On May 5th, PTC Therapeutics released results from their ongoing Phase 2 PIVOT-HD clinical trial for PTC-518, now called votoplam. Excitingly, they announced that this trial met its primary endpoint – votoplam was shown to lower huntingtin protein levels. We also learned more about the safety of this drug and some insights into how it might be changing biomarkers and symptoms of HD. Let’s get into it.

What is votoplam?

Votoplam belongs to a class of drugs known as splice modulators. The drug can be taken as a daily pill – a convenient and non-invasive method of delivery. The drug is a chemical that changes how the RNA message molecule, which encodes the instructions for making the huntingtin protein, is processed. The drug triggers the RNA message to be degraded, and as a result, less huntingtin protein is made.

The drug is not selective, which means that it lowers the levels of both the regular form of the huntingtin protein, as well as the expanded form that people with HD make. Votoplam acts systemically – this means it works throughout the whole body, not just in the brain and central nervous system like many of the other huntingtin-lowering therapies in development. In the ongoing Phase 2 trial, the pill is being tested at 5 and 10 milligram (mg) doses compared to placebo, in two different groups of people with HD; those with Stage 2 disease and those with Stage 3 disease.

The initial trial was designed to only be 12 months long, with data readouts at 12 weeks and 12 months. Then all folks were allowed to remain on votoplam in an “open label extension”, aka OLE – this is where people continue to take drug, or switch from placebo to the drug, while still be followed in the trial to get a better idea of the long term effects the drug may be having.

Endpoints in Clinical Trials

At the beginning of the clinical trials process, a series of outcomes are established that define the things that the drug maker thinks should happen in people as a result of being given a drug. Kind of like a game of billiards, where players have to call the shots before they take them. It shows intent throughout the process. These defined outcomes are called “endpoints”. This is in addition to safety parameters, which are paramount in all stages of clinical trials, and even after a drug is approved.

In a Phase 2 trial, we are generally testing to see if the drug is doing what it is designed to do based on the pre-defined endpoints, in ways we can precisely measure. In the case of votoplam, the primary endpoint was lowering the amount of huntingtin protein.

Additional measures then test if the drug might actually be benefiting disease. For the PIVOT-HD trial, PTC are usings various clinical tests to measure the progression of HD. In addition, PTC are collecting data that measures the biological progression of disease. For that, they’re using MRI to measure the volume of the brain, which we know decreases as the disease progresses. They’re also measuring neurofilament light protein (NfL), which is an indicator of the health of neurons. We know NfL levels rise as brain cells are lost to HD and the disease progresses.

What the PIVOT-HD Data Says, So Far…

In this update from PTC, they shared the data from all participants at the 12 week and 12 month timepoints, as well as some early data from folks who have reached the 24 month time point.

Safety

The most important take home message is that the drug continues to appear to be safe – there were no Serious Adverse Events (SAE) caused by votoplam. This has halted previous trials for HD in the past, so this is great news for the HD community.

Huntingtin Lowering

Secondly, the levels of huntingtin protein are indeed being lowered by votoplam. PTC shared data showing that for people taking votoplam, huntingtin levels are being lowered through the 12 month mark. This is really the make-or-break metric since huntingtin lowering was the primary endpoint for this trial.

Whether they measured in blood or spinal fluid, PTC saw that the higher dose of the drug lowered huntingtin more. This dose-dependent effect was confirmed for participants with Stage 2 or Stage 3 HD.

In the May 5th update, they hadn’t yet analyzed the 24 month samples for huntingtin levels, so that’s something we’ll be looking for in a future update.

Biomarkers

Next up – NfL. Nfl has become a critical biomarker for HD. It’s a well established way to measure the health of neurons in the brain for HD and other brain diseases. The data at 12 months was not presented for all participants so we don’t have an overall picture.

Instead, data were broken down to divide participants by HD-ISS stage. This sub-group analysis suggests that perhaps there is a slightly more positive effect in people with Stage 2 HD, but the data is less clear for people with Stage 3 HD. The good news is that they didn’t see any of the NfL level “spikes” recorded in other trials investigating other types of huntingtin-lowering drugs.

