Huntington’s disease (HD) is caused by a repeated stretch of the genetic letters C-A-G within the huntingtin (HTT) gene above a critical number. If the repeats exceed 40, then signs and symptoms of HD will begin at some point in that person’s life, if they live long enough. The disease-causing CAG stretch expands throughout life, particularly in vulnerable brain cells, which scientists think eventually triggers cell death. 

New research used cutting-edge gene editing to create human stem cells with different CAG repeat lengths and genetic spellings. They then tracked how these repeats changed over time using advanced sequencing technology. The team discovered that inserting multiple genetic “interruptions” into the CAG repeat, breaking up the pure stretch of CAGs, had major benefits. What exactly did they find and what does this mean for future therapeutics? Let’s find out!

A Cellular Time Machine

Imagine watching a disease unfold in slow motion so you could track the exact moment when things start to go wrong. That’s essentially what researchers at the University of Milan have created – a platform to watch HD develop at the cellular level, repeat by repeat, day by day.

The team, led by Dr. Elena Cattaneo, engineered human stem cells carrying different versions of the HTT gene. Using CRISPR gene editing, they swapped in HTT sequences with various CAG repeat lengths, ranging from 21 repeats (below the disease threshold) up to 107 repeats (well into the disease range).

They called this collection of cell lines the “CAGinSTEM platform,” and it could become a powerful tool for understanding how CAG repeats behave over time.

Watching Repeats Grow

One of the trickiest aspects of studying CAG repeat instability has been measuring the expansion accurately. Traditional sequencing methods can struggle with repetitive DNA. Imagine trying to accurately count 42 of the same letters in a row. It’s likely at some point you may question if you were on 31 or 32 and have to start over. The same process happens in an experiment when molecular machines try to read the number of CAG repeats.

The researchers solved this problem using a specialized type of sequencing that can read very long stretches of DNA in a single pass, maintaining information about the exact sequence composition.

Over 120 days of growing cells in dishes, the team observed that cells that start with 81 and 107 CAG repeats showed steady, linear expansion of their repeats. In contrast, cells with 45 or fewer repeats remained stable, with no major changes to their CAG number. When they turned these stem cells into striatal neurons, the brain cells most affected in HD, they saw similar patterns, with the 107 CAG line showing expansion even in neurons.

Looking at cells before and after they became neurons allowed the researchers to determine if cell division was influencing CAG expansion. While stem cells divide again and again to create more cells, most neurons don’t – they’re what scientists called “post-mitotic,” meaning “after mitosis” or “after cell division”. Because CAG expansion remained at very high repeat numbers both before and after the cells became neurons, it suggests cell division isn’t the contributing factor.

The Power of Interruption

Here’s where the study gets really interesting. Most people (over 95%) have a natural interruption in their CAG repeat: it reads CAG over and over until the end of the repetitive section, where it reads CAG-CAA-CAG, with that single CAA near the end. Previous studies in people have shown that losing this CAA interruption leads to earlier disease onset, while having an extra CAA delays onset. 

Here’s where the study gets really interesting. Most people (over 95%) have a natural interruption in their CAG repeat: it reads CAG over and over until the end of the repetitive section, where it reads CAG-CAA-CAG, with that single CAA near the end.

The researchers tested this directly in their cell platform. They created lines with 107 pure CAGs (no interruption), lines with the typical single interruption, lines with 2 CAA interruptions, and (most dramatically) lines with 4 CAA interruptions strategically placed throughout the repeat.

The results were striking. The double CAA interruption reduced instability compared to the standard single interruption. But the 4 internal CAA interruptions appeared to completely abolish repeat expansion over 120 days. The repeats simply stopped growing, both in dividing cells and in neurons. Quite intriguing!

More Than Just Stability

Stopping repeat expansion would be valuable on its own, but the researchers also discovered that the multiple CAA interruptions had other benefits, as they appeared to prevent several HD-related problems in the cells.

Neurons with the 107 CAG repeat with the regular 1-CAA interruption showed difficulty developing into the right type of neuron. They had fewer markers defining them as striatal neurons and more markers from a different brain region, suggesting their development into this specific type of neuron was a bit confused. These findings are in line with work from other labs using brain samples from people, which have shown an erosion of cellular identity of this type of neuron with expanding CAG repeats.

