HDBuzz

Depression and anxiety are common symptoms of Huntington’s disease (HD), and they can make everything harder. New research explores how sertraline, a widely-used antidepressant, affects protein production in HD cells and mice, finding that it prevents motor problems in HD mice and is linked to slower functional decline in people with HD. This study raises an intriguing question: could treating HD with sertraline do more than just improve mood? 

The Depression Factor

Living with HD is challenging enough, but depression and anxiety, two of the most common psychiatric symptoms in HD, can make everything exponentially harder. 

Imagine trying to navigate your daily life while carrying a heavy backpack filled with rocks. Even simple tasks become exhausting, your movements feel more labored, and your brain has less energy for everything else. 

That backpack represents depression and anxiety, and new research on sertraline, a commonly prescribed antidepressant, gives us an opportunity to think about how treating these conditions might lighten the load in meaningful ways.

The Protein Production Problem

The research team, led by scientists at the University of Barcelona, set out to study the molecular effects of sertraline on a specific problem in HD cells: abnormal protein production. Scientists have known for a while that cells in HD produce proteins differently than regular cells. 

Specifically, in some models of HD, some scientists have reported too much activity in a process called translation initiation, which is the initiation of protein production. Think of translation as the cellular assembly line that turns genetic instructions into functional proteins. In some HD models, this assembly line seems to run too fast, like a factory churning out products without proper quality control.

The researchers knew that sertraline can slow down protein production in cancer cells, so they wondered if it could do the same in HD. This study looked at the molecular effects of what sertraline does to protein-making machinery in HD cells and how this affects mice, and potentially people. 

Testing in striatal neurons (the brain cells most affected in HD) from mice that model HD, they found that sertraline appeared to normalize the elevated protein production this team saw. When they treated HD mice with sertraline for four weeks, the mice showed improved learning on motor tasks and coordination compared to untreated HD mice.

From Mice to People

Since the mouse results were promising, the researchers wanted to better understand the effects sertraline might be having in people with HD. So they turned to Enroll-HD, the world’s largest observational study of people with HD, which tracks tens of thousands of people over time. 

They compared people with HD taking sertraline (either alone or with other antidepressants) to people taking other medications or no antidepressants at all. They found that people taking sertraline showed a slower decline in functional capacity, meaning they maintained their ability to work, manage finances, handle domestic chores, and care for themselves better over time. Specifically, people taking sertraline showed better scores on tests measuring total functional capacity, functional assessment, and independence. 

However, the researchers didn’t see improvements in total motor scores, meaning sertraline doesn’t seem to influence movement symptoms that many people with HD experience. This could be due to the relatively small number of people in some groups or because doses used in mouse studies are much, much higher than the doses doctors prescribe to people.

They found that people taking sertraline showed a slower decline in functional capacity, meaning they maintained their ability to work, manage finances, handle domestic chores, and care for themselves better over time.

A Cellular Clue

The researchers also made an intriguing discovery about protein production in easily accessible cells. When they looked at skin cells (fibroblasts) from people with HD, they found signs of increased protein production, but only in people whose expanded HTT had fewer than 42 CAG repeats. Treating these cells with sertraline brought protein production back to normal levels.

This cellular finding suggests that the abnormal protein production the researchers are studying may occur in a small subset of people or in select models of HD. Whether this predicts who might benefit most from sertraline’s molecular effects remains an open question. Future research could explore whether measuring protein production in fibroblasts might serve as a biomarker for certain treatments.

Molecular Effects or Mood Effects?

Here’s where interpretation becomes important. This paper primarily focuses on the molecular story of how sertraline affects protein production in HD cells. The research suggests that sertraline can normalize abnormal translation in neurons and in skin cells from some people HD, suggesting the drug may be having a direct effect on cellular machinery that goes awry in HD. This finding is of interest because it could point toward new therapeutic targets.

