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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).

Our bodies are experts at looking after our DNA and are continuously monitoring for any damage that needs to be repaired to keep us healthy. Parts of DNA that are very repetitive, like the sequence causing Huntington’s disease (HD), are very tricky to look after and our body can try and fix them but make it worse! This can make the repeat sequences longer and even more toxic to our cells.  In this study led by the CHDI foundation, researchers look in detail at the proteins responsible for making those sequences longer in HD, so we can get a better idea of how they work, and how we might be able to stop them. Let’s, take a closer look.

The Faulty Zipper: How DNA repair fuels HD

DNA is made up of four letters:  A,T,G and C. Sequences of these letters make up the instructions to tell our body how to make all the different proteins we need to function and be healthy. In HD there is a longer stretch of C-A-G letter repeats in the sequence for the  Huntingtin gene. Throughout life, the size of these repeats can get longer in some of the brain cells most affected by HD. This process is called somatic expansion.

Imagine the DNA in your cells is like the zipper on a jacket, and the zipper teeth are the letters of DNA. Normally the zipper moves up and down smoothly but there can be weak patches where it is easy for a bump or loop to form. 

You have a tailor who fixes zipper mistakes, and most of the time they are extremely helpful. But at the weak spot in the zipper, the tailor sometimes makes the problem worse, and instead of flattening the bump, they add in extra teeth to the zipper. 

Now every time the zipper is opened and closed the weak spot has a chance to get bigger. In HD, the weak spot is like the C-A-G repeats in the Huntingtin DNA, and the tailor is the DNA repair machinery in the cell. This is an important guardian of the DNA in our cells, particularly for preventing changes to our DNA sequence, which could cause cancer. Despite this, long C-A-G repeats, like those involved in HD, can confuse the repair response sometimes, causing the repeats to get even longer. This process is called somatic expansion and some scientists think this can cause some brain cells to get sick. 

An important part of the DNA repair tailor involved in expansion are two proteins called MSH2 and MSH3. They work together as a team and are collectively known as MutSβ (pronounced mute-ess-behta). Previous analysis of the DNA from thousands of individuals with HD has shown us that MutSβ can impact the age that symptoms begin. Because of this MutSβ has become an exciting area of HD research, which has shown that stopping MutSβ from acting on the damaged DNA zipper might help to slow somatic expansion and progression of the disease. 

Research studies are increasingly showing us that inhibiting MSH3, or reducing the amount of MSH3 in the brain, can prevent C-A-G repeats from getting longer and may even reduce C-A-G length, making it an exciting target for new potential HD therapies. 

Taking a sneak peek at how the mismatch repair proteins work

To better understand how the MutSβ complex can make the DNA zipper worse, the authors used a technique called cryo-electron microscopy (cryo-EM). This is a way of looking at the shape and structure of protein molecules – like taking a snapshot of what they look like at at a specific moment in time. 

Imagine you want to see what a snowflake really looks like. If you let it sit on your glove for too long after it has landed, it will melt or change shape before you get to see all its intricate details. 

Cryo-EM works like a camera for tiny biological “snowflakes”. Samples are frozen quickly so that the protein is trapped in its natural shape. Many snapshots are taken, which can capture different shapes and positions the protein may form. This helps us to piece together how the proteins change conformations to carry out their jobs. 

In this study, the scientists used cryo-EM to take a picture of MutSβ both before and after it is bound to DNA.  They were able to produce 9 distinct images of MutSβ, including the following conditions:

• When it’s not stuck to DNA
• When bound to normal error-free DNA
• When bound to DNA with mismatched DNA

These images show how the MutSβ complex moves and changes shape when it spots errors in DNA. Normally, this helps the cell repair the DNA, but in the case of HD, it can make matters worse. 

The researchers found that the shape and position of MutSβ depend on whether it is stuck to DNA as well as small energy molecules like ATP. ATP molecules are like the cell’s energy packets, a bit like fuel for an engine, which can keep everything running. Both parts of MutSβ, MSH2 and MSH3, can grab ATP and use it to do repairs on DNA.  

