Scientists are working to understand some of the earliest changes to DNA repair caused by Huntington’s disease (HD) – insights that could help uncover new therapeutics and new ways to target somatic expansion, a key driver of disease progression. A molecule that helps fix DNA damage – called PAR – is lower than expected in people with the HD gene. This suggests that cells may struggle to properly repair their DNA  from the natural wear-and-tear damage that happens everyday to DNA. These findings could have implications for changes in the DNA repair process that drives somatic instability. The discovery could help researchers explore new ways to protect brain cells by boosting the cell’s natural repair systems.

Genetic Mutations and Repairs

The term genetic mutation gets thrown around quite a bit, but what does it actually mean? In short, a genetic mutation is any change to the letters of DNA – the cell’s instruction manual for building proteins. These changes can alter how the genetic code is read and used by cells, sometimes disrupting the function of proteins, the cell’s molecular machines. One striking example are mutations in the HTT gene, which significantly disrupts the activity of its coded protein, leading to HD. 

While the mutation that causes HD is inherited at birth, our cells also collect new mutations as we age. The consequence of these random age-related mutations is difficult to predict, but generally speaking, they contribute to age-related diseases like cancer and neurodegeneration. Fortunately, these age-related mutations are normal and are mostly repaired and fixed before they cause problems. 

But unfortunately, this process is not working right in HD. Previous studies have noticed that cells from people with the gene for HD tend to build up more mutations over their lives, likely a result of faulty DNA repair machinery. Faults with the DNA repair machinery lead to somatic expansion, a biological process that increases the CAG repeat length in the HTT gene in some cells over time. A new study led by Dr. Ray Truant and his team at McMaster University investigated how the HD mutation disrupts DNA repair and identified a prime suspect: defective PARylation. 

A Broken Spell Checker

Cells are equipped with sophisticated systems to fix DNA damage, and one key pathway is PARylation. PARylation involves building long chains of a molecule called PAR (Poly-ADP-Ribose) on regions of damaged DNA. These long chains act like molecular handles for DNA repair enzymes to latch onto and begin fixing the DNA. In this way, PAR chains are like the red squiggly lines in a Word document highlighting spelling errors. However, like a broken spell checker, HD cells are missing many of these red squiggly lines despite having more mutations. 

To investigate, Truant’s team first analyzed the amount of PAR chains in the spinal fluid, a substance that bathes the brain, from people with HD. Because PAR chains are produced in response to DNA damage, and people with HD have higher levels of DNA damage, they expected to find more PAR chains. 

However, what they found surprised them – people with HD had fewer PAR chains. This paradox was then examined using cells from people with HD, which did not show elevated levels of PAR chains despite having elevated levels of DNA damage. These results suggest that the machinery for building PAR chains, and thus repairing DNA, may not be able to keep up with demand!

PAR chains are like the red squiggly lines in a Word document highlighting spelling errors. However, like a broken spell checker, HD cells are missing many of these red squiggly lines despite having more mutations.

Not On PAR

Why might there be fewer PAR chains in HD cells despite having more DNA damage? To figure out why, the researchers needed to examine the underlying protein machinery. PARylation relies on two key enzymes: PARP, which builds PAR chains to initiate DNA repair, and PARG, which cuts them up once repairs are complete. 

So the researchers asked, is PARG overactive? Or is PARP underperforming? After some careful biochemistry, they found the latter seems to be true – PARP activity seemed to be reduced in HD cells, explaining the shortage of PAR chains and perhaps the increased rates of mutation. 

The team then turned their attention to HTT. Since the HTT protein acts as a scaffold, binding to lots of other proteins, they wondered if the mutated version that causes HD might interfere with HTT interacting with PARylated proteins. Because PAR chains also form on proteins in addition to DNA, they compared the proteins that HTT is known to interact with to the proteins known to be PARylated. They found that nearly half of the proteins that HTT interacts with are also PARylated.

This raises the suspicion that HTT itself could be modified by PAR. If it is, and this process is altered by mutant HTT, it might explain the differences in the PAR chains they saw in HD cells. 

HTT and PAR Chains

To test if HTT interacts with PAR chains, the team used a high-tech microscope to track where HTT and PAR chains are found in living cells. Although PAR chains and HTT did not overlap most of the time, they did overlap on chromosomes when cells divide. 