But it’s equally important to consider sertraline’s primary job: treating depression and anxiety. When depression lifts and anxiety eases, everything becomes more manageable. Your energy improves, your motivation returns, you sleep better, and daily stressors don’t hit as hard. All of these changes can improve how well you function day-to-day, even if the underlying HD pathology hasn’t changed.

Lightening the Load

Consider how depression and anxiety might worsen HD symptoms. If you’re depressed and anxious, stress hormones course through your body, your muscles stay tense, you move less because you lack motivation, and you’re more likely to avoid activities that could maintain your skills. You might struggle more at work, find household tasks overwhelming, or withdraw from social connections that provide support. It can be like trying to function day-to-day while carrying around a 40 pound backpack. 

But what happens if you put that backpack down? Remove the depression and anxiety, and suddenly you’re more likely to stay active, engage with therapies, maintain your job, and participate in activities that keep both your mind and body working well.

The motor symptoms of HD haven’t disappeared, the actual disease progression hasn’t changed, but you’ve removed barriers that were piling onto existing challenges. This doesn’t make the benefits any less real or important, it just means the mechanism might be indirect. Like removing that heavy backpack, treating psychiatric symptoms might make it easier to maintain function and navigate daily life with HD.

Finding Your Right Combination

It’s important to note that sertraline is just one tool in the toolbox for managing HD symptoms. The researchers couldn’t identify clear effects on motor function in the Enroll-HD dataset, which reminds us that no single medication addresses all aspects of this complex disease. Finding the right combination of medications to improve both mood and motor symptoms often takes trial and error for each person.

If you’re experiencing depression, anxiety, or worsening motor symptoms, working closely with your healthcare provider(s) to find the right medication combination is crucial. Several medications can help with depression and anxiety, and different medications can address motor symptoms. 

What works beautifully for one person might not work as well for another, so open communication with your medical team about what’s working and what isn’t helps guide adjustments.

What This Means Clinically

This research doesn’t suggest that sertraline is a disease-modifying treatment for HD. What it does suggest is that sertraline may have some effect on abnormal cellular processes in HD, and people taking it appear to maintain function better over time. 

Whether the functional benefits come from correcting molecular abnormalities, from treating depression and anxiety, or from both, the practical implication is the same: addressing psychiatric symptoms in HD matters.

Depression and anxiety in HD aren’t just uncomfortable side effects that people should be expected to tolerate. They’re treatable conditions that, when left unaddressed, can worsen the challenges HD creates. Treating these symptoms is legitimate medical care that could have broader benefits than we might expect.

If you’re experiencing depression, anxiety, or worsening motor symptoms, working closely with your healthcare provider(s) to find the right medication combination is crucial.

Talk to Your Doctor

If you or your loved one is living with HD and experiencing symptoms of depression or anxiety, persistent sadness, loss of interest in activities, excessive worry, difficulty sleeping, or changes in appetite, talk to your healthcare provider. 

These symptoms aren’t just uncomfortable; they may actively worsen the functional challenges people with HD are facing. Effective treatments exist, and addressing these symptoms might help more than you think.

Your doctor can help determine whether medications for depression, anxiety, or motor symptoms make sense for you or your loved one, considering your specific situation, other medications being taken, and overall health. Finding the right combination might take some adjustment, but the effort is worthwhile.

The Bottom Line

This research offers molecular insights into how sertraline could affect protein production in HD cells, showing that it could be able to normalize changes in neurons and in cells from some people with HD. The finding that people taking sertraline maintained better function over time is encouraging, whether those benefits come from molecular effects, from treating depression and anxiety, or from both.

The most immediate takeaway is that treating psychiatric symptoms in HD is important medical care, not optional comfort. Whether sertraline proves to have unique disease-modifying properties or simply works exceptionally well at treating depression and anxiety in HD, people who received it maintained better function. That’s meaningful, and it reinforces the value of comprehensive symptom management in HD.