The snapshots of MutSβ from this study show that it starts out in an open clamp shape. This open clamp can grab onto DNA and scan along it, looking for errors in the DNA zipper. When a mistake is found, the clamp snaps shut, and can slide along DNA, powered by ATP. This kicks off the next steps of the repair process. Once its job is done, MutSβ uses more ATP to get itself off the DNA. 

Why do we care about the MutSβ structure?

By figuring out the shape of MutSβ in as fine detail as possible, especially when carrying out its job repairing DNA, we can find pockets on the protein surface which a future drug could stick onto to stop this process working. Like looking for the right key which perfectly fits a specific keyhole. If we know what the protein looks like, we can perfectly design a drug that should bind somewhere tightly on the protein and stop it from working. Ultimately being able to stop or even reverse C-A-G repeat expansion could be a great therapeutic route for HD, as well as other diseases which are also caused by repeat expansion, including several spinocerebellar ataxias and spinal and bulbar muscular atrophy. 

Summary:

• MutSβ (MSH2 + MSH3) is a DNA repair machine that normally helps prevent cancer-causing mutations.
• In HD, MutSβ can sometimes accidentally make CAG repeats in the HTT gene longer which is thought to lead to neuronal death and faster disease progression. 
• New data about the 3D structure of the MutSβ proteins and how this molecular machine works will aid the design of drugs which can inhibit its activity, preventing the elongation of CAG repeats.

Learn More

Original research article, “Elucidation of multiple high-resolution states of human MutSβ by cryo-EM reveals interplay between ATP/ADP binding and heteroduplex DNA recognition” (open access).

A small study from Brazil tested whether stem cells from human dental pulp, the soft tissue inside teeth, could help people with Huntington’s disease (HD). The results hint at small improvements on some movement measures, but the study had few participants who were tracked over a short timeframe, and many questions remain that raise red flags.

The allure of stem cells

Stem cells have long captured the imagination of scientists and families affected by neurodegenerative diseases. These versatile cells can divide and transform into different cell types, offering the hopeful possibility that they could repair or replace damaged brain tissue.

Stem cell treatments have been successful for other diseases, like spinal cord injuries and immunodeficiency diseases. They’re also emerging as treatments for some degenerative conditions, like macular degeneration, where vision is lost because cells in the retina die.

In HD, where neurons gradually die over decades, stem cells offer an appealing vision. But so far, they haven’t delivered on that promise and no stem cell–based therapy has proven to slow or stop HD progression.

Stem cells can be derived from a variety of sources. Embryonic stem cells come from embryos (perhaps unsurprisingly). Adult stem cells are more tissue specific and are found in the brain, bone marrow, or gut. And pluripotent stem cells can be created in the lab from skin cells or blood.

What have teeth got to do with HD?

The new twist in this latest study from Brazil is where the stem cells come from. Researchers used human dental pulp stem cells, collected from the soft tissue inside teeth, to create an experimental therapy called NestaCell. These cells are thought to perhaps support neurons and reduce inflammation.

Could stem cells from our teeth really help protect the brain in HD? The team hoped to answer that question by studying intravenous infusions of stem cells.

The study in a nutshell

The researchers, led by Dr. Joyce Macedo Sanches Fernandes and colleagues, ran a Phase II randomized, double-blind, placebo-controlled trial, the gold standard for testing a new therapy. 

People with HD were enrolled and randomly assigning them to one of three groups:

• Low dose: 1 million cells per kilogram of body weight, 13 participants
• High dose: 2 million cells per kilogram of body weight, 12 participants
• Placebo: an inactive infusion, 7 participants

Participants received nine intravenous infusions over 11 months. The main outcome for determining success of the trial was the Unified HD Rating Scale (UHDRS) Total Motor Score (TMS), a measure of movement problems. Other measures included Total Functional Capacity (TFC) (daily living skills), Total Chorea Score (involuntary movements), and MRI scans to track changes in brain structure.

What did they find?

Safe and well tolerated

First, the good news: NestaCell appeared safe. No serious side effects were linked to the treatment, and the overall rate of mild side effects was similar across groups. That’s an encouraging first step for any new therapy.

Hints of benefit

The researchers also reported some improvements in HD symptoms. Both treated groups showed better scores on the UHDRS-TMS (movement) than placebo. The higher-dose group also improved in functional capacity, suggesting possible benefit in daily life activities.