In folks who have been taking this drug for 24 months, levels of NfL in blood samples were found to be lower than expected. This data might suggest that votoplam may be having a protective effect on brain cells in a longer timeframe. Typically, we would expect an increase in NfL levels of about 12% per year in someone with HD. For people on votoplam, NfL levels decreased 9% for those on 5 mg and decreased about 14% for those on 10 mg. This is very promising data but it is important to note that this finding is from a much smaller number of participants than the 12 month data, so it should be interpreted cautiously. Additionally, everyone at the 24 month time point was in Stage 2 of disease at the start of the trial.

Brain MRI Scans

Another piece of data that PTC shared were changes in brain volume. These data were harder to interpret – at 12 months, there didn’t seem to be a clear trend of how votoplam could be influencing changes in brain volume.

This could be for several reasons that make brain volume changes tricky to measure, like the influence of brain cell loss vs. brain swelling. If there is brain inflammation, it could look like volume is higher, but it may not be for a good reason. Another variable here could be timing – 12 months might just not be long enough to see meaningful changes in brain volume. So the jury is still out on how votoplam could be influencing brain volume.

Clinical Readouts

Another set of data that was tricky to interpret were the clinical readouts. To determine how votoplam may be influencing progression of HD, PTC looked at:

• Total Functional Capacity (TFC) – a collection of tests that measures someone’s ability to live and function independently.
• Total Motor Score (TMS) – a clinical assessment of HD-associated movement symptoms.
• The Symbol Digit Modalities Test (SDMT) – which asks people to match numbers to symbols to measure visual attention and thought processing speed.
• The Stroop Word Reading test (SWR) – which measures the ability to concentrate through cognitive interference.
• The Composite Unified Huntington’s Disease Rating Scale (cUHDRS) – a sensitive collection of all the above tests that measures the ability to function day-to-day while also assessing movement control, capacity to pay attention, and memory. Since cUHDRS is a collection of TFC, TMS, SDMT, and SWR, its score can be influenced by each of the separate readings.

Overall, cUHDRS seemed to improve slightly for people with less advanced, Stage 2 disease at 12 months. The improvements appeared to be primarily driven by the TMS and SDMT, suggesting these modest improvements were related to movement and thinking. However, SDMT improvements were only seen in the higher (10 mg) dose group.

For people with more advanced, Stage 3 disease, the results were less clear at 12 months. The cUHDRS showed a very small improvement for folks in this group on the low (5 mg) dose, but those on the higher (10 mg) dose didn’t see the same improvement. There also wasn’t a clear indication for what specific metrics were driving the cUHDRS scores.

For the data we have from the Stage 2 folks who have reached the 24 time point so far, the clinical readouts look similar – there are favorable improvements in cUHDRS which appear to be happening in a dose-dependent manner. In these data, this positive trend seems to be driven by improvements in TFC and SDMT, suggesting improvements in functional capacity and cognition. However, the improvements for TMS from 12 months didn’t hold, meaning changes in movement symptoms don’t seem to be driving the improvement here like we saw at 12 months.

Pharmacology: Dose Matters

An interesting question that arises from this update is how much huntingtin lowering do we need? The modest clinical benefits suggested by the data from PIVOT-HD are happening with 24% (low dose) to 39% (high dose) huntingtin lowering. This suggests that perhaps we don’t have to lower huntingtin levels as much as we previously thought – to around 50%. But it also begs the question – if we lower huntingtin more with votoplam, will we see stronger clinical effects?

For those with Stage 2 disease, PTC saw some signs of clinical improvements at the low dose (5 mg), which seemed to improve further at the high dose (10 mg), suggesting that maybe more drug and more lowering could be better. However, for folks at Stage 3, the results didn’t suggest that more drug had a better outcome – this could be due to several reasons. It may be that people at Stage 3 are taking different medications that influence the clinical tests being measured. For example, medication for chorea-related movements could influence motor tests. Or, the results might suggest that the earlier we treat people, the more effective the drug will be. Another possibility moving forward it that we may need to tailor a drug’s dose to the stage of disease of the person being treated.

