
• The breakthrough: Scientists used a refined CRISPR tool (called base editing) to insert these potentially protective CAA interruptions into the HTT gene.
• In the lab: In human cells, CRISPR base editing worked in ~80% of cells, seeming to halt expansion and improve cell health.
• In mice: After CRISPR was delivered via viral injection, about 20% of brain cells had protective changes and CAG repeats appeared to stop growing.
• Bonus: Similar success was seen in mouse models of another repeat disorder, Friedreich’s Ataxia.
• The catch: More work is needed to:
  • Prove symptom improvement
  • Minimize unintended effects
  • Scale delivery to the much larger human brain
• Why it matters: This work shows that CRISPR could be used to interrupt repeat expansions in living brain tissue, offering real hope for treating HD and similar genetic disorders.

Learn More

Original research article, “Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice” (open access).

team of researchers from Roche and University College London (UCL) have developed a new clinical measure called the Huntington’s Disease Digital Motor Score (HDDMS). This score compiles data collected remotely using smartphones, to track certain signs and symptoms of Huntington’s disease (HD). This new technology helps collect rich datasets and could help reduce the number of people needed to power clinical studies. Let’s get into what the team did and what this means for the HD community. 

Gathering clues about the early signs of HD

Trying to spot some of the subtle early signs of HD, or how symptoms progress over time can be a lot of detective work from HD clinicians and scientists. Especially since HD can affect each person differently, the clues are not always big and obvious. Instead, symptoms and the way they change can be like tracking down lots of smaller clues and hints that need to be pieced together to help figure out what is really happening for a given person. 

For scientists and doctors studying HD, monitoring the subtle changes in symptoms of the disease is often like this type of detective work. One of the most characteristic groups of symptoms in HD is changes to movement, which can be impacted in many ways. This includes balance, walking, involuntary jerking motions, and how fast people with HD can tap their fingers. 

Each symptom is a clue about how the disease is progressing, which is important to understand in detail, so we can better measure the precise changes which come as HD progresses, and how they might differ between people. With many exciting clinical trials underway or in the pipeline, we are keen to see if these new experimental therapies can slow down or halt these symptoms, especially the earlier and more subtle features of disease. 

But catching these clues early and accurately has been a huge challenge. Traditional clinic visits for people with HD to see their neurologist only give snapshots in time. This means that subtle changes can go unnoticed until later stages, slowing down research and making it harder to tell if new treatments are really working.

A Digital Detective: The HD Digital Motor Score (HDDMS)

To help solve these problems, a team of researchers from UCL and Roche have developed a new kind of detective tool called the HDDMS. This is a score created from simple movement tests and measurements that can be recorded by anyone with HD via their smartphone, wherever they are. 

The measurements collected are part of the HD digital monitoring platform. Just like a detective gathering evidence, participants complete a series of quick motor tests using a smartphone app. These help to measure:

• Standing balance
• Finger tapping speed
• Walking patterns
• Involuntary movements (sometimes called chorea)

The app collects a lot of data as people go about their everyday lives. This means that data can also be collected more frequently than traditional data collection processes, where the person would have to go in to see their neurologist for each test. From all of these tests, the HDDMS combines lots of subtle movement clues into a single score that reflects how well motor function is holding up in people with HD, and how this is changing over time.

A lower score means better motor control; less clues for HD symptoms are found and the detective’s case is still cold. On the other hand, a higher score means more progression, and the clues show the disease is progressing.

Why This New Digital Detective Is a Game-Changer

The researchers tested this digital detective tool using data from over 1,000 people with HD, collected across four different studies. That’s a lot of data! 

Here’s what they found:

More sensitive than traditional tools: The HDDMS was about twice as sensitive in detecting real changes in motor symptoms compared to the commonly used clinical score, the composite unified Huntington’s disease rating scale, or cUHDRS. This means that scientists are able to pick up on clues earlier and more clearly than before.

Reliable and consistent: The score is very consistent when repeatedly calculated, just as a good detective would never miss the same clue twice.

Speeds up clinical trials: Because the HDDMS detects changes faster, it could help researchers run smaller and shorter clinical trials. This means testing new drugs might take less time and involve fewer people, speeding up the hunt for effective treatments.

Convenient and remote: People can complete the tests at home in just five minutes and may no longer need to travel to a clinic for long assessments. It’s like having a detective’s magnifying glass in your pocket, ready to spot clues anytime. This is especially great for people with HD who live in remote areas, very far from their neurologist, or have mobility issues. 

Professor Ed Wild from UCL, one of the lead scientists on this project, explains:

“Our findings suggest that incorporating the HDDMS in clinical trials will help to give clearer answers about whether a potential treatment is working, with fewer participants or shorter lead times than conventional measures…. HDDMS is evaluated in a five-minute assessment in people’s homes, [making] it convenient and potentially more meaningful than in-clinic measures of motor impairment.”

The Bigger Picture: Why Tracking Movement Matters

Movement problems are one of the most visible aspects of HD. They affect daily life, making walking, balance, and fine motor skills harder as the disease progresses.

By accurately tracking these changes, scientists get critical clues about how HD unfolds in each person with more precise timepoints through the process. This helps not only in testing new therapies but also in understanding the disease better.

This is a bit like a detective catching a villain earlier in a mystery, before they cause more havoc. The HDDMS gives doctors and researchers a sharper magnifying glass to track the disease’s subtle moves, allowing for faster intervention and better support.

The Road Ahead for the HDDMS

Of course, no detective tool is perfect. The HDDMS has mostly been tested in people who already show symptoms of HD, and more work is needed to see how well it works in very early or more advanced stages of the disease.

Also, while it detects changes quickly, researchers are still learning how well it predicts long-term outcomes, just like how a detective’s case might unfold over years.

Still, the potential is huge! As smartphone and wearable technologies improve, these digital tools could become standard detectives in monitoring not just HD, but other neurological diseases.

Spotlight on Hope

This new digital motor score is a beacon of hope in the HD research world. By turning everyday devices into powerful detective tools, it promises to accelerate research, reduce patient burden, and help uncover the hidden clues of HD progression. All of this brings us closer to effective treatments and better lives for everyone affected.

So next time you pick up your phone, remember, it might just be the detective helping to solve one of medicine’s toughest mysteries.

TL;DR

• HD Digital Motor Score (HDDMS) is a new smartphone-based tool to track HD motor symptoms remotely.
• It uses simple tests (balance, tapping, walking) via an app accessed at home, which is quick to complete.
• The HDDMS is twice as sensitive as traditional measures, like cUHDRS.
• This means smaller trials could be possible with richer datasets.
• The HDDMS has been tested and validated on data from 1,000+ people across 4 studies.
• It could become a standard tool for HD and other brain diseases, helping bring treatments faster, with less burden for patients.

Learn more

Full article: “A digital motor score for sensitive detection of progression in Huntington’s disease” (open access).