However, the 4-CAA-interrupted line seemed to maintain normal striatal neuron development. This suggests that 4 CAA interruptions preserve the genetic identity of the striatal neurons!

The team also examined how the DNA and other molecules were organised in a region called the nucleus of the cells, an area of growing interest in HD research. Cells with 1 CAA interruption in 107 repeats had a smaller nucleus on average, more compact DNA that isn’t turned into protein, and disrupted structures important for regulating which genes stay turned off during development. The 4-CAA interruptions normalized all of these features, restoring nuclear size, DNA organization, and features used to control levels of different genes.

Interestingly, some cellular disease aspects weren’t improved by the CAA interruptions. Neurons with interrupted repeats still showed abnormal cell shape similar to the cell line with 1 CAA interruption in 107 repeats, with shorter neuron branches (dendrites) and smaller cell bodies. This suggests that these particular features may depend on the protein encoded by the HTT gene and its repeats, rather than on DNA instability or repeat purity.

The DNA Matters, Not Just the Protein

For many years, HD research focused almost exclusively on the toxic protein. But this study reinforces a paradigm shift happening in the field: the DNA sequence itself, including its purity and tendency to expand, seems to also play a direct role in disease.

And here’s where it gets a little bit wild – CAA and CAG both code for the protein building block glutamine. So inserting CAA interruptions doesn’t actually change the protein! Yet these interruptions seem to prevent repeat expansion and prevent cellular problems. We told you it was wild…

This seems to support the “two-stage” model of HD as it relates to the CAG expansion: you inherit a CAG repeat that isn’t overtly toxic initially, typically allowing for decades of healthy life, but it expands over your lifetime in certain brain cells until it crosses a threshold and triggers cell death.

While some researchers have theories about what exact length triggers toxicity related to CAG expansion and how exactly this happens, no one knows for sure. One theory is that the pure CAG repeat forms stable DNA structures that promote slippage and expansion when the gene is copied. CAA interruptions could disrupt these structures, preventing the expansion process.

A Therapeutic Possibility?

The findings from this recent work raise an intriguing question: could introducing CAA interruptions be therapeutic? Recent proof-of-principle studies have used CRISPR base editing to convert some CAGs to CAAs in cells and mice, with encouraging results. However, translating gene editing to post-mitotic human neurons in living brains faces enormous technical challenges – delivery efficiency, precision, and safety all remain major hurdles.

Perhaps more immediately, the CAGinSTEM platform itself offers value for drug discovery. Researchers can now screen for potential medicines that either reduce repeat instability or mitigate its downstream cellular effects, using these well-characterized, quality-controlled cell lines that seem to faithfully recapitulate some aspects of HD pathology.

And here’s where it gets a little bit wild – CAA and CAG both code for the protein building block glutamine. So inserting CAA interruptions doesn’t actually change the protein! Yet these interruptions seem to prevent repeat expansion and prevent cellular problems.

Natural Protection?

The study also hints at an intriguing possibility that some people might carry naturally occurring internal CAA interruptions that protect them from disease despite having pathogenic-range CAG repeats.

While never observed in the existing databases with information on people who have HD, such protective variants could exist in presymptomatic individuals who never develop symptoms.

The Bottom Line

It’s important to note that studies like this, that grow a specific type of cell alonel in a dish, don’t recapitulate what’s happening inside the brain, which is made up of many different cell types all connecting and communicating with each other. These types of studies are good at getting an idea of what certain types of cells are doing on their own, and how those disease-related changes could contribute to and impact the entire system.

This study adds evidence to other work that suggests CAG repeat purity directly affects both repeat instability and cellular dysfunction in HD, while developing a tool researchers can use to ask questions around this finding.

By preventing the formation of long, pure CAG stretches through strategic interruptions, researchers may be able to block repeat expansion and prevent multiple HD-related effects in neurons, all without actually changing the glutamine protein length. Wild!

The work continues to shift our understanding of what drives HD pathology, emphasizing that it’s not just about the protein you make, but about the DNA sequence you inherit and how it changes over time. While therapeutic applications for these findings remain speculative, the CAGinSTEM platform offers researchers a powerful new tool for understanding HD mechanisms and testing potential interventions.