For now, the data showing differences in Stage 2 and Stage 3 open up the question: does votoplam have a different clinical effect based on disease stage? As we continue to collect more data from the PIVOT-HD trial, it could help guide inclusion criteria for potential future clinical trials.

Lessons for Other Drugs in Trials or Pending Trials?

A further important finding from this update is that non-selective lowering of both the regular and expanded huntingtin protein seems to be fairly safe. This is good news for other so-called “total huntingtin” lowering approaches being developed or in the clinic, such as tominersen and AMT-130.

Another important question this trial brings up is brain vs. body – how important is it to target huntingtin lowering throughout the body, or just in the brain? How much does expanded huntingtin created outside the brain contribute to Huntington’s disease? And, are there other disease-related effects caused throughout the body? To answer these questions, it will be important for scientists to compare votoplam clinical trial data to other huntingtin-lowering approaches that specifically target the brain.

Cautious Optimism

While the new data from PIVOT-HD is promising, there are still data to analyze and unanswered questions. For example, we’re still waiting on huntingtin lowering data from the 24 month time point. Additionally, the effects on some of the clinical endpoints measures still aren’t entirely clear, but are trending in what appears to be a positive direction for some groups.

However, the data presented in the May 5th update appears to continue to give green flags for votoplam. This positive news could lead PTC to enter discussions with the FDA for a potential accelerated approval of votoplam, using the metrics defined in December, but the company didn’t indicate if this was the path they would be taking. Their next hurdle is to do more data analysis and digest the data with their new partner Novartis to determine the next steps for votoplam.

We all know heart health matters – but what if the same habits that keep your heart strong could also protect your brain? A new study reveals a link between cardiovascular health and lower levels of neurofilament light (NfL), a key biomarker of brain cell damage for Huntington’s disease (HD) research. So what does this mean for people with HD? Let’s dig into what HD families can take away from this new study that shows what’s good for your heart, is also good for your brain.

Heart Health and Brain Biomarkers

This study focused on the American Heart Association’s Life’s Simple 7, a set of lifestyle and health factors that promote heart health. The researchers aimed to determine whether people who follow these guidelines also show biological signs of better brain health.

The Life’s Simple 7 factors include:

• Eating a healthy diet
• Engaging in regular exercise
• Maintaining a normal body mass index (BMI)
• Not smoking
• Managing blood pressure
• Controlling cholesterol levels
• Regulating blood sugar levels

The researchers analyzed data from the Chicago Health and Aging Project (CHAP), a long-term study tracking the health of older Black and White adults from 1993 to 2012. A 19 year study provides a stellar dataset! Specifically, they focused on more than 1,000 participants aged 65 and older to see if those who scored higher on cardiovascular health also showed healthier brain biomarkers.

To assess brain health, the researchers looked at two important blood-based biomarkers, neurofilament light, or NfL, and total tau, or t-tau.

NfL as a Key Brain Biomarker

NfL is a protein that is released when nerve cells are damaged. So, higher levels suggest there is more neuronal damage. In neurodegenerative diseases like HD, as symptoms progress and brain cells are lost to the disease, levels of NfL rise. Because of this, NfL is used as a biomarker in many brain diseases and is gaining a lot of traction in HD research as more studies suggest that it’s strongly connected to the progression and severity of disease.

Perhaps most importantly, some of the newest research around NfL suggests that changes in the level of this protein can be detected before symptoms even start, making it an incredibly sensitive, and valuable, tool for tracking not only disease progression, but also the effectiveness of drugs. That last part is critical as the field moves toward testing drugs earlier, in groups of people before they even start showing signs and symptoms of HD.

So what happened in this new study when they looked at NfL levels in people with higher and lower cardiovascular health as they aged? The study’s findings were quite striking.

Connecting Heart and Brain Health

Participants with higher cardiovascular health scores had lower NfL levels, suggesting that they had less neuronal damage. And we’re not talking just slightly, the numbers were incredibly impressive!