Additionally, when they turned off PAR chain production by blocking PARP activity, HTT no longer overlapped, suggesting that PAR chains might be guiding HTT to chromosomes during cell division. Although the importance of HTT and PAR chains overlapping during cell division was not investigated further, it does suggest there could be a functional interaction between them! 

To strengthen their case, the researchers used a couple more techniques to confirm the interaction between HTT and PAR chains. First, they looked closely at the molecular structure of the HTT protein and found many slots that looked like they could fit a PAR chain. Then, using a high-resolution microscope, they directly visualized the PAR chains produced by PARP with and without HTT present. They noticed PARP produced far more elaborate PAR chains when HTT was around, suggesting that HTT was stimulating PARP activity. Importantly, mutant forms of HTT did not have any stimulating effect on PARP activity, possibly explaining the reduced production of PAR chains in people with HD. 

In cells without the HD gene, HTT stimulates PARylation and promotes efficient DNA repair. However, in HD, the mutant HTT protein fails to stimulate PARP, leading to fewer PAR chains, impaired DNA repair, and an accumulation of mutations that could participate in neurodegeneration.

Implications for HD and Beyond

These findings paint a clear picture: in cells without the HD gene, HTT stimulates PARylation and promotes efficient DNA repair. However, in HD, the mutant HTT protein fails to stimulate PARP, leading to fewer PAR chains, impaired DNA repair, and an accumulation of mutations that could participate in neurodegeneration. 

These findings are exciting because they help researchers better understand the underlying defects in HD cells, but perhaps more importantly, they open up therapeutic possibilities. 

Much of the interest surrounding PARP is due to the publicity it has received in an entirely different domain of research – cancer, where dozens of molecules targeting PARP have already been teased out. Because drugs designed to modulate PARP activity have already been tested for safety, they could potentially be repurposed for HD, accelerating its path to clinical trials. Although any repurposed drugs would still need to be thoroughly tested, this research opens up exciting new therapeutic roads that may address the issue of mutations building up, a critical problem with cells in HD.

Learn More

Original research article, “Poly ADP-ribose signaling is dysregulated in Huntington disease” (Open access).

Imagine waking up one day and realizing that the world around you no longer looks the same. Faces are harder to recognize, navigating familiar streets feels confusing, and reading a book becomes a frustrating puzzle. This unsettling scenario is a reality for many people affected by Huntington’s disease (HD). Dr Juan Carlos Gómez-Esteban and his team of researchers from Spain, investigated if HD affects the brain’s ability to process and understand what people can see. They also researched when these changes in processing and understanding occur in people with HD. 

Bringing HD Into Focus

You might be wondering why is it important to focus on how people with HD see and understand things? This is because the part of the brain that is most affected by HD, called the striatum, is not just responsible for controlling movement – it also helps the brain process and understand what we see. As HD progresses, it becomes more and more difficult for the brain to handle visual information, making everyday tasks that used to be second nature, more and more challenging.

Picture trying to cross a busy street but struggling to judge how fast cars are moving. Or meeting an old friend but not recognizing their face right away. These are the kinds of frustrating, everyday obstacles that can come with visual thinking problems in HD. Understanding these challenges is crucial, not just for diagnosing HD earlier, but for developing therapies and treatments that help people with HD, navigate the world more confidently and independently.

Seeing the Early Signs

This study involved 181 participants, including people spanning different stages of HD. Beside each stage, we included the Huntington’s disease Integrated Staging System (HD-ISS) that best describes these categories. For more information on HD-ISS categories, please see our article about this system. A control group of individuals who do not have HD were also recruited to the study. This is because the researchers wanted to find out whether HD affects visual thinking skills, and if so, when these changes begin. People with HD were grouped into one of four categories for the purpose of this research:

Category 1 – People who have had the genetic test for HD and have a reduced penetrance allele (slightly lower number of CAG repeats, spanning 36-39 CAGs). This means that it is uncertain if these individuals will or will not go on to develop the symptoms of HD in their lifetime.