Summary

• The platform: Researchers created quality-controlled human stem cell lines with different CAG repeat lengths and compositions in the huntingtin (HTT) gene
• Advanced tracking: Using long-read DNA sequencing, they measured CAG repeat changes over time in both dividing cells and neurons
• Length matters: Cell lines with 81-107 CAG repeats showed linear expansion over time, while shorter repeats remained stable
• Pure vs. interrupted: Standard repeats with one CAA interruption near the end still expanded; adding a second CAA interruption reduced expansion
• Complete blockade: Inserting 4 CAA interruptions throughout the repeat seemed to stopp expansion in both dividing cells and post-mitotic neurons
• Cellular rescue: The 4-CAA interruptions prevented multiple HD cellular effects, including impaired striatal neuron development, disrupted nuclear organization, and altered gene levels, all without changing the glutamine protein length
• DNA-driven disease: The findings contribute to the theory that repeat purity and instability, not just polyglutamine protein length, directly drive HD pathology
• A research tool: The CAGinSTEM platform offers a robust system for studying HD mechanisms and screening potential therapies

A new Huntington’s disease (HD) clinical trial has reached an important milestone: the first participants have now been dosed in POINT-HD, a Phase 1 study testing a new, selective huntingtin-lowering drug. RG6496 is designed to only lower levels of the expanded form of huntingtin (HTT), preserving levels of regular HTT. This exciting new milestone is only possible because of the courage and generosity of participants and their families, who are helping to move HD research forward for everyone. Let’s get into this new trial and what drug they are testing. 

HD Biology 101 

Before we dive into the details of this clinical trial, a quick recap on some HD biology fundamentals. Every person has two copies of the HTT gene, one from their mum and one from their dad. 

In people with HD, one of these copies contains an expanded stretch of DNA that leads to production of a faulty, “expanded” HTT protein, while the other copy makes the healthy, or regular unexpanded, HTT protein. Both copies of the gene are active, so people with HD typically produce both regular and expanded HTT throughout their lives. 

Because HD is inherited in a dominant way, having just one expanded copy is enough to cause the disease, and each child of an affected parent has a 50% chance of inheriting the expanded gene.

What is POINT-HD?

POINT-HD is a Phase 1 clinical trial sponsored by the company Roche. The study is testing an investigational drug called RG6496, which they developed in partnership with Ionis Pharmaceuticals. This drug is designed to only lower levels of the faulty, expanded HTT protein that causes HD, while leaving the regular protein intact.

Phase 1 trials are primarily focussed on safety. This is the first time RG6496 is being tested in people, so the main goals are to understand how safe it is, how it behaves in the body, and how people tolerate it. Researchers will also measure levels of expanded HTT protein in spinal fluid, which can help guide future studies.

POINT-HD is separate from Roche’s other HD trials, including the ongoing Phase 2 GENERATION-HD2 study of tominersen and a Phase 1 gene therapy study they are working on with Spark Therapeutics. Both of these other trials seek to lower total HTT levels – both the regular and expanded proteins. 

A selective approach to lowering HTT

RG6496 belongs to a class of drugs called antisense oligonucleotides, or ASOs. This ASO targets the HTT message molecules, which are the copies made of the HTT gene by the cells’ machinery that encode the instructions to make the HTT protein. Like other ASOs in HD research, it is given by lumbar puncture, also known as spinal tap, into the fluid that bathes the brain and spinal cord.

What makes RG6496 different from tominersen, the other ASO the company has developed, is that it is designed to be selective. Rather than lowering HTT protein levels from both copies of the gene, sometimes referred to as total HTT, it aims to reduce only the expanded version, while sparing the healthy HTT protein.

The drug does this by targeting a tiny genetic difference, called a single nucleotide polymorphism (known as a SNP, pronounced “snip”), that sits on the expanded HTT gene in some people with HD. This “genetic signpost” allows the drug to distinguish between the faulty and healthy gene copies.

Based on large genetic datasets, including Roche’s global HD epidemiology work, around 40% of people with HD are thought to carry this particular SNP on their expanded HTT gene. Only people who carry this genetic marker are eligible to potentially receive RG6496.

