Disclaimer: I have written this piece from a position of privilege – as an HD family member that has been fortunate to receive an education that allows me to deeply understand the nuances of Huntington’s disease. I know what it means not only at the biological level, but also at the family level. I am profoundly aware of the desire for a disease-modifying drug. But my hopes are tempered through the privileged lens of understanding complex scientific data and interpretation. Here, I report facts and my opinion of those facts with no vested interest in any specific therapeutic approach. If Prilenia feels errors have been made, they are invited to reach out and any factual corrections will gladly be made.

Recently, there have been a few press releases from Prilenia Therapeutics about their advancement of the drug pridopidine toward regulatory approval for the treatment of Huntington’s disease (HD). There’s also been mixed messaging about findings from pridopidine clinical trials and statements made by the company. Let’s break down what the research really says and what the recent press releases mean in the bigger picture.

MermaiHD Trial

We’ve written about the long and storied path of pridopidine before. It’s been tested in a number of different clinical trials, by a few different companies. Over the years, the use of pridopidine has shifted. Once thought to have utility for helping to regulate movements associated with HD, it’s now being tested for potentially slowing the disease course.

In 2008, pridopidine (previously called Huntexil) was tested in a European Phase 2 trial called MermaiHD. Back then, the company running the trial, NeuroSearch, thought the drug could be used to help with changes in movement control caused by HD.

Specifically, they thought the drug could help people control their voluntary movements that get more stiff and rigid as HD progresses. While people on pridopidine had slight improvements in movement control, the effect wasn’t large enough to determine that it was caused by pridopidine, and the trial failed to meet its endpoints.

HART Trial

Around the same time, NeuroSearch also carried out the HART study in America. Again in this study, there wasn’t a conclusive improvement in voluntary movements associated with stiffness and rigidity.

After the HART study, they pooled that data with the MermaidHD study to find that with this combined dataset, there did seem to be an improvement on voluntary movements. However, both the US FDA and European EMA determined that a larger trial was needed to conclude what effect pridopidine was truly having on HD-associated movement changes.

PRIDE-HD Trial

After this, the rights and ownership for the drug changed hands. The new owners, Teva Pharmaceuticals, wanted to test if a higher dose of pridopidine was needed to see a positive effect on HD movements. Enter the 2013 trial called PRIDE-HD.

In PRIDE-HD, a key goal was to see if pridopidine could improve total motor score – a robust collection of tests that assign a numerical value to movement symptoms associated with HD. Unfortunately, again, pridopidine failed to meet its primary endpoint and did not show an improvement in total motor score.

A change in direction

At this point, scientists went back to the drawing board to try and better understand the drug. They did more experiments and when they emerged, they had a new model for how pridopidine might improve brain health.

Now, the idea was that pridopidine might not just control HD-associated movements, but might modify disease course. This would mean pridopidine isn’t just treating the symptoms of HD, but is treating the disease itself – a huge difference.

New goal for PRIDE-HD

With this new theory, the drug developers added a few new goals mid-way through the PRIDE-HD study. The primary endpoint of testing movement was the same, and wasn’t met, but they also added a second test – total functional capacity, or TFC.

TFC is measured through a collection of tests that determine how well someone functions day-to-day. Things like the ability to hold a job, manage finances, and perform domestic chores. These abilities decline as HD progresses.

So did pridopidine improve TFC in the PRIDE-HD study? Kind of. Out of the 4 doses tested, only the lowest dose showed improvement on the TFC scale. These results were inconsistent, TFC wasn’t a primary endpoint of the trial, and there wasn’t enough data to draw a firm conclusion – so for the drug to have a chance of getting licensed, yet another trial would be needed.

Big conclusions were drawn – too big

Despite these inconsistent findings, Teva interpreted the results from PRIDE-HD to mean that the drug was slowing the progression of HD. This was a big message for the data that was generated. Quite frankly, too big of a message. This conclusion cannot be substantiated with the results from this trial.

Why not? It’s important to understand that improving or stabilizing TFC does not necessarily mean that something has slowed HD progression. For example, successful treatment of depression in a person with HD could enable them to resume work, improving that person’s TFC by 1 or 2 points – but not because the underlying progression of the disease has been slowed.