Category 2 (similar to Stage 0 of the HD-ISS) – The person has tested positive for HD (CAG number is 40 or more) but does not yet display any recognisable symptoms.

Category 3 (similar to Stage 2 of the HD-ISS) – The person with HD begins to experience symptoms. There may be noticeable changes in their motor abilities, mind, and mood symptoms. The individuals affected may still be fairly independent at this stage.

Category 4 (similar to Stage 3 of the HD-ISS) – The person with HD experiences fully developed HD symptoms, which significantly impacts their daily life. Individuals at this stage require significant support with their activities of daily living.

As HD progresses, it becomes more and more difficult for the brain to handle visual information, making everyday tasks that used to be second nature, more and more challenging.

Measuring What the Eyes Cannot See

To investigate if HD affects visual thinking skills (the brain’s ability to process and understand what people with HD can see), participants completed a variety of tasks that could measure these skills. These tasks assessed different ways people see and understand things. For example: remembering what we see; understanding where things are and how they move; focussing on what we see; how quickly we make sense of what we see.

But what tasks were used to measure these abilities? How well participants could remember what they see, was assessed by asking participants to copy a shape presented to them by drawing it. After a small amount time delay, the participants had to draw this shape again, from memory. Another example of a task that measured how well participants could remember what they see, involved showing participants a set of different shapes. After, the participants had to remember what shapes they were shown, and in what order they were displayed.

The team of researchers also investigated how well the brain was functioning, more generally. Brain functioning was assessed in each participant by performing tasks that measured vocabulary skills, attention levels, and problem-solving abilities. It was important to include these more general measures to understand how the brain’s ability to understand what people can see may ‘fit’ into wider brain functioning.

Together, the variety of tasks performed helped Dr. Gómez-Esteban and his team to build a better picture of how visual thinking abilities change in people with HD who are at different stages of the condition, as well as compared to individuals who do not have HD.

Through the Lens

Here’s the twist: Dr. Juan Carlos Gómez-Esteban and his team did not find any major differences in general thinking skills between people who did not have HD, people with the reduced penetrance allele (Category 1), and people who have tested positive for HD, but do not yet display any symptoms (Category 2).

But here’s where it gets interesting: visual memory abilities (think back to the task involving drawing shapes from memory) differed between the groups in this study. People with reduced penetrance (Category 1) had greater visual memory abilities compared to people with HD, who do not yet display recognisable HD symptoms (Category 2).

What’s even more intriguing is that when looking at people with HD experiencing early symptoms (Category 3) and people experiencing fully developed HD symptoms (Category 4), visual memory abilities remained relatively unchanged. This could suggest that a change in visual memory abilities could be one of the first signs of changes in thinking in people with HD. This could make visual memory skills a valuable clue in spotting HD early on.

It’s not just about what the eyes see – it’s about how the brain makes sense of it. Understanding this connection could make all the difference.

Seeing the Bigger Picture

Understanding how HD affects the brain’s ability to make sense of what we see could lead to an earlier diagnosis of HD and better treatment options. If having reduced visual memory abilities tends to appear before motor symptoms, testing for this could help to identify signs of HD sooner in individuals giving them more time to plan and seek support.

Visual memory changes could be an early warning sign of HD, offering a chance for earlier diagnosis and treatment. It’s not just about what the eyes see – it’s about how the brain makes sense of it. Understanding this connection could make all the difference.

Spotting visual memory changes in people with HD is not just about early diagnosis, it’s about making life better. So, if you or your loved one with HD can be forgetful when trying to remember a familiar face, keeps losing their phone or glasses, or keeps getting lost in the grocery store, you could consider using some helpful visual reminders.

Learn More

Original research article, “Characterization of visual cognition in pre-manifest, manifest and reduced penetrance Huntington’s disease” (open access.

For Huntington’s disease (HD), a lot of attention goes to the genetic change that causes HD, but new research is shining a light on something else – our epigenome. The word literally means, “above” the “genome”, or above the genetic code. It’s a layer of chemical marks that are added to genes to regulate their activity. Think of the epigenome like a traffic control system for our genes. It’s responsible for deciding when a gene should “go” (get activated) or “stop” (stay quiet). When things go awry, like in HD, that traffic system breaks down.