While having a limiter on this clinical trial might seem discouraging, this study aims to test the proof-of-concept for this approach. If it works, Roche could then work to identify other SNPs that can be targeted for the remaining 60% of the population with HD. If successful, the end goal will be to treat as many people with HD as possible!

Who can take part in this trial?

POINT-HD plans to enroll 40 adults aged 25 to 65 who have early or mild HD symptoms and meet additional study criteria. Before becoming enrolled participants, volunteers are screened to see whether they carry the target SNP required for the drug to work.

The study has two parts and will last around two years in total:

Part 1 will last about seven months and is placebo-controlled. Participants are randomly assigned to receive either a single dose of RG6496 or a placebo, with three out of four participants receiving the study drug.

Part 2 is an open-label extension lasting about 13 months, in which all participants receive RG6496.

Participants will attend regular clinic visits and complete some digital tasks on a study-provided smartphone. 

Where is the study running?

POINT-HD has kicked off with study sites in New Zealand and Australia, where the first participants have now been dosed. These countries are attractive places for many companies to start early-stage clinical trials as they have fast regulatory and ethics approvals, as well as strong clinical infrastructure with lots of tax incentives for companies to work there. Together with high participant engagement and efficient trial systems, this allows studies to start quickly, and hopefully generate high-quality data, all to help accelerate drug development.

The study is also expected to open soon in Argentina, with additional countries and sites to follow once regulatory and ethics approvals are in place. Details about participating sites will be posted on public trial registries such as ClinicalTrials.gov and on Roche’s ForPatients website as the study expands.

A thank you to participants

Every clinical trial begins with people who are willing to be first. Phase 1 participants, in particular, step into the unknown so that researchers can learn whether a new idea is safe enough to pursue further.

The start of dosing in POINT-HD is a moment to recognise those individuals and families, as well as the HD patient organisations and advisors who helped shape the study. Their involvement ensures that trials are not only scientifically sound, but also as respectful and practical as possible for the people taking part.

POINT-HD is still at a very early stage, and much more research will be needed before anyone knows whether RG6496 could one day become a treatment. But each new study adds another piece to the puzzle, and another reason for cautious optimism as HD research continues to move forward.

Summary

• A new Phase 1 Huntington’s disease trial has begun dosing, testing RG6496, a first-in-human, selective HTT-lowering drug.
• RG6496 is designed to lower only the disease-causing, expanded HTT protein, while preserving the regular protein that is important for healthy cells.
• The drug targets a specific genetic marker found in about 40% of people with HD.
• POINT-HD is primarily focused on safety, tolerability, and how the drug behaves in the body, while also measuring levels of expanded HTT in spinal fluid to guide future research.

Learn more

One mystery that many scientists think holds the key to curing HD is its mysterious age of onset. Although people with HD carry the expanded gene from birth, they generally don’t develop symptoms until later in life, suggesting something bad is brewing beneath the surface! One explanation, which has gained significant traction in recent years, is a process called somatic instability, where the expansion worsens over a person’s life. Recent work from the lab of Dr. Jeff Carroll at the University of Washington investigated several genetic techniques to understand what causes somatic instability and whether huntingtin-lowering therapeutics might slow it down. 

An Unstable Repeat

To understand somatic instability, let’s briefly revisit how genes work. Normally, genes like huntingtin, or HTT, are copied to make messenger molecules, called mRNA, through a process known as transcription. These genetic messages can then be used as a template to make proteins through another process called translation. 

However, in HD, the HTT gene contains extra genetic letters (C-A-Gs) that repeat too many times, causing its mRNA message to create an abnormal protein. In some cells, these repeating CAGs can grow even longer over someone’s life, leading to mRNA that is increasingly repetitive. By the time symptoms appear, these CAG repeats may have grown into the hundreds in certain cells. The continuously expanding CAG repeat in HTT, called somatic instability, is a leading theory for why the onset of HD is typically delayed into adulthood. 

Many ongoing clinical trials are focused on reducing the amount of HTT produced from the faulty gene. However, it’s unclear if lowering HTT levels will slow down the growth of the CAG repeat in the HTT gene. Although somatic instability is a prime suspect for causing HD’s delayed onset, it’s still only a correlation. Regardless, it’s certainly worth investigating what causes it and whether HTT-lowering therapies, which are already in clinical trials, can affect it. 