Summary

• Researchers studied how sertraline (an antidepressant) affects abnormally fast protein production in Huntington’s disease (HD) cells 
• Sertraline normalized protein production in HD mouse brain cells and prevented motor coordination problems in mice
• Analysis of the Enroll-HD database showed people taking sertraline maintained better functional capacity (ability to work, manage daily tasks, stay independent) over time, though motor scores didn’t improve
• Sertraline normalized abnormal protein production in skin cells from people with HD with fewer than 42 CAG repeats, suggesting additional work could look at the potential of protein production as a biomarker
• Benefits in people could come from sertraline’s molecular effects on protein production, from treating depression and anxiety (which themselves worsen HD symptoms), or potentially both
• Sertraline is one tool in the toolbox against HD to treat depression and anxiety. Finding the right combination of medications for mood and motor symptoms takes trial and error with your doctor
• Whether sertraline helps by fixing cellular problems or by lifting the “backpack” of depression and anxiety (or both), treating psychiatric symptoms in HD is important medical care that may have broader benefits than expected

Learn More

Original research article: “Sertraline treatment prevents motor dysfunction in a Huntington’s disease mouse model and functional decline in patients” (open access).

Welcome back to the HDBuzz monthly research roundup! November was a busy month, with new developments in everything from gene therapy and stem cells to DNA repair, genetic modifiers, and protein folding. Here’s a friendly guide to what scientists learned this month, why it matters, and what it might mean for the future of Huntington’s disease (HD) research and treatment.

uniQure and FDA No Longer in Alignment on Approval Pathway for AMT-130

The most closely watched HD gene therapy program, uniQure’s AMT-130, hit a significant regulatory road bump as uniQure shared a press release stating they are no longer in alignment with the U.S. Food and Drug Administration (FDA). While the company had hoped to use an “external control group” (data from registries such as Enroll-HD) to support their application for approval, the FDA says it won’t accept this approach.

This doesn’t mean the data from the AMT-130 clinical trial shared last month don’t hold true. But it does mean the FDA wants uniQure to use more traditional comparison data before moving forward with a possible approval. Regulatory strategy can change a timeline even when the science looks promising.

This is a reminder that scientific progress and regulatory progress don’t always move at the same speed. Gene therapies for HD, like AMT-130, are still promising, but the path to approval might take longer or require new types of evidence.

SOM3355 moves toward a Phase 3 trial

In more positive news, SOM3355, a drug originally developed for other neurological conditions, received encouraging regulatory signals from both the European Medicines Agency and the U.S. FDA. A Phase 3 clinical trial is now in preparation. SOM3355 is not a disease-modifying therapy; instead, it targets symptoms, potentially addressing movement difficulties, behaviour, or mood.

While the hunt for disease-modifying treatments continues, symptom-focused drugs can make an immediate difference in quality of life for people with HD. If Phase 3 results are positive, SOM3355 could become a valuable new option for treating HD symptoms.

A “tooth fairy” stem-cell therapy enters early clinical testing

A small clinical trial tested a novel approach: infusing people with HD with dental pulp stem cells obtained from human teeth. The treatment was safe, and some participants showed small improvements on clinical measurements. But the study was small, only ran for a relatively short time, and the underlying of the biology of the rationale for how this approach might be working remains uncertain.

It’s an encouraging sign that researchers are exploring bold and diverse ideas, but the HD community should remain cautious. Larger, controlled trials are needed before drawing conclusions about whether this therapy can truly help.

Intermediate CAG repeats behave more like HD than once thought

Scientists took a deep look at “intermediate” CAG repeats; CAG numbers that fall below the traditional disease threshold but above typical “normal” ranges. Using ultra-sensitive methods, they found that even these intermediate alleles can undergo somatic expansion, the same DNA-instability process that drives HD onset and progression.

Surprisingly, this expansion didn’t neatly predict symptoms or disease. People with similar repeat instability differed widely in clinical outcomes. This supports the idea that HD risk exists on a spectrum. CAG length is important, but it’s not destiny, and DNA repair, genetic modifiers, and other biological factors might shift that risk substantially.