For every 1-point increase in cardiovascular health score, participants had 3.5% lower NfL levels. Those with the highest heart health scores had nearly 19% lower NfL levels than those with the lowest scores. In other words, better heart health seemed to be linked to healthier brain cells!

These results suggest that actively working on your heart health, whether it’s through diet changes, incorporating more exercise, or effectively managing risk factors like blood pressure, could have a tangible impact on reducing a key marker of damage to your brain cells. So taking care of your heart could get you a brain benefit as a side effect.

The Long-Term Impact

The researchers didn’t just look at one snapshot in time. They followed over 800 of the study’s participants for a decade to see how NfL levels changed over time. What they found was that NfL levels naturally increased with age in all participants. However, those with better cardiovascular health had a slower rate of increase.

The effect of improved cardiovascular health was compelling – participants with low cardiovascular health scores saw an annual increase of 7.1% in NfL, while those with high scores had a lower increase of 5.2% per year. Over a 10 year timeframe, that really adds up!

The take home message here is that maintaining good cardiovascular health through heart-healthy habits over the long term could actually help slow down brain aging over time.

What About T-Tau?

This study also looked at another biomarker from people’s blood – total tau, or t-tau. T-tau is a protein that has increased levels in neurodegenerative diseases, particularly Alzheimer’s.

Interestingly, the study did not find a significant link between cardiovascular health and t-tau levels. This suggests that while heart health may play a role in reducing neuronal damage (as measured by NfL), it may not directly impact the processes that lead to tau-related neurodegeneration.

Why Are NfL and T-Tau Different?

While this study can’t say for sure why heart health plays a role in NfL levels as people age, but not t-tau levels, they did offer some possible explanations.

One thought is that NfL might be more directly influenced by vascular factors, things like blood flow and the health of blood vessels in the brain. Since the health of blood vessels, including those that run through our brain, are directly impacted by cardiovascular health, this could explain differences in NfL levels. Less healthy brain blood vessels could create a less supportive environment for our neurons, causing them damage.

However t-tau is thought to be more closely related to the actual clumping of tau proteins and the formation of neurofibrillary tangles, which are a hallmark of Alzheimer’s and other tau-related diseases, but not general brain health like NfL. So it could be that the biological pathways affected by cardiovascular health don’t have a major effect on driving tau protein accumulation.

It does seem clear though that the relationship between heart health and brain health is complex, and there are probably different biological processes at play.

The Effect Across Different Groups

The researchers also explored whether these connections varied across different populations. They found that the link between better cardiovascular health and lower NfL levels was seen in both men and women and across both Black and White participants. So sex and ethnic background didn’t seem to influence the association between heart and brain health.

Another group they specifically looked at was people who carry the APOE4 gene, which is a well-known genetic risk factor for Alzheimer’s disease. In this group, they found an even stronger association between better cardiovascular health and lower NfL levels. This could be an important finding for people who know they have this genetic predisposition.

A possible interpretation here is that people who are already at a higher risk for Alzheimer’s might see an even bigger benefit from taking care of their heart. While it’s tempting to speculate the same may be true for HD because of some similar mechanisms shared by the two diseases, the effect in HD wasn’t specifically examined in this study.

When they looked at people who already had some form of cardiovascular disease at the start of the study, the connection was less clear. They think this means that the largest benefit in brain health, as measured by NfL, may be gained before heart problems arise, meaning the biggest benefits might come from prevention and long-term healthy heart habits rather than treatment.

The Big Picture: Happy Heart, Happy Head

The study highlights that maintaining good cardiovascular health might help protect against brain aging and neurodegeneration. This adds to growing evidence that heart-healthy habits can be a powerful tool for reducing dementia risk.

The findings from this new study could be relevant for HD families, since we know that NfL levels rise as the disease progresses. When it comes to changes in NfL because of brain cell breakdown, many researchers think if we can hold NfL levels in check, that could suggest we’re stabilizing the progression of HD. Many groups are working toward a pharmaceutical approach to control NfL levels. This new research adds to that, suggesting that heart-healthy habits could help maintain general brain health.