Dialling Down Huntingtin 

In a new study, a team at the University of Washington tested whether HTT lowering affects somatic instability. From previous work, they had used a type of therapy called Antisense Oligonucleotides (ASOs), which bind mRNA and send it to the cell’s trash can, to lower HTT levels in mice. They followed up on these experiments and discovered that ASOs also reduced CAG repeat growth by about 50%. This is good news because several ongoing clinical trials are already investigating ASOs.

Although the ability of ASOs to reduce target mRNA levels is well understood, the researchers were surprised that it stunted the growth of CAGs in the HTT gene. They suspected the ASOs might also disrupt mRNA at its source – a process called transcription. Recent work by other groups has linked rates of transcription with the growth of CAGs, such that the more the HTT gene is used to make mRNA, the quicker the CAGs build up. This hypothesis led the team to investigate exactly how ASOs were slowing CAG growth. 

The researchers considered two possible ways ASOs might be slowing somatic instability. 

1. The HTT protein itself was responsible for somatic instability, and by reducing the production of HTT, ASOs reduced somatic instability. 
2. The process of switching on the HTT gene was causing somatic instability, and by reducing transcription, ASOs reduced somatic instability. 

To find out how ASOs might affect somatic instability, the researchers injected a similar molecule into mice, called siRNA, which reduces HTT protein but does not affect transcription. When HTT protein levels were lowered using siRNA, they did not see any effect on somatic instability. This doesn’t mean siRNA wasn’t exerting a beneficial effect, just that siRNA wasn’t reducing somatic instability in the cells the team looked at. However, it does indicate that ASOs are slowing CAG growth by disrupting transcription, and not by lowering protein levels. 

Fewer Deliveries, Less Potholes?

To visualize the difference between siRNA and ASOs, imagine the HTT gene as an old road traveled by semi-trucks making deliveries, and the packages represent mRNA messages. With each year that the road is driven on, its potholes and cracks worsen, just as HTT’s CAG repeat worsens the more it’s used to make protein. Reducing HTT levels with siRNA is like reducing the number of packages, but the same number of trucks are still on the road – they are just emptier! ASOs, however, reduce the number of trucks, and fewer trucks mean less wear and tear on the road, and thus slower CAG growth. 

The researchers tried a more direct approach to test the connection between somatic instability and transcription. They turned to a genetically modified mouse model of HD where HTT transcription can be switched on or off, like a switch, by adding a special chemical to their drinking water. In mice where HTT transcription was switched off, they observed somatic instability slowing down. In addition, the longer HTT transcription was turned off, the less the CAG repeats grew. These results, in addition to their ASO experiments, provided good evidence that transcription was partially responsible for somatic instability. 

Zinc Finger Roadblocks

Although switching HTT on or off by adding a chemical to drinking water sounds fantastic, it only works in this specific type of genetically modified mice, which we sadly are not! So the researchers turned to a more practical approach using Zinc Finger Proteins (ZFPs), which are genetically modified proteins that attach directly onto CAG repeats and block transcription. From our analogy, ZFPs are like giant roadblocks cutting off traffic. If the delivery trucks driving over the road (representing transcription) are causing the potholes to worsen (CAG growth), then halting the traffic should slow somatic instability. 

To test ZFPs, they used a virus to deliver their DNA instructions into mouse brains. One side of the mouse’s brain got a version of the ZFP that latches onto the CAG repeat and shuts down transcription, and the other side got a version of the ZFP that binds HTT but does not shut down transcription. The ZFPs that block transcription showed an impressive 70% reduction in somatic instability. Surprisingly, ZFPs that bind to HTT but don’t block transcription still had a modest 42% reduction in somatic instability. This is good news because completely shutting down HTT transcription might be unsafe because HTT still performs important functions inside brain cells. So keeping HTT partially on while slowing somatic instability might represent a safer therapeutic approach. 