MRI scans hinted at slower brain tissue loss in treated patients, though these differences weren’t statistically significant, meaning they could be due to chance.

So the treatment seemed safe, and some numbers moved in the right direction. That’s intriguing, but not enough to be sure of real clinical benefit.

Why we should be cautious

As tempting as it is to get excited, there are several big reasons to view these results with caution.

1. Small study and short follow-up

With just 32 people who completed the trial who were divided among three groups, this was a small trial. Each group included roughly a dozen people, so a few participants doing unusually well (or poorly) could shift the averages. 

And the study lasted less than a year, almost certainly too short to know if any benefit would persist in a disease that changes slowly over decades. It’s also a limited timeframe in which to measure longer-term negative effects that could arise, like tumors, which are normally tracked in stem cell studies. 

So the treatment seemed safe, and some numbers moved in the right direction. That’s intriguing, but not enough to be sure of real clinical benefit.

2. No clear mechanism

It’s also unclear how injecting this type of stem cell might be helping. The researchers suggest these cells secrete helpful factors that reach the brain, but in reality, stem cells injected into the bloodstream are normally quickly filtered out. There’s no solid evidence that these cells can cross the blood-brain barrier or directly influence specific drivers of HD. In other words, there’s no convincing biological explanation for why this should work.

The researchers also mention findings from their own preclinical work in mice that these injected dental stem cells rarely reach the brain. The cells first go to the lungs before making their way to the rest of the body, with only about 2% ending up in the brain. Additionally, their other studies seem to show that the cells don’t “engraft” long-term, meaning they don’t take up permanent residence in the mice. While this is good for avoiding the creation of tumors (always a major concern for stem cell studies), it also means they may not stick around and perform positive functions either.

3. Selective improvements

Only some measures improved, and there was no clear dose-response pattern (higher doses didn’t clearly lead to better results). The MRI “trend” wasn’t statistically significant. When a few outcomes show changes but others don’t, and when the effects are small, there’s a real risk that the apparent benefits are due to random chance rather than the treatment itself.

Stem cells and HD: a long, bumpy road

Stem cell therapies for HD have been studied for decades, from foetal cell transplants in the 1990s to bone marrow-derived mesenchymal stem cells more recently. Despite repeated efforts, none have convincingly slowed or reversed HD progression in controlled trials.

Why? It turns out that the brain’s complex wiring is extremely hard to rebuild. Injected stem cells don’t easily integrate into neural networks and simply putting them in the body, especially via the bloodstream, doesn’t guarantee they’ll reach or repair the brain. NestaCell adds an interesting new chapter to this story, but it doesn’t fundamentally change the underlying challenges.

Other groups are exploring brain-repair strategies grounded in clearer biology. Recent work suggests that it may be possible to coax the adult brain into regenerating the specific neurons lost in HD, potentially restoring circuitry rather than just supporting it. In parallel, scientists are developing techniques to reprogram glial support cells into new, functional neurons, offering a more targeted “replace what’s lost” approach. These early-stage efforts are still far from the clinic, but they point to a future of regeneration therapies that rest on more solid science.

Hope, hype, and healthy scepticism

Stem cell studies often generate excitement, and headlines, because the idea of “regenerating” the brain is so compelling. But for the HD community, it’s crucial to distinguish scientific hope from premature hype.

NestaCell adds an interesting new chapter to this story, but it doesn’t fundamentally change the underlying challenges.

While this study’s results are interesting, they don’t provide strong evidence that dental pulp stem cells can alter HD progression. Larger, longer, and independently run trials will be needed before anyone can claim this is a real treatment.

Families should also be wary of unregulated stem cell clinics, which are up and running across the world and sometimes use early academic studies like this to advertise costly, unproven therapies. Until treatments are tested rigorously and approved by regulators, they should be considered experimental.

What happens next?

The authors suggest that NestaCell should move on to a larger Phase III trial to confirm efficacy and safety in a bigger group of patients. That’s an ambitious next step, and one that will require careful justification, especially given the lack of a clear mechanism and the modest nature of the results.

In the meantime, the HD research community can view this as a creative, if unconventional, attempt to explore new ideas. It’s a reminder that science advances by testing even unlikely hypotheses, but that strong evidence, not wishful thinking, is what ultimately drives progress.