To be clear, a drug that improves the ability of people with HD to function would be fantastic. And a drug that slows the progression of HD would be super fantastic! But there is a clear distinction between those two.

Improvements in function cannot directly be interpreted as slowing HD progression – that requires much more solid evidence, from direct measures like MRI scans or biomarkers that can tell us whether something has rescued brain cells, or from much longer-term improvements in symptoms.

PROOF-HD Trial

Following the results from PRIDE-HD, pridopidine changed hands again, this time to Prilenia Therapeutics. Another trial was begun to test the ability of pridopidine to modify disease course of HD. This new Phase 3 trial began in 2020 under the name PROOF-HD.

This time, the primary endpoint was TFC, which it did not meet. People who took pridopidine in the PROOF-HD trial did not show any improvement in day-to-day functioning as measured by TFC. Again, this was a negative pridopidine trial. The trial also failed to meet its secondary endpoint, an overall assessment of HD severity called the composite Unified Huntington’s Disease Rating Scale (cUHDRS).

However, one would be hard-pressed to understand this, based on the headlines about the PROOF-HD trial. Again, there were controversial interpretations that have touted PROOF-HD as a success.

Drug interactions

Previous results had suggested an interaction between pridopidine and drugs that reduce dopamine activity in the brain. Dopamine is a chemical that helps control movement, memory, and mood. The interaction between pridopidine and these dopamine-altering drugs is perhaps unsurprising, given that pridopidine was originally designed to alter dopamine activity to help with HD movements.

Drugs that reduce dopamine activity in HD include commonly-used medications like tetrabenazine for chorea, or ‘neuroleptic’ drugs like olanzapine and risperidone, which are used to help control some of the most difficult symptoms of HD like aggression, impulsivity, paranoia, delusions, or suicidality. Physicians don’t take prescribing these medications lightly, and often do so to reduce the risk that a person with HD will harm themselves or others.

Prilenia decided, in advance, to do a ‘subgroup analysis’ of the PROOF-HD trial results in people who were not taking any of these dopamine-altering drugs. This group had only 79 people with HD compared with the full trial population of 499 people with HD. They reported that this subgroup had benefited from treatment on cUHDRS and one measure of cognition, but not the TFC.

A troubling narrative

Of the drug, Prilenia CEO Dr. Michael Hayden is quoted as saying, “Pridopidine has delivered consistent efficacy benefits across multiple key measures of HD”. We at HDBuzz do not agree that the data collected to date support this interpretation.

Pridopidine has been tested in more trials than any other drug in the HD landscape, and has consistently failed to deliver the benefits anticipated by the companies running the trials. Apparent improvements seen in one aspect of HD have not been replicated when tested in subsequent trials.

What if it’s true that pridopidine works in people not taking neuroleptics? That would be good news! But to make this claim and have the regulatory agencies believe it, another clinical trial would generally be needed, focusing exclusively on this group and enrolling enough people to test this robustly. This is a valid scientific hypothesis, and it’s reasonable to test it with such a trial.

However, that’s not what Prilenia are planning.

We were troubled by an announcement from a recent, non-peer-reviewed poster summary supported by Prilenia where the authors claimed to show links between neuroleptic treatment and the progression of HD. This is a very difficult thing to prove with existing data and statistics, since neuroleptics are generally given to people whose HD symptoms are worse, or whose HD is progressing more rapidly.

It is certainly important to study how different medications might impact HD progression. But when a company whose unapproved drug may rely on people not taking neuroleptics, starts supporting research into whether neuroleptics may be bad for people with HD, we worry about what conclusions HD families might draw, and we worry especially about people stopping medicines that are protecting themselves and others from harm.

Hope vs. hype

At HDBuzz, we’re less worried about the science around pridopidine – in every trial, the results are what you get, and continuing to test theories based on those results is reasonable, if the sponsor thinks there is a real effect to be found in a particular group of people. This process is what needs to be done until we get better drugs for HD.

What troubles us is the message being put out about pridopidine, downplaying the big things it has failed to do, and emphasizing less compelling findings in subgroups or individual endpoints. We worry that people from HD families – families like mine – could end up with a much more favorable impression than is warranted of pridopidine being the first disease-slowing drug for HD. Unfortunately, all the evidence so far does not support that hope.