Therapeutic Directions

Collectively, these results show that dialing down HTT’s transcription not only reduces the amount of toxic HTT protein in the cell but might also slow its CAG growth. Although slowing CAG growth sounds like a home run, it’s important to reiterate that we still don’t know for sure if somatic instability is causing disease onset – it’s just a promising lead! In addition, reducing HTT transcription, which was linked to slowed somatic instability, might cause entirely unrelated problems in the cell. In our analogy, blocking package deliveries would stop the potholes from forming, but this would also surely create an angry bunch of customers waiting for their packages! 

Clinical trials using ASOs are already underway, and therapies based on ZFP are being worked on. Although there’s plenty of room for optimism, there are some important caveats. First of all, the mice used in these experiments are genetically engineered with an extreme CAG repeat mutation, because they otherwise wouldn’t show symptoms due to their short lifespan. And whether these therapies will translate effectively or safely into humans is another big question mark. For example, although ASOs and ZFPs might be tolerated within the very short lifespan of a mouse, we don’t know the long-term safety or effectiveness in humans. Regardless, we’ll be following every development closely and sharing updates as soon as they are released! 

Summary

• CAG repeats in the HTT gene keep expanding over life, and this somatic instability may contribute to HD’s delayed onset.
• ASO treatments slow repeat expansion by reducing HTT transcription, not just HTT protein levels.
• Multiple experiments, including siRNA, switchable transcription, and Zinc Finger Proteins, confirm that less HTT transcription means less CAG growth.
• Therapies targeting transcription look promising, but it’s still unclear whether slowing somatic instability will change HD onset in humans.

Learn more

Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding

Ever since large genetic studies in Huntington’s disease (HD) revealed that the longer the CAG expansion, the earlier symptoms appear, we’ve known that repeat length matters. Recent work has highlighted just how that repeat length increases within vulnerable brain cells — from about 50 CAGs to over a thousand. 

Understanding how these expansions happen, and how they influence the disease, is crucial for developing the right therapeutic strategies. Can we correct the expanded DNA in affected cells? Well… maybe the cells can do it themselves!

The players in a molecular tug-of-war

DNA-repair genes can strongly influence when HD symptoms begin. For years, researchers have been asking: what do these genes actually do to the faulty stretch of DNA that causes HD? And can we harness this knowledge to delay symptom onset — perhaps long enough that the disease never develops?

A new study in Nature Communications from Petr Cejka’s group reconstructs, molecule by molecule, how two opposing DNA-repair teams compete inside our cells. One team mistakenly lengthens the CAG repeat when trying to fix it, while another trims it back. This elegant biochemical dissection finally shows why players such as MSH3, MLH3, and FAN1 have such a strong impact on disease onset — and opens new routes to slow or even prevent HD.

Why DNA repair matters in HD

DNA is stored in the nucleus forming a double helix, the letters on each strand pair precisely, like the matching teeth of a zipper.

But when the CAG sequence in the huntingtin (HTT) gene becomes too long, the strands no longer line up perfectly. One side can end up with extra “teeth,” creating a mismatch that bulges out from the helix — what scientists call an extrusion loop (imagine a zipper with a kink on one side!).

Everyone inherits some CAG repeats in their HTT gene, but in general, people with 40 or more eventually develop the disease. When these repeats get longer, the DNA can’t zip up neatly anymore, and the cell’s repair machinery rushes in to fix it. And here is where the tug-of-war game starts. Repair can go two ways: some machinery complexes smooth things out and stabilize the DNA, while others accidentally make the repeat longer and longer.

The “expansion crew”: MutSβ and MutLγ

DNA repair usually acts like a spell-checker, scanning for errors, mismatches, or small loops that appear when our DNA is copied. In HD, however, part of the repair team creates the problem.

It’s a literal tug-of-war between two DNA-repair pathways acting on the same repeat. Which side wins likely determines whether CAGs grow or shrink in a given cell.

Two complexes — MutSβ (made of MSH2 + MSH3) and MutLγ (MLH1 + MLH3) — recognize the extrusion loop that forms when there are lots of CAG repeats. Instead of removing the loop, the expansion crew uses the loop as a template and fills in extra CAGs.The result? The repeat grows even longer. MutSβ and MutLγ turn a normal repair job into a “copy-and-paste” mistake that expands the CAG number.