Summary

• Stem cells derived from human dental pulp (from teeth), delivered by IV infusion
• 32 people with HD participated in a small Phase II randomized trial to test this therapy
• The treatment appeared safe and results suggest small improvements on some measures for signs and symptoms of HD, but no clear or consistent benefits
• This study contributes to our understanding of stem cell therapies in HD, but this drug is not ready for clinical use as the results are preliminary and biologically unclear
• Larger, independent studies are needed before anyone should consider “tooth stem cells” a real therapy for HD.

Learn more

Fernandes JMS et al. Stem Cell Research & Therapy (2025). “Phase II trial of intravenous human dental pulp stem cell therapy for Huntington’s disease: a randomized, double-blind, placebo-controlled study.” https://doi.org/10.1186/s13287-025-04557-2

Why do some people with intermediate CAG repeats, a genetic “gray zone” in Huntington’s disease, develop neurological symptoms while others do not? This article covers a recent study that tackled this question by looking for somatic expansion, which is a tiny changes in DNA, in individuals across various CAG repeat sizes. Using ultra-sensitive research technology on blood samples, the team discovered that intermediate CAG repeats do experience expansion, but the changes are typically very small. While this confirms that intermediate repeats are part of a continuous spectrum of genetic instability, the research found no clear link between this expansion in blood and the presence of symptoms. This article covers what this new research reveals about the genetic landscape of HD.

The HD Gray Zone

Huntington’s disease (HD) develops when people have a repetition of the genetic letters C-A-G in their huntingtin gene. People with 40 or more repeats will develop the disease during their lifetime, while people with 36-39 repeats have what scientists call “reduced penetrance”, meaning some develop symptoms while others don’t. 

Repeat lengths of 27-35 are called “intermediate alleles”. “Intermediate” meaning the repeat falls between the range that will and won’t cause diseases, and “allele” being the copy of the huntingtin gene someone inherited from their mom or dad. While these repeat lengths are not considered disease-causing, they present uncertainty for families. These intermediate alleles can expand when passed from parent to child, potentially reaching disease-causing lengths in the next generation. Also, some people with intermediate CAG numbers develop neurological symptoms despite being below the traditional HD threshold. 

This situation places intermediate CAG lengths in a controversial “gray zone,” raising fundamental questions: What does this mean for the future? Do these DNA sequences change over time within a person’s lifetime? Could such changes explain why some intermediate allele carriers develop symptoms while others don’t?

The Research Question

Scientists have long known that DNA can change over a person’s lifetime, through various processes. Some are as simple as mutations caused by damage from sun exposure, and others are more complicated and less understood. A recent hot topic in HD research involving DNA changes is a process called “somatic expansion.” 

Somatic expansion is a biological process where CAG repeats can expand in different cells of the body over time in people with the gene for HD. Interestingly, these expansions tend to be largest in brain cell types that are most vulnerable to death in HD. Many researchers think these increasing CAG expansions may contribute to when and how symptoms develop.

A research team led by Dr. Maria Ramos-Arroyo tested the idea that people with intermediate CAG repeats might also experience somatic expansion, and that this could explain why some intermediate CAG repeat carriers develop neurological symptoms while others don’t. To test this idea, they used ultra-sensitive DNA sequencing to study 355 people across the entire CAG spectrum, including 191 individuals with intermediate repeat lengths.

The Study Results

Ultra-sensitive techniques reveal small changes

The team used a very sensitive test, called MiSeq (pronounced “my seek”) sequencing, on blood samples from people in this study. MiSeq is a technique sensitive enough to detect DNA changes that routine genetic testing would miss. From this, the team found that people with intermediate CAG repeats do experience somatic expansion. However, these changes are quite small. When expansion occurs, it is typically limited to just one or two additional CAG repeats in a small fraction of DNA molecules.

Inherited length matters more than time

The researchers also found an important pattern in what influences these expansions. The length of inherited CAG repeat size has a much stronger impact on somatic expansion than age does. For intermediate CAG repeats, each additional CAG repeat in the inherited sequence had about 40 times more impact on expansion than each additional year of age. That’s a huge difference!