Hope that a drug will work is useful – but only when that hope is grounded in truth.

We want people from HD families to participate in trials for drugs with a good chance of working. Drugs that have strong scientific reasoning and solid evidence to support asking people and families to make the sacrifice of time, effort, and risk.

We have the right to expect that trial results will be presented plainly and understandably. Trials that fail to meet their outcomes should not be presented as positive, and companies with vested interests should be extremely careful about commenting on how HD clinicians and their patients choose from currently available treatment options.

Getting an application accepted for review

Most recently, we’ve heard news from Prilenia about advancing pridopidine through the European regulatory agency, the EMA. Their recent press release titled, “Prilenia’s Pridopidine for Huntington’s Disease Accepted for European Marketing Authorisation Review” is notable for its use of the word “Accepted” considerably earlier than the word “Review”.

What the press release actually says is that Prilenia has put together the paperwork to ask the EMA to consider the results from pridopidine to date, and the EMA has accepted the submission of their application.

Getting applications accepted for consideration is a process that every approved drug goes through. But it’s also a process that every refused drug goes through. Applying to get into a university is very different from being accepted. We’re reliably informed by an expert familiar with EMA procedures that this step is not that big of a deal.

Most of the time, we don’t hear about when companies go through these minor steps. Press releases generally aren’t issued for these commonplace steps throughout the regulatory process. While it’s broadly good that Prilenia are ensuring the HD community gets regular updates on where they are in the regulatory chain, we want to make sure that the news isn’t causing undue hype. We’re more keen on seeing the full, peer-reviewed results of the PROOF-HD trial in a scientific journal.

What we know

Pridopidine has been tested in various clinical trials with various primary endpoints, all of which have sadly failed to be met. Regardless of the messaging being put out from Prilenia, thus far pridopidine has produced negative results from every major endpoint in every trial. Period.

We’re not even remotely happy about this: we love drugs that work, and we love trials that prove it. We even love negative trials – when the results are presented clearly, without spin, and give a scientifically-grounded path ahead, whether that’s planning another trial or calling it quits.

The goalpost for the intended use of pridopidine continues to shift: to control movements, to modify disease course, to modify disease course for those not on neuroleptics. It’s fantastic that Prilenia continue to study pridopidine in the lab! It’s in everyone’s best interest that researchers understand medicines from as many angles as possible. However, we need to make sure the intended use of a drug is shown through positive clinical trial results.

An application has been submitted to the EMA for consideration. So far, this doesn’t mean much. An application was submitted. It will be reviewed.

Seeking truth

Scientists are truth seekers. At HDBuzz, we believe researchers have a duty to accurately relay scientific findings to the patient communities seeking answers for a cure. For truth.

If hope that a drug will work becomes so blind that it turns to hype, something has gone wrong. Results from clinical trials, by design, are not subjective. Reporting results should also not be subjective. Messaging matters. Headlines matter. Ensuring that the patient community receives and understands the full, balanced truth matters.

The team at HDBuzz honestly does hope that pridopidine delivers on everything Prilenia says it does, and more! We all want a drug that makes a positive difference to people with HD, but right now there is only data from 79 people to support moving this drug forward. In our opinion, that isn’t sufficient for regulatory approval – time will tell whether the regulators have the same view or are persuaded otherwise.

Until we get there, HDBuzz will be here to report the truth and tease out the hope from the hype. We’re sorry if our take is disappointing, but we make no apology for keeping openness, frankness, and science at the heart of our reporting.

Stem cells grown in 3D in a research lab can mimic some features of Huntington’s disease (HD). They also hold promise for transplantation studies to potentially add back cells that are lost in HD. But what would happen to those new cells? Would they get along with the cells still in the brain that have the HD gene? And what can this system teach us about ongoing clinical trials aimed at lowering the HD-causing message in only parts of the brain? Read on to find out!

The power of stem cells

Stem cells hold a certain mystique. They can either retain their “stemness”, remaining a stem cell, or to turn into something else altogether. Contained within each one is the ability to become almost any cell type in the human body. Scientists can coax them into becoming a heart cell, or a muscle cell, or even a brain cell, providing scientists with a powerful research tool that can be used to answer questions about people’s brains in health and disease.