While the relationship between heart and brain health is complex, this research supports a compelling idea: taking care of your heart could be one of the best ways to take care of your brain. So next time you hit the gym or choose a salad over fries, remember – your brain is probably benefiting too!

Imagine a vast and intricate factory, humming with activity. This factory isn’t manufacturing cars or electronics but rather the essential components that keep our bodies running. Inside each cell, thousands of tiny workers, known as proteins, perform highly specialized tasks. These proteins are responsible for everything from building cellular structures to sending messages and cleaning up waste. But just like any efficient factory, the cell must carefully manage its production line – ensuring that the right proteins are produced at the right time, in the right amounts, and in response to changing conditions. When this system runs smoothly, the cell thrives. When it breaks down, like in Huntington’s disease (HD), problems can emerge.

Blueprints and Production Lines

Every factory needs blueprints to guide production. In the cellular factory, these blueprints are stored in DNA, the genetic material housed in the nucleus. DNA contains instructions for making proteins, but these instructions aren’t directly used on the factory floor. Instead, the DNA blueprint is copied into messenger RNA (mRNA), a process akin to a worker transcribing key information onto a portable notepad.

The mRNA then travels to the ribosomes – tiny molecular machines that serve as the cell’s production lines. At the ribosomes, the mRNA instructions are read, and amino acids, the building blocks of proteins, are assembled in the correct order. This process, known as translation, ensures that proteins are built precisely according to their design specifications.

But just as an efficient factory must regulate how many products it produces, cells tightly control protein production to prevent waste and ensure smooth operation. In HD, a mutation in the huntingtin gene (HTT) throws a wrench into this finely tuned system, causing problems on the protein production floor.

A Flawed Instruction Manual

The HTT gene provides the instructions for making the huntingtin protein, but in people with HD, this blueprint contains a critical error: an expanded CAG repeat sequence. Normally, the HTT gene includes between 10 and 35 CAG repeats, but in HD, this number swells beyond 36, and the excess repeats create a distorted protein structure.

This flawed blueprint sets off a cascade of problems. The expanded CAG sequence results in an abnormally long polyglutamine (polyQ) stretch in the huntingtin protein. Research led by Dr. Judith Frydman from Stanford University suggests that the expanded HTT protein overwhelms the cell’s quality control systems, leading to toxic interactions with other essential proteins.

Production Line Jams

They think this happens, in part, because of a small, previously overlooked note on the blueprint of the HTT gene – a regulatory sequence called an upstream open reading frame (uORF). This uORF is like an instruction at the top of the blueprint that tells the factory workers to slow down before starting full-scale production of the HTT protein. In healthy cells, this regulation keeps HTT protein levels in check.

However, when cells experience stress, they think this regulatory note gets ignored. Instead of slowing down, ribosomes speed up HTT production, potentially worsening the disease. This work suggests that the problem isn’t just the final protein product that’s causing issues in the cell but also the way its production is controlled.

The real trouble begins when ribosomes hit a tricky part of the HTT blueprint – the infamous CAG repeat stretch. These repeats cause the ribosomes to stall and collide, much like a traffic jam on a production line. The more CAG repeats there are, the worse the jam gets.

This ribosome stalling may not just slow things down; it may create faulty, incomplete protein fragments that are even more prone to forming toxic clumps. The researchers used advanced techniques to track ribosome movement and found that the longer the CAG stretch, the more often these traffic jams occurred. This insight shifts the focus from the final protein clumps to the production process itself.

The Factory Assistant—eIF5A

Cells have ways to deal with these production line slowdowns. One key player is a protein called eIF5A. eIF5A acts like an assistant on the factory floor, helping ribosomes get past difficult-to-read sequences, like some that appear in the HTT gene.

But in HD, it seems that the mutant HTT protein hijacks eIF5A, pulling it away from its normal job. With less eIF5A available to guide production, ribosomes struggle even more to process HTT correctly, leading to more stalling, more fragments, and more cellular stress. The researchers found that eIF5A levels drop in HD mouse models as the disease progresses, further linking it to the problem.