Genetic Traffic Lights

Imagine a busy intersection – traffic is carefully orchestrated with different colored lights, telling drivers when to stop and when to go. If a signal turns yellow, drivers know that the light is in a transition between letting those cars go, and telling them to stop. These yellow lights are similar to what scientists call “bivalent” marks.

Bivalent genes carry both activating signals (the green light) and repressive signals (the red light) at the same time – like a yellow traffic light. This allows the gene to be ready to turn on quickly when needed, but also to stay off when it’s not. In HD, something goes wrong with these bivalent marks.

Stuck on Green

A surprising finding from this new work, led by Karine Merienne from the University of Strasbourg in France, is that certain genes that are normally “turned off” are staying “on” in the neurons of mice that model HD. The repressive signal (the “red light”) is lost, and the gene becomes more likely to turn on, as if the green light is stuck on. This means that genes which generally stay quiet in brain cells can get activated when they shouldn’t, potentially causing harm to the neuron.

Those stuck green signals are happening in genes that are involved in the early development of the brain. These are genes that help guide how a neuron develops and what kind of neuron it becomes. In a brain without HD, these genes are turned off after the brain develops, but in HD, they seem to be active for longer.

This is similar to what others have recently found, with data suggesting that HD may lead to genetic changes that cause certain brain cells to lose their identity, turning off genes that help define them as unique types of neurons. Until now, we didn’t really know how this might be happening.

The changes defined by Karine’s team were seen in HD mice, where developmental genes – key players in brain development – were activated in mature neurons. These persistent green traffic signals can make them more accessible for activation, which researchers think could contribute to problems in how neurons function.

“Traffic Cops”

There are special molecular machines in the cell that normally help keep this process in check, two of which are called PRC1 and PRC2. These complexes act like traffic cops, ensuring that genes stay in their proper lanes – some genes should stay off, and others should be on at the right time. PRC1 and PRC2 usually help maintain the “red light” by placing repressive marks on genes, keeping them quiet.

But in HD, it seems like these traffic cops are being overwhelmed. The “red light” is no longer functioning properly, and the genes that should stay quiet (the developmental genes) are getting the green light to turn on. This leads to those genes being active when they shouldn’t be, which could cause the neurons to behave inappropriately.

Researchers have discovered that PRC1 isn’t just losing its repressive marks, but the proteins it relies on to work, seem to also be switched out for less mature versions. Think of it like the traffic cops being replaced with rookie officers who aren’t as good at controlling the traffic. This shift could be a major reason why PRC1 is less effective at stopping the activation of developmental genes seen in the mouse model of HD.

A Building Traffic Frenzy

One of the most interesting findings is that this disruption doesn’t just happen all at once – it gets worse over time. As the HD mice age, more and more genes begin to be activated inappropriately. It’s as if the “green lights” keep getting stuck on, while the “red lights” continue to fail. The researchers suggest that this progressive breakdown of genetic traffic regulation may cause the neurons to age much faster than they would in a brain without HD. It’s like the cells are “aging” more quickly on a genetic level, which might underlie an earlier decline in their function.

Researchers followed these changes in HD mice and found that over time, the number of genes showing altered epigenetic marks kept increasing. In particular, they saw developmental genes becoming more active as the mice aged. Adding to that, they saw this effect specifically in neurons in the striatum, the part of the brain most affected in HD.

In these cells, the epigenetic marks that normally keep these genes in check were decreasing, while marks that signal activation were increasing. It’s as if the brakes were failing, and the gas pedal was stuck to the floor – such frantic driving would rapidly age most people!

Fixing the Traffic System

Understanding how these epigenetic changes contribute to HD opens up exciting possibilities for new treatments in the future. If we can find ways to correct the breakdown in PRC1 and PRC2 function, or restore the balance of the red and green lights at the level of gene regulation, we might be able to slow progression of the disease.

For example, therapies could aim to fix the loss of repressive marks, which would restore the “red light” and keep developmental genes from turning on inappropriately. Other treatments could target the switch in PRC1 proteins, making sure the “mature” traffic cops are in place, keeping the genes under control.

Furthermore, therapies that address the accelerated aging of neurons could help protect the brain from the damage caused by these epigenetic changes. By slowing down the “epigenetic aging” process, we might be able to prevent the brain cells from losing their function too quickly.