For brain diseases like Huntington’s disease (HD), there’s a second powerful potential application for stem cells – transplantation. As a neurodegenerative disease, HD causes the gradual loss of brain cells. This primarily happens in a central portion of the brain, called the striatum, and in the outer wrinkly bit of the brain, called the cortex.

Several groups of researchers are exploring approaches that would allow them to harness the power of stem cells to replace cells that are lost over the course of HD. We recently wrote about the work Dr. Leslie Thomspon is advancing for stem cell transplants from our coverage of the Hereditary Disease Foundation conference. But what would happen to the new cells? Would they adopt features of HD?

Dr. Elena Cattaneo and her team from the University of Milan, in Italy, recently published a study aiming to answer some of these questions. Elena’s lab are world leaders in using stem cells to research HD. In this new paper, they sought to better understand the effect that cells with the gene for HD have on cells without the HD gene. This might help inform future cell transplantation studies and trials aimed at lowering the disease-causing message since those drugs are unlikely to hit every cell in the brain equally.

Mini brain in a dish

Typically, when cells are used in lab experiments, they’re grown flat on the back of a dish. But if you’ve ever seen another person, you know that people aren’t 2D! So more sophisticated technologies allow researchers to grow cells in 3D.

The fancy term for these 3D cells is “organoids”, aka “mini brains”. We’ve previously written about these lab-grown brains and what researchers have learned from them. While mini brains can adopt some of the cellular features of a brain, such as connections between different cells, they don’t actually have the ability to transmit thoughts and feelings.

While these mini brains look deceivingly unsophisticated on the outside (like a little whitish, pinkish snot to be honest!), they’re elegantly complex on the inside. The cells form intricate networks between brain cells that can be seen communicating with one another under the microscope. These mini brains give researchers a way of understanding in 3D how HD affects connections and communication between different cells.

Scientists know that in a human brain, HD reduces the ability of cells in the outer cortex to communicate with the inner striatum. This communication breakdown leads to a loss in those connections over time. When those connections go unused for extended periods of time, it can create an unhealthy environment for the brain cells, and they may eventually die.

A positive influence

Elena and her team see something similar in their mini brains that have the HD gene. At the molecular level, brain cells communicate across a very small gap called the synapse. This is where the tips of brain cells meet to send bubbles of information back and forth to one another. In HD, the number of bubbles is reduced over time. In this new paper, the team sees the same thing in HD mini brains – there is less communication at the synapse than in mini brains without the gene for HD.

A key experiment in the new paper from Elena’s lab asked what happens to cells in mini brains when cells without the gene for HD are combined with cells that have the gene for HD.

The team performed a very detailed analysis of the genetic messages contained in the mixed population mini brains, seeing that they more closely resemble the mini brains without the HD gene rather than the ones with the HD gene. This suggests that the cells without the HD gene have a positive influence on those with the HD gene. Good friends to have around!

They also looked at the synapses in these mixed population mini brains. They found the communication being sent from the synapse was greatly improved! It more closely matched the mini brains without the gene for HD. This suggests the cells without HD might be helping the cells with HD to communicate better.

The team also identified some features that weren’t totally rescued by the presence of the cells without the gene for HD. In the mixed population mini brains there were still some changes at the genetic message level. Additionally, the number of cells that died in the mixed population mini brains wasn’t totally rescued. This suggests that while cells without HD help the mixed population mini brains, they can’t overcome every feature caused by the HD gene.

Informing ongoing and future trials

Overall, this type of research can help determine the therapeutic potential for using stem cells to slow progression and treat HD. It is also informative for ongoing trials that lower levels of the disease-causing genetic message.

While the goal for some of those trials is to lower the message by about 50%, that won’t occur in every cell in the brain. Because of that, those cells with reduced HD genetic message will exist in a mixed population with cells that have more of the HD genetic message. Data from studies like those highlighted here help researchers understand exactly what may happen at the molecular level when such mixed populations of cells with and without the gene for HD exist.

An important point the research team was able to tease out in this paper is that the cells without HD have a positive influence on the cells with the HD gene. But the opposite is not true. The cells that have the HD gene don’t seem to alter programs in the cells without HD. This is important for future transplantation studies because it suggests cells without HD that are added may have a positive effect, but the cells already in the brain with HD possibly won’t have a negative effect on the new cells. A win, win!