The consequences of ribosome stalling and eIF5A depletion extend beyond HTT production. Ribosome collisions trigger a cellular stress response, activating systems meant to degrade defective proteins. However, when too many ribosomes stall, the system becomes overwhelmed, leading to a pileup of misfolded proteins and further cellular dysfunction. This could help explain why HD affects so many different cellular functions beyond just the presence of protein clumps.

Fixing the Factory

Understanding how the problem starts at the production level could open new doors for treatment. The study explored whether slowing down the overall protein production process could help. They used a chemical tool to reduce the initiation of protein production, effectively easing the burden on the ribosomes. This approach reduced the formation of toxic HTT fragments, suggesting that fine-tuning protein production could be a potential therapeutic strategy.

That specific chemical tool doesn’t have good drug-like properties so isn’t suitable for clinical trials. However, it opens the door for developing treatments that would be. One approach is to develop drugs that help cells degrade toxic proteins more efficiently, preventing harmful buildup. Another strategy could involve enhancing the cell’s natural quality control mechanisms, boosting its ability to recognize and eliminate defective proteins before they cause damage.

This research challenges a long-standing focus on protein aggregates as a central problem in HD. Instead, it highlights the role of faulty protein production – ribosome stalling, translation errors, and eIF5A depletion – as possible drivers of the disease. By targeting these early steps in protein production, scientists may find new ways to intervene before the mess even starts.

This shift in focus represents a crucial step toward understanding and ultimately treating Huntington’s disease, offering hope that by fixing the factory, we can prevent an assembly line breakdown before it happens.

April was blooming with fresh updates from the world of Huntington’s disease (HD) research, and we’ve got your highlights right here! At HDBuzz, we’re always on the lookout for promising science, innovative ideas, and stories that bring hope. This month, we covered exciting breakthroughs in basic research, important clinical trial updates, and fresh perspectives on the HD community’s tireless push toward treatments. Let’s dive in!

Do Antidepressants Affect Cognitive Decline? There’s More To The Story For Huntington’s Disease

New research shines a light on how treatment regimens evolve for people with Huntington’s disease. A study from Enroll-HD shows that as HD progresses, most people tend to use more medications – often to manage shifting symptoms like mood changes early on, and movement or behavioral issues later. Antidepressants, especially SSRIs, are among the most common, and are a critical tool in the toolkit for people living with HD.

But new findings from a separate dementia-focused study suggest that SSRIs might come with cognitive risks. But don’t toss your meds! Because this study isn’t a one-to-one comparator for HD. The big takeaway? SSRIs and other antidepressants are a fundamental piece in treating HD.

Personalized care matters more than ever. The insights from these papers underscore the power of open, ongoing conversations between HD families and care teams to tailor treatments over time. With knowledge in hand, patients and doctors can make informed choices that best support health and quality of life.

Stars in the Sky: Psychosis in Huntington’s Disease

Psychosis can be a challenging part of HD, but research is helping shine a hopeful light on this often-overlooked topic. A study found that psychosis symptoms affect about 1 in 6 people with HD and may change how movement symptoms like chorea show up, reminding us that each person’s HD journey is unique.

By openly exploring mental health in HD, this research helps break stigma, spark important conversations, and offer practical coping strategies for individuals and families. It’s a powerful reminder that no one is alone, and that every person with HD adds their own irreplaceable light to the world.

Piecing It Back Together: Growing new neurons for Huntington’s disease

A groundbreaking new study has flipped the script on what could be possible in HD by showing that the adult brain might be able to regrow the exact neurons lost to the disease – and plug them right back into the brain’s circuitry. Using two special proteins as neuron “fertilizer” and “guides,” researchers prompted the brains of adult mice to grow new, functional medium spiny neurons – the key cells lost in HD.

Even more exciting? These new cells not only looked like the right type of nerve cells, but it seems that they connected, can communicate with other cells in the brain, and improved movement in HD-model mice. While this isn’t a treatment yet, it’s a major leap toward possible brain repair therapies and brings powerful new hope: maybe we can do more than slow down the loss caused by HD – maybe we can rebuild.