Cracking the structure of DNA repair: MutSβ in the spotlight

Repeat expansion in HD is strongly influenced by DNA mismatch repair, the system cells use to fix errors in DNA copying. Researchers have revealed new high-resolution structures of MutSβ, one of the key repair complexes involved in CAG repeat instability.

These structures show how MutSβ recognizes and binds DNA loops (including those formed by repeated CAG sequences), and they hint at why its activity sometimes makes things worse rather than better. Understanding these molecular machines could help scientists design therapies that slow or prevent somatic expansion, potentially delaying onset or slowing progression for people with HD.

A tiny genetic tweak that boosts the cell’s cleanup crew

A newly identified genetic variant may help delay HD onset by ramping up the cell’s recycling and cleanup pathways, especially autophagy, the system cells use to remove damaged proteins and waste. This is part of a growing wave of research showing that genetic modifiers (genes other than HTT) can accelerate or delay symptoms.

Modifiers are rewriting the story of HD. Even people with the same CAG repeat length can show dramatically different ages of onset. Understanding these modifiers might someday help researchers design treatments that mimic their protective effects.

Untangling protein folding in HD

Expanded huntingtin protein can misfold and forms harmful aggregates, but the details of this process have been notoriously hard to nail down. New structural biology tools are giving researchers a clearer look at how the expanded protein folds incorrectly, and how that misfolding leads to toxicity.

The metaphor in the article’s title captures it well: imagine trying to fold a shirt that suddenly has sleeves three times longer than expected. Better understanding of misfolding opens the door to new strategies, molecules that stabilize huntingtin, prevent aggregation, or help cells clear misfolded proteins more efficiently.

What we learned this month

Across November’s articles, several themes emerge:

1. Risk and progression are nuanced

Intermediate CAG alleles and genetic modifiers show that HD is perhaps more complex than a single genetic change.

2. DNA repair remains a key driver of HD biology

Multiple studies point to somatic repeat expansion as a central player, a target for future therapies.

3. Discovery science is thriving

From high-resolution protein structures of genetic variants, basic research continues to uncover the molecular foundations of HD.

4. Clinical innovation is broadening

Gene therapy, small molecules, and even stem-cell approaches are all being explored, each with its own challenges and opportunities.

5. Regulator–industry alignment matters

The AMT-130 story shows that even promising science can hit speed bumps. Patience and persistence are part of progress.

Looking ahead

As 2025 winds down, HD research is more active, more interdisciplinary, and more globally connected than ever. Whether it’s genetic modifiers, new drug targets, or next-generation clinical trials, momentum is building on many fronts simultaneously.

Stay tuned for the HDBuzz end-of-year review, where we’ll recap the most important HD research stories of 2025, and look forward to what’s coming next.

Imagine a busy clothing factory. Proteins are like newly sewn shirts coming off the machines. They’re floppy, wrinkled, and can create a giant mess if they’re left unfolded. Normally, the cellular clothing factory employs “chaperone proteins” that act like skilled pressers. They grab each shirt, apply energy from a hot iron, and carefully fold it into the right shape so everything stays neat and tidy. 

But Huntington’s disease (HD) creates abnormally shaped clothes that can throw the chaperone folders off. When that happens, proteins, like irregular shirts, tend to be folded incorrectly, get tangled up, and create a huge mess. In new work published in Nature Communications, a team of researchers dove into how they could improve the protein folding process in HD by engineering extra chaperone folders. So what did they find, and what does this mean for HD?

Folding a shirt with 12-foot arms

HD is caused by an expanded stretch of genetic letters in the huntingtin gene that produce an extra-long protein, called expanded huntingtin. That extra-long protein creates harmful clumps that form inside cells. If the cell is a busy clothing factory, expanded huntingtin is like a shirt with 12 foot arms – hard to fold and store properly, causing a big mess.

Usually, there are helper proteins, called “chaperones,” that work throughout the cell to make sure other proteins fold correctly and prevent them from clumping. However, in diseases like HD, this chaperone system can become overwhelmed. There’s just too much expanded huntingtin for them to keep up with.