The “contraction crew”: FAN1 to the rescue

Enter FAN1, a nuclease — essentially a pair of molecular scissors — that can do the opposite. FAN1 recognizes these DNA loops and cuts them directly at the site of the problem. Working with helper proteins, the FAN1 crew removes extra repeats instead of adding new ones.

FAN1 also has a clever second trick: it physically blocks MutLγ from partnering with MutSβ, stopping the expansion machinery before it even starts.

A molecular tug-of-war

By setting up both reactions side by side in a test tube, the team revealed a literal tug-of-war between two DNA-repair pathways acting on the same HTT repeat. Which side wins likely determines whether CAGs grow or shrink in a given cell.

Connecting biochemistry to human genetics

The discovery that DNA repair genes affect when symptoms appear didn’t come out of the blue — it started with genome-wide association studies (GWAS) enabled by donated DNA samples from thousands of people with HD. These large-scale studies searched the entire genome for genetic variations that modify the age of onset. The clear message was that genes involved in DNA repair — like MSH3, MLH3, and FAN1 — are major players.

This new biochemical model beautifully explains why those GWAS signals point to repair genes. Variants that boost MutSβ or MutLγ activity (in MSH3 or MLH3) speed up CAG expansion and lead to earlier symptoms, while variants that enhance FAN1 activity can slow expansion and delay onset.

Scientists had long seen these correlations — now, thanks to the Cejka team’s molecular reconstruction, we can finally connect the dots between human genetics and the actual DNA chemistry that could be driving Huntington’s disease.

Why this matters

Understanding these precise mechanisms isn’t just fascinating biology — it’s a roadmap for how we could develop therapies. If we can tilt the balance toward contraction or stabilization, we might slow or even halt the disease process itself.

Some companies are already pursuing this idea:

• ASOs targeting MSH3 or inhibitors of MutSβ aim to reduce expansion activity are being developed by Ionis Pharmaceutical, LoQus23 Therapeutics and Pfizer
• Harness Therapeutics is trying to boost FAN1 function, or mimicking its blocking effect on MutLγ, could offer another route to protect HTT from runaway expansion

What’s next?

Although strong evidence suggests that somatic repeat expansion drives when symptoms begin, this remains a working model. Researchers are now trying to map how these repair processes differ across brain cell types and how they interact within living tissue.

Learning how cells naturally correct their own DNA errors could inspire treatments that let them fix Huntington’s disease from within.

The key challenge is balance: the same DNA-repair systems that sometimes lengthen the HTT repeat also protect the rest of our genome. The ultimate goal will be to fine-tune these pathways to suppress CAG expansion without compromising DNA integrity elsewhere.

If this model holds true, it could open an entirely new therapeutic avenue — targeting DNA repair itself to delay or even prevent Huntington’s disease.

Summary

• HD onset is strongly influenced by genes involved in DNA repair.
• MutSβ (MSH2–MSH3) and MutLγ (MLH1–MLH3) cooperate to nick CAG DNA, adding extra repeats.
• FAN1 and its crew cut the CAG loop instead, removing excess repeats. FAN1 also blocks the MutSβ–MutLγ partnership, preventing expansions.
• These opposing reactions explain why enhancing FAN1 or reducing MLH3/MSH3 activity could delay HD onset.

Learn more

Mechanism of trinucleotide repeat expansion by MutSβ–MutLγ and contraction by FAN1.

On December 4, 2025, uniQure announced they have received the final meeting minutes from their October 29 pre-Biologics License Application (BLA) meeting with the FDA regarding AMT-130. The minutes confirm what was reported in early November: the FDA currently believes the Phase I/II data are unlikely to provide the primary evidence needed to support a BLA submission at this time.

While the most recent press release doesn’t provide new information beyond what we already knew, it does represent an important procedural step. uniQure now has the official written record from the FDA meeting, which will be crucial as they work to chart the path forward.

What Happens Next

UniQure has stated they are carefully evaluating the FDA’s feedback and plan to urgently request a follow-up meeting with the agency in the first quarter of 2026. This meeting will be critical for understanding exactly what additional evidence or analyses the FDA requires.