Moving treatments forward

While stem cells and mini brains are super cool, there are some limitations to their use. Firstly, they don’t truly mimic what’s happening inside a human brain in a living person. Nothing in a lab dish can. This is why it’s important to study potential treatments in a functioning brain, like in a mouse, and eventually run clinical trials in people.

Additionally, the mini brains that contained cells with and without the gene for HD were mixed before they were made. Meaning the mixed population was there from “birth”. In the case of a person with HD, the cells or treatment would be added after the person had a fully formed brain.

Despite the caveats, this work represents a cool approach for better understanding how cells without the gene for HD may act if they were added to a brain with HD. It also sheds light on what may happen in a brain when some cells have the gene for HD while others have less of that message.

The human brain, both inside a lab dish and out, is incredibly complex, so knowing as much as possible about how HD affects cellular and molecular features will help move treatments forward.

We’re back for the last day of the Hereditary Disease Foundation conference!

Serendipitous finding?

Up first is HDBuzz co-founder and editor emeritus, Jeff Carroll. Jeff’s lab studies HD in mice and cells in a dish and investigates different potential treatments.

The first story Jeff is telling us about is developing tools that lower HTT. He’s using something called an ASO, or antisense oligonucleotide. You may have heard of these if you followed Roche’s trials since tominersen is a HTT-lowering ASO.

Jeff’s team saw that when they lowered HTT with ASOs, the degree of somatic instability seemed to go down. But it turns out this is not because of the reduced amount of HTT protein, but a strange quirk of how ASOs work to target genetic message molecules. This doesn’t mean that HTT-lowering ASOs will reduce somatic instability in the key cells HD researchers are targeting. The doses would have to be crazy high to achieve this and then there might be unwanted off target effects. Still, an interesting observation – science is weird!

The ability of the ASOs to influence somatic instability got Jeff curious if other tools that lower HTT also affect somatic instability. So he repeated his experiments with another tool to lower HTT called zinc finger proteins, or ZFPs. These work in a completely different way to ASOs, binding the CAG repeats in the DNA molecule itself, not the genetic message molecule (RNA).

Again, they see that ZFPs decrease the amount of somatic instability in the mouse models they studied. Jeff speculates that this could pave the way for new approaches to think about treating somatic instability, by decorating the HD gene DNA with things like the ZFP molecules.

The second story Jeff is telling us about is his work with ASOs to specifically lower the expanded copy of HTT. He’s collaborated with Wave Life Sciences on these experiments.

He’s being mindful of the super toxic HTT1a fragment we wrote about yesterday from a talk by Gill Bates. Since these are the form of HTT that causes sticky protein clumps, Jeff looked to see if those were affected in mice treated with these ASOs. And they were! The HTT clumps in mice treated with the HTT-lowering ASOs were dramatically lower.

They also see that the changes to which genes are switched on or off more in HD are restored when the mice are treated with the ASOs. Jeff thinks that treatments that affect genes turning on or off might also have an added bonus of influencing somatic instability.

He finished with a call to arms to look into this idea more and encouraged drug developers to ensure that they’re also hitting HTT1a with their drugs.

Beyond the barrier

Up next is Nick Todd who is going to talk to us about using focused ultrasound to do a better job of getting drugs into the brain. The brain has a protective barrier that keeps things from the blood out that could cause harm to the delicate brain cells.

This barrier is also a headache for drug hunters as it often keeps out drug molecules from getting into the brain – this is why HTT-lowering ASOs, like those from Roche and Wave, are delivered by spinal tap, as they are too large to get across this barrier.

Focused ultrasound can cause this barrier to open temporarily, potentially allowing drugs to get from the blood to the brain. Nick is showing that he can control this system to a very fine level of detail to open up the barrier in very specific areas for defined timeframes.

This approach has already been tested in 30 clinical trials – wow! So far, these have primarily been in cancer, but are moving to neurodegenerative diseases, like Alzheimer’s and Parkinson’s. Nick and a collaborative team from Boston are hoping to apply this technology to HD.

Right now, Nick and his team are testing this approach in mice that model HD to work out if it is feasible and if there are any safety issues that need to be figured out. Once this is done, they want to start testing the delivery of gene therapies in mice with this technology. This approach looks very promising in other models and for other diseases, so we’re excited to have Nick using this approach for HD!