If the cell is a busy clothing factory, expanded huntingtin is like a shirt with 12 foot arms – hard to fold and store properly, causing a big mess.

PEX19: solo folding machine

Chaperones need a constant supply of energy in the form of a molecule called ATP, and a team of other helper proteins, to do their job correctly. Since they depend on this support system, it makes chaperones complicated to turn into medicines – they require too much energy and teamwork. It’s like trying to use a whole factory instead of just one machine to do a job. This study focuses on a specific type of chaperone called PEX19, which is unique because it works without the need of energy (ATP) or any helper protein. 

PEX19 normally helps certain proteins get to a part of the cell called the peroxisome. Peroxisomes are little recycling and detox factories inside your cells, working to break down waste and harmful substances, such as fats and poisons, to keep the cell healthy by converting them into harmless water and oxygen. Because PEX19 works by itself and does not require ATP, it could potentially be harnessed to address protein clump formation without the need to engineer a treatment that incorporates partner proteins. 

Clearing clumps in multiple models of HD

The main goal of this research was to find a way to prevent the clumping of the expanded mutant huntingtin protein that contributes to the onset of HD symptoms. The researchers thought that, given its unique characteristics, they could modify PEX19 at the molecular level to target and remove harmful huntingtin clumps. To this end, they produced different modified versions of the PEX19 chaperone and tested which version prevented the formation of protein clumps in different organisms that model HD.

First, they engineered tiny little yeast cells that produce the huntingtin protein. If left untreated, protein clumps form that make the yeast sick. The researchers added to the yeast cells two specially designed versions of PEX19, and observed that this treatment stopped huntingtin clumps from making the yeast sick. 

Next, they added these two versions of PEX19 to human HD cells grown in a lab dish, and observed that huntingtin protein clumps formed much more slowly. Finally, they treated HD fruit flies with their most effective version of PEX19 and observed that these sick flies lived longer and could climb better, a skill that deteriorates in flies with the gene for HD. They think this was because the sticky clumps in their brains were reduced.

The team observed that man-made variations of PEX19 can prevent the initial formation of protein clumps, but they cannot break apart clumps that had already formed, because this requires significant energy.  

Stopping the mess before it starts

These interesting observations suggest that an energy-independent chaperone, PEX19, can be engineered to target and prevent the formation of huntingtin protein clumps in yeast, human cells, and fruit fly brains. This suggests that the two special versions of PEX19 may have therapeutic potential against HD in humans. 

In addition to these takeaways, the researchers identified the specific mechanism by which these two PEX19 versions inhibit protein clumps, an insight that is crucial for the development of drugs that mimic the actions of PEX19. The team observed that man-made variations of PEX19 can prevent the initial formation of protein clumps, but they cannot break apart clumps that had already formed, because this requires significant energy.  

It’s the difference between neatly folding each unwieldy, floppy-sleeved shirt right after it’s sewn, versus tackling a huge, messy mountain of them. Although this is a limitation of engineered PEX19, the fact that the chaperone is energy-independent and does not require many helper proteins still makes it an attractive candidate for therapeutic development.

Tweaking the folds for a better fit

This research makes a significant contribution by introducing a novel strategy for developing therapies for Huntington’s disease and potentially other protein aggregation disorders. It demonstrates the feasibility of engineering an ATP-independent chaperone to target and reduce the clumping of a disease-causing protein. This approach offers an alternative to traditional chaperones that rely on complex cellular machinery and energy, which can limit their effectiveness in diseased cells.

Future work should focus on further optimizing the engineered PEX19 variants to enhance their specificity and potency by fine-tuning PEX19 architecture to bind better to the huntingtin protein. Additionally, testing these variants in more complex mammalian models and eventually in clinical trials would be crucial for their development as a therapeutic agent for Huntington’s disease.