Knockouts for the win: how expanding CAGs drive disease

Scientists are closing in on a promising new strategy to slow down HD by targeting somatic expansion. A new study from the Yang lab at UCLA reveals that blocking certain DNA repair genes – especially Msh3 and Pms1 – could reduce harmful CAG repeat expansion in brain cells of mice.

This genetic tweak seemed to reverse many of the molecular changes seen in HD, improved brain health, and even restored some movement in mice. While mice aren’t people, this research builds on years of collaborative work and supports a growing wave of evidence that tackling somatic expansion could be a powerful way to possibly delay or prevent symptoms of HD.

Roche provides an update on tominersen: What’s next for this huntingtin-lowering drug?

Roche has shared an encouraging update on their HTT-lowering therapy, tominersen, currently being tested in the GENERATION HD2 trial. An independent safety committee reviewed the data and gave a green light to continue – great news for the HD community.
Even better, there are no new safety concerns, and the higher dose of tominersen (100 mg) is now considered the more promising path forward. Everyone in the trial will continue with this dose, and the study is still on track to finish in 2026. It’s a positive step in a challenging journey – progress is happening, and hope remains strong!

Ten Golden Rules for Navigating Huntington’s Disease Research News

In today’s whirlwind of tweets, TikToks, and tantalizing headlines, it’s easy to get swept up in the hype – but real, meaningful progress toward HD treatments is absolutely happening! To help everyone stay informed without being misled, HDBuzz has refreshed our Ten Golden Rules for spotting solid science versus sensationalized spin.

Originally published in 2011 and now updated for 2025, these guidelines are your trusty toolkit for navigating HD research news with clarity, hope, and confidence. From exciting early lab results to promising clinical trials, each snowflake of research builds toward the glacier of real progress – and we’re here to help you spot the difference between genuine breakthroughs and clickbait.

Stopping C-A-G Repeat Expansion In Its Tracks

A new study from University College London targets somatic expansion by showing that lowering a key DNA repair protein called MSH3 could stop the harmful C-A-G repeat expansions that some scientists think might drive HD. Using a genetic therapy approach called antisense oligonucleotides (ASOs), researchers seemed to halt – and in some cases even seemed to reverse – these expansions in lab-grown HD brain cells.

Even better, the treatment seemed well-tolerated in a special mouse model, setting the stage for future clinical trials. While not in trials yet, this exciting work opens the door to an approach several groups are moving forward that they hope might delay the onset and progression of HD, adding to the growing list of innovative strategies aimed at tackling the root causes of HD.

Hope in Full Bloom: HDBuzz Launches Spring Giving Campaign!

HDBuzz is thriving – and it’s all thanks to you! Over the past year, we’ve doubled our article output, expanded our team with fresh voices, launched new social media channels, and received donations from readers like you to help us become an independent non-profit organization. Now, with a tidal wave of HD trial results on the horizon, we’re gearing up for our biggest reporting year yet—and we’re asking for your help.

Our Spring Giving Campaign, “Hope in Full Bloom,” is in full swing and it’s your chance to keep clear, independent HD research news free and accessible for families worldwide. Our goal is to raise to $30,000 before May 27. Let’s grow together – donate today and help HDBuzz stay strong and bloom bright!

A new study led by researchers at University College London explored a promising new way to potentially slow down Huntington disease (HD) by reducing the levels of a key DNA repair protein, called MSH3. Using antisense oligonucleotides (ASOs)—a type of genetic therapy that targets RNA—the researchers successfully stopped C-A-G repeat expansions in lab-grown brain cells derived from people with HD. Their findings highlight a potential treatment approach that could help delay onset of symptoms and progression of HD.

How Expanding C-A-G Repeats May Drive HD

HD is a genetic brain disorder caused by an expansion of C-A-G repeats in the huntingtin (HTT) gene. Everyone inherits two copies of the HTT gene, one copy from each of their parents. While everyone has some C-A-G repeats in their two HTT genes copies, people with HD inherit a copy HTT with too many C-A-Gs.