A new upcoming trial (!) to replace lost cells

Up next is Leslie Thompson – a total rockstar in the HD space. She was part of the team that went to Venezuela to help identify the gene that causes HD and runs a productive HD lab that works on various aspects of HD. One of the models she uses to study HD is stem cells.

For a long time now, one idea people have had to treat degenerative brain disease like HD, is to replace the cells that are lost over time – something called cell therapy. There are a lot of different ways scientists are researching this approach, including adding cells back with surgery.

There has been success with this approach in other disease fields, like a type of epilepsy. A cell therapy recently received FDA approval for people that live with this type of epilepsy, 60% of whom in the trial went from having 5-6 seizures a day to none. Impressive and exciting!

A global team of expert HD researchers have been working together to try and get a cell replacement therapy off the ground. This is no mean feat: they need to make the right type of cells that have certain markers and that are able to survive and thrive after transplant.

So far, Leslie and her team have tested this approach in mice that model HD with great success. The motor and movement symptoms of the mice improved after they were given the stem cell therapy. They also saw increases in molecules that are known to be protective for the brain and reduced amounts of sticky HTT protein clumps. They also saw restoration of other molecular markers indicating that the brain has more healthy neurons. Very cool!

Having healthy cells in the brain after transplant is one thing but, ideally, you want to see these new cells making connections with other nerve cells in the brain. Using cool imaging methods, they could see new connections formed between the transplanted and existing brain cells!

Leslie and her team are advancing this stem cell therapy toward the clinic and are gearing up to start a Phase ½ trial. She and her team are being ultra-cautious so that the stem cells that will get transplanted won’t cause tumors. So far, all tests indicate tumors won’t form.

The great news is the team have approval to start the trial. Once they receive funding, the trial will get underway under the name REGEN4HD. Participants will receive one dose of the therapy and different amounts of the cells will be tested to find the amount which works best.

The aim of the trial will be to check the safety of this therapy in people. Although they have done lots of testing in different animal models, there are still many possible risks with a therapy like this, which adds cells to the brain and is delivered by brain surgery.

HDBuzz will keep you updated as we learn more about this new trial using a totally different approach! We have many irons in the fire now for HD therapeutics which is giving the HDBuzz team lots of hope.

Improving ASO technology

Next up is Holly Kordasiewicz from Ionis Pharmaceuticals. Ionis is the company that initially developed the HTT-lowering ASO that is now called tominersen and is being tested in clinical trials by Roche in the ongoing trial GENERATION-HD2.

GENERATION-HD2 is happening across more than 70 sites in 15 different countries and is now at ~75% enrollment of trial participants. This trial is a huge undertaking with lots of complicated logistical considerations.

Holly is giving the crowd details on how Ionis develops their drugs and how they’ve been modified over time for improvements. If you loved your organic chemistry classes, this talk is for you! Lots of chemical structures are being shown.

Different chemical decorations on ASOs can really impact how well they work as drugs, as well as the possible side effects they might cause. ASO chemists are constantly improving these molecules to give the drugs the best chance of delivering the desired effects.

These small changes also help to improve how long the drugs stick around in the body, so spinal injections are needed less frequently. The chemical decorations also affect how the drugs spread through the body, including getting across structures like the blood-brain barrier.

Ionis are testing out technology where a small protein molecule is tacked onto the ASO. They give this modified ASO to mice by regular injection into their bloodstream. The protein handle helps the ASO move from the bloodstream into the brain tissue – very exciting!

This could mean that ASOs for brain diseases, like HD, could eventually be delivered by regular injections, not the more arduous spinal tap procedure. This would put less burden on folks receiving these drugs and be a real game changer.

Somatic instability as a therapeutic target – MSH3

Our next speaker is David Reynolds from LoQus23. LoQus23 is one of the companies working to target one of the HD modifiers, called MSH3. By stopping the actions of MSH3, LoQus23 believes this will potentially slow down HD signs and symptoms by halting somatic instability.

Unlike many of the approaches we have heard about so far today, they are making small molecules that target MSH3 and stop it from working. The challenge with this approach is that MSH3 has many lookalikes in the cell, so they wanted to ensure that any molecules they made ONLY target MSH3. So far, they have found molecules which look very promising on this front.