These intermediate alleles can expand when passed from parent to child, potentially reaching disease-causing lengths in the next generation. Also, some people with intermediate CAG numbers develop neurological symptoms despite being below the traditional HD threshold. 

A continuous pattern emerges

The results remind us that CAG length represents a continuous spectrum rather than distinct categories. The data revealed that somatic expansion behavior follows a clear continuum. People with longer inherited CAG repeats showed progressively more expansion, with intermediate CAG lengths fitting naturally between normal and disease-causing lengths. This confirms that intermediate length repeats are not a separate biological category, but part of this larger spectrum.

Brain shows higher expansion rates than blood

When researchers examined brain tissue from one person with 33 CAG repeats who had developed symptoms, they found that brain regions showed higher expansion rates than blood, with the movement-related area of the brain (putamen) showing the most change. This matches patterns seen in people with HD, but it’s important to remember that this analysis was limited to a single individual.

No clear link to symptoms

Importantly, this study found no clear link between somatic expansion and symptoms in intermediate CAG repeat carriers. The researchers studied 78 people with intermediate CAG lengths that had neurological symptoms (85% had movement, 27% had cognitive, and 29% had behavioral symptoms) but there didn’t seem to be a difference in their blood expansion levels compared to symptom-free carriers. This suggests that somatic expansion alone doesn’t explain why these people had symptoms of HD while others with similar intermediate CAG lengths did not.

What Do These Results Mean?

For carriers of intermediate repeat lengths and their families, these findings do not change the current state of clinical practice or predictive testing. Because there isn’t a clear link between the level of somatic expansion in blood and the presence of neurological symptoms, this means that measuring CAG expansions for people with intermediate lengths cannot be used to predict an individual’s future health. Furthermore, because the genetic changes involving somatic expansion are detectable only with advanced research methods, they would not be identified by the standard genetic tests available to families.

From a scientific perspective, the confirmation of a continuous spectrum of CAG lengths is a significant step forward. It shows that intermediate CAG lengths follow the same genetic processes as HD-causing repeat lengths, just at much lower levels. 

However, there are still hurdles in using these findings for HD families to help them know if intermediate length carriers will develop disease symptoms. The design of this study captures only a snapshot in time rather than following individuals over years, limiting our understanding of how these changes develop. Additionally, the difficulty of detecting these subtle expansions limits the scale of studies that can be conducted. 

But the added knowledge that CAG repeats, even in the intermediate range, 1) exist on a continuum, 2) also experience repeat expansions, and 3) are sometimes associated with symptoms, give researchers a better understanding of HD. With that information, scientists can work toward advancements that will eventually give us a better understanding of what influences symptom development. 

The results remind us that CAG length represents a continuous spectrum rather than distinct categories.

Future Research Directions

Researchers can build on these findings and ask questions about who will go on to develop symptoms and why. To do that, the scientists need to consider the research hurdles identified in this study. 

The path forward will likely require a combination of more detailed tracking of people over time and larger-scale studies. Following individuals over many years would allow researchers to track both genetic changes and symptom progression within the same people as they age. Expanding to larger numbers of people would also be valuable, though this remains challenging given the specific nature of the genetic sequencing tests used in this study. More accessible biomarkers could facilitate larger studies.

This study provides a more detailed map of the genetic landscape of the huntingtin gene, confirming that even people with intermediate CAG repeat lengths are part of a continuum of somatic instability. While it does not establish a link between this instability and symptoms, it clearly defines the challenges and priorities for the next research steps that could help scientists understand who will or won’t go on to develop symptoms.

Summary

• Somatic CAG expansion occurs across a continuum: Intermediate CAG lengths show small but detectable expansion that fits the same patterns we see in full HD expansions.
• There doesn’t appear to be a clear relationship between expansion and symptoms: Within the scope of this study, the level of somatic expansion in blood did not clearly explain why some people with intermediate CAG repeat lengths develop symptoms while others don’t.
• More research is needed: Larger studies that track people over time will be essential to better understand symptom development in people with intermediate CAG repeat lengths, potentially improved by more accessible biomarkers.

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Original research article, “Somatic CAG repeat instability in intermediate alleles of the HTT gene and its potential association with a clinical phenotype” (open access).