Red Lights Ahead?

The discovery of accelerated epigenetic aging in HD gives us a fresh perspective on the disease and offers hope for new treatment strategies. By understanding the role of bivalent promoters, and the malfunctioning PRC1 and PRC2 complexes, researchers could be uncovering how neurons in HD may age prematurely and lose their function.

This new knowledge not only improves our understanding of how HD progresses, but it also opens up the possibility of therapies that could target the underlying epigenetic changes. While there is still much to learn, these findings mark an important step forward in the search for ways to pump the brakes on Huntington’s disease.

Imagine the gene that causes Huntington’s disease (HD) as a vast river. At its source is the CAG repeat – a genetic letter code that dictates how the river will flow. As the river moves downstream, it transitions into the letter code CCG, forming a continuous current. But what if, hidden beneath the surface, tiny genetic changes interrupt these codes to act like dams or rapids, altering the speed and course of the river? These rare changes can impact when and how HD symptoms appear, sometimes with the potential to shift the disease timeline by over a decade.

CAGs and the Flow of Proteins

To understand the role of these genetic interruptions, we need to take a step back and look at what genetic sequences actually do. Our DNA is like a set of instructions, written in a four-letter code (A, T, C, and G). Specific sequences of these letters form codons – three-letter words that tell the cell which amino acids to use when building proteins. Amino acids are the building blocks of life, like stones forming a riverbed, shaping the flow of biological functions.

The huntingtin (HTT) gene, which carries the instructions for HTT protein, contains a repeating sequence of CAGs. We all have this repetitive CAG stretch within our HTT gene. Each CAG tells the cell to add an amino acid called glutamine. In people with HD, the CAG stretch is too long. This creates an excess of glutamines that change the HTT protein’s behavior.

Most of the time, a genetic test provides a definitive answer – if someone has 35 or fewer CAG repeats in their HTT gene, they won’t go on to develop HD. If someone has over 40 CAG repeats in their HTT gene, they should go on to develop HD if they live long enough, and they have a 50% chance of passing the gene on to their children. But there’s actually a bit more nuance to the genetics:

• 27-39 CAGs: The “gray zone”. With CAG lengths in this range, there’s an increased risk that future generations could develop HD, and some people themselves may develop symptoms, while others won’t.
• 27-35 CAGs: People in this range likely won’t go on to develop HD, but they have an increased risk of their children developing HD.
• 36-39 CAGs: Some people in this range will develop symptoms of HD, while others won’t. So far, the research suggests this could be controlled by things like lifestyle factors, genetic modifiers, or other variables we haven’t yet figured out.

CCG and Proline: Rocks in the River

We talk a lot about the CAG repeat in HD research, since this is the genetic change that leads to the disease. But there’s actually a second set of repeating letters within the HTT gene. Right after the CAG repeat stretch, there’s a repetitive sequence of CCG letters, which code for the protein building block proline.

Proline often acts like a bend or kink in the protein’s structure, similar to how submerged rocks can disrupt the smooth flow of water. Some studies suggest that having more CCG repeats near the CAG stretch may slightly alter how the huntingtin protein folds or interacts with other molecules in the cell. However, the exact function is not fully understood.

Until now, the CCG proline stretch likely wasn’t on the radar of HD families. Researchers have long known it was there, but its potential role in influencing disease onset or progression wasn’t clear. Only recently have scientists begun to recognize that this genetic feature might subtly shape the course of HD, much like an unseen current beneath the surface of a river.

When the Dam Breaks – LOI Variants

In most people, as the genetic river flows, the CAG region usually includes a small change – CAA. CAA is a synonymous switch to CAG, meaning it also codes for glutamine. Though CAA and CAG both lead to the same amino acid, CAA acts like a natural dam, stabilizing the sequence and keeping the river’s flow more stable.

But in rare cases, these interruptions are lost – this is what scientists call Loss of Interruption (LOI) variants. For example, without the CAA interruption, the uninterrupted CAG section is longer, making the river flow more forcefully.