Matt Kapusta, uniQure’s CEO, emphasized the company’s commitment: “We are committed to collaborating with the FDA to advance AMT-130 to patients and their families as rapidly as possible. The support we have seen these last weeks from the Huntington’s disease community, including patients, families, caregivers, clinicians and advocates reinforces the urgency of the unmet need in Huntington’s disease.”

UniQure has stated they are carefully evaluating the FDA’s feedback and plan to urgently request a follow-up meeting with the agency in the first quarter of 2026.

The Community Responds

The HD community has not remained silent through the whiplash of the FDA’s about-face from just 5 months prior, when they stated that data from the ongoing trials would be sufficient to support accelerated approval. 

In response to this challenging moment, major HD advocacy organizations have come together to issue a Statement of Unity (see More Info section below). Help4HD, HDReach, Huntington’s Disease Society of America, Huntington’s Disease Foundation, and the Huntington’s Disease Youth Organization have pledged to work in partnership to champion the voices of those impacted by HD, particularly when communicating with regulatory bodies like the FDA. This collaboration will focus on broader, shared priorities that affect the many therapeutic approaches currently being developed for HD, ensuring that the lived experiences of families are heard and represented in regulatory discussions.

Multiple Change.org petitions urging the FDA to uphold its accelerated approval pathway for AMT-130 have gathered significant momentum, with tens of thousands of signatures from families, caregivers, and advocates gathered in a matter of weeks – 41,805 at the writing of this article. These petitions and their strong support highlight the urgent unmet need in HD and the devastating impact the regulatory uncertainty has on families who finally saw hope on the horizon.

If you’ve not yet signed these petitions and would like to add your voice, you can find them here:

• Bring Hope to Huntington’s Disease Families: Urge the FDA to Uphold Accelerated Approval
• Accelerate Breakthrough Drug Approval for Huntington’s Disease – uniQure AMT-130

The Data Remain Strong

It’s crucial to remember that nothing about the FDA’s position changes the clinical data themselves. AMT-130 still appears to show a 75% slowing of disease progression compared to matched controls, the strongest evidence we’ve ever seen for a disease-modifying therapy in HD. The treatment continues to show a manageable safety profile with no new drug-related serious adverse events reported since December 2022.

Looking Beyond U.S. Borders

While the U.S. regulatory path has hit an unexpected obstacle, AMT-130 continues to advance in other parts of the world. UniQure has stated they are progressing discussions with regulatory agencies in the European Union and United Kingdom. 

If AMT-130 receives approval in these regions, it would benefit people with HD globally, as clinical data from any regulatory jurisdiction strengthens the evidence base and could ultimately support approval elsewhere.

While the timeline is less certain than we hoped, the goal of bringing an effective disease-modifying therapy to the HD community remains firmly in sight, and it’s clear that the HD community is ready to stand up and fight to make that happen sooner than later.

Why This Matters

The regulatory back-and-forth has been emotionally exhausting for the HD community, and we share in your frustration. However, this is not the end of the road for AMT-130. As we’ve said before, this represents a “save point” in HD drug development, a place where solid evidence exists that we can build upon, learn from, and advance forward. The data showing that HTT-lowering seems to slow disease progression remains a landmark achievement, regardless of regulatory timelines.

UniQure has voiced its commitment to seeing AMT-130 through this process. The company has the official meeting minutes, they’re preparing for urgent follow-up discussions, and they’re exploring multiple regulatory pathways. While the timeline is less certain than we hoped, the goal of bringing an effective disease-modifying therapy to the HD community remains firmly in sight, and it’s clear that the HD community is ready to stand up and fight to make that happen sooner than later.

We’ll continue to follow developments closely and keep the HD community informed as new information emerges.

Summary

• UniQure received official FDA meeting minutes from October 29 meeting, confirming Phase I/II data currently unlikely to support BLA submission
• Company plans to request urgent follow-up meeting with FDA in Q1 2026 to determine path forward
• Major HD advocacy organizations issued Statement of Unity, proposing to coordinate efforts with regulatory agencies
• Community petitions gathered 41,805+ signatures urging FDA to uphold accelerated approval pathway
• Clinical data remain unchanged: AMT-130 appears to slow disease progression by 75% with strong safety profile
• UniQure advancing regulatory discussions in EU and UK as parallel pathways
• This represents a regulatory delay, not the end of AMT-130’s development

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