Research has shown that in certain brain cells, particularly medium spiny neurons – the cells most affected in HD – these C-A-G repeats can continue to grow over time in a process called somatic expansion.

Many scientists believe that this ongoing C-A-G expansion in specific brain cells plays a role in determining when symptoms first emerge. Because of this, researchers have been exploring ways to slow or stop somatic expansion in hopes of delaying the onset of symptoms and slowing how fast the disease progresses.

What Can We Learn About Drug Targets From Genetic Studies?

Large genetic studies of people with HD have linked certain genes responsible for proofreading the genetic code, including MSH3, to the age at which symptoms first appear. Normally, MSH3 helps fix small mistakes in the genetic code, but in HD, it can actually promote repeat expansion, causing CAG repeats to get bigger and bigger.

Other genetic studies in people with HD also suggest that lowering MSH3 could be a promising treatment. Interestingly, a small natural genetic hiccup in the MSH3 gene, which causes people to produce slightly less MSH3, has been linked to slower disease progression, less CAG repeat expansion, and a delay of about one year in symptom onset in people with HD who have this variant.

Other types of genetic variations of MSH3 that lead to even bigger reductions of MSH3 levels have been associated with delaying HD symptoms by more than 10 years. Because MSH3 is not essential for survival and most people born with lower levels of it generally live normal lives, MSH3 has emerged as a promising drug target for HD.

A Genetic Approach to Reducing MSH3

In this study, researchers tested whether drugs designed to lower levels of the MSH3 protein could slow C-A-G repeat expansion. To do this, they used ASOs, which are short synthetic DNA-like molecules designed to bind to the MSH3 message in the cell and prevent the production of MSH3 protein, causing the levels of this protein to drop.

In dishes in the lab, the researchers grew medium spiny neurons, a type of brain cell found in the striatum – the area most affected in HD. These cells were dosed with the ASO, which led to a strong reduction in MSH3 levels. The effect the scientists saw was dose-dependent, meaning that the more ASO they added, the more the levels of MSH3 were lowered in these cells.

MSH3 Lowering Puts The Brakes On C-A-G Repeat Expansion

Importantly, the study found that lowering MSH3 stopped C-A-G repeat expansions in these neurons. In fact, the more MSH3 was reduced, the more the expansion process slowed down. At very high levels of MSH3 lowering, the CAG repeats not only stopped expanding but even began to shrink. This is a very exciting finding because it suggests that drugs lowering MSH3 might be able to reverse some of the genetic changes that occur in HD, which could be very beneficial.

To explore how this therapy might work in living organisms, the researchers developed a special mouse model that carries the human MSH3 gene. This was essential because the ASO being tested specifically targets the human version of MSH3, so the model needed to accurately reflect the drug’s intended future target – MSH3 in people.

They injected the ASO directly into the brains of these mice and found that MSH3 levels were successfully reduced across multiple brain regions, including the striatum – the area most affected in HD. This means that the drug was able to effectively spread out in the mouse brain, getting into brain cells in many different regions. Most importantly, the ASO was well tolerated, showing no signs of toxicity in these mice related to lowering MSH3.

What This Means for HD Research and Future Treatments

These findings provide strong evidence that targeting MSH3 with ASOs could be a safe and effective way to slow, stop, or even reverse C-A-G repeat expansions in HD. By preventing these repeats from growing, this strategy could potentially delay the onset of symptoms and slow disease progression.

Several biotech companies, including Rgenta Therapeutics, LoQus23, Latus Bio, and Harness Therapeutics, are now working on therapies to target somatic expansion in HD, and MSH3 targeting ASOs could be an important addition to these efforts. We expect to hear more from many of these companies later in the year at the Huntington Study Group meeting, which will be held in Nashville, Tennessee in October this year.

While this study was done in lab-grown neurons and mice, the next step would be to test this approach in human clinical trials to determine whether it could be a viable treatment option for people with HD. Stay tuned for more updates as this research progresses!