Summary

• The clumping of an expanded huntingtin protein inside cells contributes to Huntington’s disease (HD). 
• Traditional protein chaperones that could prevent formation of protein clumps require significant energy (ATP) and helper proteins, making them unsuitable as simple treatments.
• This study analyzed many different versions of PEX19, a unique chaperone that functions independently and does not use ATP, for their ability to inhibit the formation of huntingtin protein clumps in human and animal cells. 
• The research team identified two engineered versions of PEX19 capable of preventing huntingtin protein clumps in yeast, human cells, and fruit flies.
• The engineered PEX19 variants can prevent new clumps but are unable to break down existing ones. 
• The results offer a simplified approach for potential HD therapies and may inspire future research into optimizing these variants and testing them in mammalian models and clinical trials.

Learn MoreOriginal research article, “Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin” (open access).  

SOM3355 is an investigational therapy aimed at managing multiple symptoms of Huntington’s disease (HD) and recently crossed two key regulatory milestones. In September, the European Medicines Agency (EMA) issued a positive opinion supporting orphan drug designation for SOM3355. Now, following a productive End-of-Phase-2 meeting in the United States, the US Food and Drug Administration (FDA) has agreed that SOM Biotech’s proposed Phase 3 study and subsequent open-label extension could form the basis of a future New Drug Application.

For the HD community, these developments underscore a growing effort to expand our therapeutic toolbox, particularly for the broad and shifting range of symptoms people experience throughout the course of the disease.

Why These Decisions Matter

HD affects movement, thinking, mood, and behaviour, and these symptoms change over time as the disease progresses. There are currently no approved disease modifying therapies which can slow or halt symptom progression. However, several medications are approved to treat certain symptoms, but often only address one aspect of HD at a time.

For example, VMAT2 inhibitors and medications designed to improve movement symptoms for people with HD. While effective for many, these drugs do not address other challenges such as irritability, anxiety, restlessness, or sleep disturbances. Because of this, people with HD often take multiple medications at once. This can increase the risk of side effects, drug-drug interactions, and can create complex treatment schedules which are difficult to stick to.

A motivator for companies like SOM Biotech is that this patchwork approach creates a need for additional therapeutic tools, including options that might simplify treatments for multiple symptoms while reducing possible side effects and the complexities of juggling multiple prescriptions.

What Do We Know About SOM3355?

SOM3355 is a drug which is thought to do lots of things at the same time. Not only is it a beta-blocker, but it can also act as both a VMAT1 and VMAT2 inhibitor. VMAT proteins help package neurotransmitter molecules like dopamine into little bubbles inside brain cells. By targeting both of these systems, drugs like SOM3355 may help influence the overactive motor circuits involved in movement symptoms of HD while potentially offering broader symptom support, like for anxiety and other mood-based symptoms.

SOM Biotech reports that SOM3355 showed positive signals in both proof-of-concept and Phase 2b trials in HD. However, details from these studies have not yet been fully published or peer-reviewed. Still, the results were encouraging enough for both the EMA and FDA to green-light the next steps.

Two Agencies, One Direction: Moving Toward Phase 3

The EMA’s decision to support orphan drug designation signals that SOM3355 may offer a “significant benefit”, a specific requirement under EU rules. This doesn’t guarantee effectiveness; it simply reflects regulators’ assessment that further study is justified.

Meanwhile, the FDA’s End-of-Phase-2 meeting confirmed agreement on the design of the pivotal Phase 3 trial. The planned study, expected to begin in late 2026, will enroll individuals with mild to severe HD. Participants will receive either 600 mg of SOM3355 daily or a placebo for 12 weeks. Afterward, they may enter a nine-month open-label extension, during which all participants are given the option to receive the drug. This extension will help gather longer-term safety data and explore whether any sustained benefits emerge over time.

Orphan drug designation from the EMA and alignment with the FDA on Phase 3 trial design do not mean SOM3355 is proven to work. But they do indicate that regulators see a rationale and path forward for continued development, and that early clinical data justify taking the next step. SOM Biotech’s leadership noted that alignment with both agencies strengthens confidence that SOM3355 is being advanced along a clear, standardized regulatory path.