In new work from the lab of Dr. Michael Hayden at the University of British Columbia, researchers suggest that this could be leading to earlier onset of HD symptoms.This work has identified four types of LOI variants:

• CAG-CCG LOI: This accounts for a longer, uninterrupted stretch of both glutamines (CAG) and prolines (CCG). Losing interrupters in both the CAG and CCG repeat sequences seems to be the most impactful, potentially shifting symptom onset an average of 12.5 years earlier.
• CCG LOI: Some people only lose an interruption in their proline-encoding CCG repeat sequence, while maintaining a CAG glutamine interruption. Surprisingly, this also potentially altered onset by about 12.5 years.
• CAG-LOI: Conversely, some people maintain their proline-encoding CCG repeat interruption, but lose the glutamine-encoding CAG repeat interruption. This was a potential early-onset factor, with an estimated 6.9-year shift. However, the researchers couldn’t say for sure that this genetic variant was the factor that impacted age of onset. The authors suggest the issue in pinpointing how this LOI impacts symptom onset is probably due to the limited number of people they found with this change.
• CAG interruption duplication: A completely different genetic change they found was a duplicated interruption. So instead of having one CAA interrupt the glutamine-encoding CAG repeats, there were at least 2. Their findings here were particularly surprising. Contrary to what would be expected based on the loss of interruption data, they found that this duplicated interruption also accelerated disease onset, potentially by about 3.8 years. While this doesn’t seem to match with interruptions delaying onset, it does suggest we don’t fully understand exactly how these particular changes in the genetic code of the HTT gene contribute to HD.

A Rare but Important Discovery

It’s important to remember that the variants with the largest impacts examined in this study are exceedingly rare. For example, the CAG-CCG LOI is found in only 0.04% of people with HD. So the change in symptom onset being measured in this study was found in only a small subset of people with HD – primarily in those whose CAG repeat number placed them in the gray zone. The vast majority of individuals with HD have a typical pattern of interruptions, meaning their diagnosis and prognosis wouldn’t change even if they were tested for LOI variants.

However, for those on the edge of the diagnostic spectrum, these variants could provide new insight into why some people with a borderline CAG length develop symptoms while others don’t. This discovery also highlights the complexity of HD genetics – showing that even small changes in the genetic river’s flow could have significant effects downstream.

Why Does This Matter?

For most people from HD families, this granular level of genetic detail isn’t necessary – standard genetic testing, which measures the CAG repeat length, provides enough information to predict risk. Right now, for the vast majority of HD families, knowing about interruptions in the CAG (glutamine) or CCG (proline) repeats can’t offer any additional medical or social support.

However, for those with an intermediate number of CAG repeats, between 36 and 39 CAG repeats, the presence of an LOI variant could be the difference between developing HD or not. These individuals are in the “gray zone”, where some will develop symptoms, and some won’t. The authors of this new work suggest that understanding whether individuals in the gray zone have an LOI variant could provide a clearer picture of their risk of developing HD.

For example, someone with 37 repeats who also carries an LOI variant may be more likely to develop HD than previously thought. Conversely, someone with the same CAG length but no LOI variant may have a lower risk than the raw number suggests. However, it’s important to note that standard genetic tests for HD only measure CAG repeat length, but don’t typically detect these LOI variants. So this isn’t data that’s readily accessible to most people.

The Future of Precision Genetics in HD Research

As research progresses, scientists are working toward more personalized approaches to HD diagnosis and treatment. Understanding LOI variants may help refine risk predictions, offering clearer answers to individuals in the gray zone with 36 to 39 CAG repeats. In the future, it’s possible to imagine that treatments could even be tailored based on these genetic details, much like adjusting a dam to regulate water flow.

For now, the key takeaway is that these variants are scientifically fascinating and could offer insight into the underlying mechanisms of HD. However, for the majority of people with HD, they remain a niche concern. The fundamental driver of HD is still the length of the CAG repeat. But by exploring these rare variants, researchers are learning more about what makes HD flow. Just as rivers carve landscapes over time, genetics shape the course of HD in ways both predictable and surprising. Understanding these hidden currents can help us navigate toward better diagnostics, treatments, and ultimately, a cure.

If you have questions about your own or your family’s genetic test results, we recommend speaking with a genetic counselor or healthcare provider.

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.