How Could SOM3355 Fit Into the HD Treatment Landscape?

This update on SOM3355 represents another attempt to expand our set of tools for managing HD symptoms. For many people with HD, addressing chorea alone is not enough. Behavioural changes, sleep disturbances, mood swings, and cognitive challenges often have a larger impact on independence and well-being.

A medication capable of targeting several of these issues simultaneously, while keeping side effects manageable, would be a valuable addition. Whether SOM3355 can fulfil that role will depend on forthcoming Phase 3 data.

Additionally, as individuals can respond differently to medications, more treatments mean a greater chance of finding a good personal fit for each person with HD.

Looking Ahead

SOM3355 is still an investigational drug, and only a Phase 3 trial can determine whether it is safe and effective enough to seek approval. But the combined momentum from the EMA and FDA reflects a shared interest in expanding symptom-management options for HD, a goal long voiced by both families and clinicians.

As more investigative treatments move through the pipeline, each step forward adds to the collective momentum. And whether they ultimately succeed or fail, each candidate expands what we understand about treating HD. The decision for SOM3355 marks another step toward a future where families have more, and better, options for managing the symptoms of HD.

Summary: 

• SOM3355, a multi-target drug candidate for managing HD symptoms, received a positive orphan drug opinion from the EMA and alignment from the FDA on its Phase 3 plan. 
• Early trials showed encouraging signals, and although full data aren’t yet published, regulators agree the evidence justifies moving forward. 
• A global Phase 3 trial is slated for 2026, testing 600 mg daily vs. placebo for 12 weeks, followed by a 9-month open-label extension. 
• If successful, SOM3355 could offer broader symptom relief than current single-target treatments, potentially simplifying care for people with HD.

Learn more: 

Press release: SOM Biotech secures clear registrational path for SOM3355 in Huntington’s disease after FDA End-of-Phase 2 Meeting

Press release: SOM Biotech receives positive EMA COMP opinion on European Orphan Drug Designation for SOM3355 for treatment of Huntington’s Disease

Scientists often use genetics, the study of DNA, to understand the cellular changes that cause disease. By comparing people’s DNA with their symptoms, they can pinpoint specific genetic differences, called variants, that influence the severity of a disease. Huntington’s disease (HD) is well-suited for genetic analysis because of its well-understood genetic roots – an expansion mutation in the HTT gene. In HD, the genetic letters CAG repeat too many times, and this repetition leads to the disease. Since this discovery, scientists have searched the entire genetic makeup of tens of thousands of people for variants that modify when HD starts, called the age of onset. Defining these variants and testing their therapeutic potential could lead to the development of drugs that delay when HD signs and symptoms appear. 

Genetic Patterns

Unlike most brain diseases, HD offers a unique opportunity for genetic analysis because a simple blood test can determine if someone will develop the disease, and its timing is somewhat predictable. As an example, someone with 42 CAGs might start to show symptoms in their 40s or 50s, but someone with over 100 CAGs is likely to show symptoms as a child. Because the onset of symptoms is correlated to the length of a person’s CAG expansion, scientists can comb for additional genetic variations that change the expected age of onset. 

For example, while someone may or may not get Alzheimer’s Disease, people with the HD mutation are certain to develop the disease if they live long enough, and this predictability means scientists can look for variants that delay or prevent the expected age of onset. These predictions aren’t perfect (usually within ~10 years), but when combined with large groups of people, these techniques can identify genetic variations that affect disease timing. This is a powerful approach for identifying potential therapeutic targets. 

In a new study, work spearheaded by Dr. Katherine Croce from the lab of Dr. Ai Yamamoto at Columbia University took advantage of HD’s predictability to search for people whose expected age of onset did not match their actual age of onset. By comparing a person’s age of onset to their DNA, they found a tiny genetic variant in a gene called WDFY3 that appeared to delay the onset of HD by between 6 to 23 years – potentially a massive amount! 

However, this effect was only observed in a single HD family. (Albeit a very large HD family from Venezuela.) In addition, this genetic quirk is only found in around 1% of the population, and HD is already a rare disease, so confirming this effect in other HD families could be difficult. 

Cleanup on Aisle Brain

Without more human data to confirm WDFY3’s protective effect, the researchers turned to animal models. By introducing the same WDFY3 variant into a mouse that models HD, the researchers investigated whether they could recreate the protective effect. Remarkably, changing just a single genetic letter in the WDFY3 gene reduced neuron loss in the striatum, the vulnerable brain region in HD, and also lowered various stress signals associated with disease, such as the buildup of toxic protein clumps. These protein clumps form because the expanded HTT protein doesn’t fold correctly, causing it to pile up in large garbage deposits that promote neuron death.

The team next asked how this tiny genetic change in WDFY3 could have such a huge impact. To find out, they looked at the protein made by WDFY3, called ALFY, which carries out the gene’s function in the cell. Genes like WDFY3 are the blueprints for protein machines, like ALFY, that perform various activities in the cell. 

Surprisingly, the genetic variation in WDFY3 was not affecting the activity of ALFY, but was instead boosting the amount of ALFY floating around in the cell. When the researchers artificially increased the amount of ALFY in cells without the protective variant, they still observed a similar protective effect. These results suggest that the WDFY3 variant protects neurons not by changing what ALFY does, but by simply increasing how much of it is produced. So what is ALFY doing, and why does having more of it help keep neurons healthy?

Boosting the Brain’s Clean Up Crew

Previous research has shown that ALFY helps tag old misfolded proteins for removal. ALFY is like a custodian sticking bright orange stickers on old equipment that needs to be hauled away for disposal. By marking these piles of protein garbage, the cleanup crew knows what to haul away. 

Based on ALFY’s known function, the researchers thought that higher ALFY levels simply improve the efficiency of the cell’s cleanup systems. If this were true, then raising ALFY levels should protect against toxic proteins building up in other brain diseases, like Parkinson’s Disease or Alzheimer’s Disease. These diseases, like HD, have a major problem with protein garbage piles building up. And sure enough, they found that higher levels of ALFY seemed to protect neurons in mice that model these brain diseases as well, suggesting a common pathway was at work. 

Collectively, these experiments show that a tiny genetic change in WDFY3, which may delay the onset of symptoms in HD, likely works by boosting the production of its protein product ALFY. Like hiring extra custodians, more ALFY helps keep neurons tidy by clearing away the toxic misfolded proteins that accumulate in HD and contribute to damage in neurons. These results are doubly exciting because other brain diseases like Parkinson’s Disease and Alzheimer’s Disease face similar problems and could equally benefit from having more ALFY around. 

Therapeutic drugs aimed at boosting ALFY could mimic the protection seen in people with the original WDFY3 variant the researchers identified. Although no such drugs currently exist, the idea of improving the brain’s cellular cleanup crew could offer promise for multiple brain diseases, not just HD. If treatments to safely boost ALFY can be discovered, they may unlock a way to slow or prevent the protein buildup that contributes to brain cell breakdown in not just HD, but other brain diseases as well. 

Summary

• Huntington’s disease (HD) is uniquely suited for genetic studies because CAG length predicts (roughly) when symptoms will start.
• Researchers searched for people whose actual age of onset didn’t match their predicted onset to find genetic modifiers.
• A rare variant in WDFY3 was found in one large Venezuelan HD family and may delay onset by 6–23 years.
• The variant boosts levels of the WDFY3 protein ALFY, which helps cells clear misfolded protein “garbage.”
• In mice that model HD, increasing ALFY reduced neuron loss and toxic protein buildup, even without the protective genetic variant.
• Raising ALFY also protected neurons in mouse models of Parkinson’s and Alzheimer’s, suggesting a shared protective pathway.
• No ALFY-boosting drugs exist yet, but targeting this cleanup system could become a promising treatment strategy for HD and other brain diseases.

Learn More

Original research article, “A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy” (open access).