They are using special microscopes to look at exactly how and where their molecules bind onto MSH3. These molecules work by handcuffing the MSH3 protein molecule. That locks MSH3 in place, preventing it from doing its job in the cell, which leads to CAG expansions.

The scientists at LoQus23 use cells in a dish to see if their molecules alter somatic instability. A challenge with this is that somatic instability is a slow process, making these experiments quite long. LoQus23 has optimized this and can get a readout in just 2 weeks.

In this system, they only need to add a very small amount of their drug to see a big impact on somatic instability – great news! They use all kinds of chemistry tricks to show this is an “on target” effect i.e. it is happening because the molecules are hitting MSH3. They’re currently working to test these molecules in mouse models of HD and hope to be able to share if the molecules work at the next big HD scientific conference.

Somatic instability as a therapeutic target – PMS1

Up next is Travis Wager from Rgenta. He will be telling us about his team’s work creating drugs that target PMS1, which works to drive somatic expansion in HD and other diseases.

People whose bodies make more PMS1 tend to get HD symptoms earlier, whereas other people who make a less effective form of PMS1 get symptoms later. This points to the fact that PMS1 could be a great drug target to treat HD.

Rgenta’s approach is to target the message molecule of PMS1, causing it to get jumbled which will lower the amount of the PMS1 protein that is made. It looks like Rgenta has done a great job of finding molecules which do just this, with very low doses needed to see the reduced PMS1 levels.

Next, they looked at how changing PMS1 levels with their molecules affected somatic instability. They saw a significant slow down in this regard – which is great news.

PTC’s trial is ongoing

Now we will hear from Amy-Lee Bredlau, from PTC therapeutics. They have developed a small molecule, called PTC-518, which works to change the way the HTT message molecule is processed, causing it to get sent to the cell’s trash can, and reduce the amount of the HTT protein that is made.

PTC-518 is under investigation in a Phase 2 study, and we wrote about their interim update a little while ago.

The headline from that update is that things look very promising for PTC-518; it is effective at lowering HTT in the blood and in the central nervous system, and also appears to be generally safe. Great news!

We look forward to seeing the final results of this trial and learning more about PTC’s future plans for this drug. We will keep you all updated on all fronts.

Aggressive behavior in HD

Our next speaker is Amber Southwell, who will be telling us about a new mouse model she’s created to better study and understand aggression that some people with HD experience. Amber tells us that there are different kinds of aggression. Reactive aggression, that occurs after a trigger, even if seemingly small, is the type of aggression that’s been described in people with HD, and also in mice that model HD.

Amber does lots of experiments with mice. She noticed that some of her HD models had aggressive behavior even with normal handling. So she dug into this observation more to try and figure out if that was caused by HD, or perhaps by something else.

There are lots of different mouse models of HD, all of which differ in the forms and amounts of the HTT protein that they make. Amber thinks that these differences are likely why certain traits and signs of HD are observed in some mice, but not others.

Amber controls interactions between mice in several scenarios, films them, then scores their behavior data. It turns out her hunch was right, one type of HD mouse does seem to be generally more aggressive in certain scenarios than other HD mice.

However, in other scenarios, there was little difference between different types of HD mice and the control mice. One thing which did seem to hold true, is that HD mice are not very good at assessing perceived threats and are easily triggered to exhibit aggressive behavior.

Amber eloquently highlights that for a long time, many psychological symptoms people with HD experience were thought to be a reaction to the hardships of living with HD. But increasingly, we are finding out that depression, aggression etc. are in fact symptoms of the disease itself.

There are regions of the brain attributed to these type of behaviors in people and some scientists have observed changes in these regions in brain scans of people with HD. Amber and her team are now investigating these brain regions in their mouse models.

A prescription for sleep

Our next speaker is Zanna Voysey, who studies sleep in HD to see if there’s a link between problems with sleep and disease onset and progression. Zanna is also interested in using medication to treat this aspect of HD.

For people with HD, many experience insomnia or fragmented sleep. Similarly, people often move around a lot even whilst they are sleeping. This can really impact people’s quality of life and exacerbate other symptoms, so research into this is very welcome.

These sleep symptoms actually start very early in HD and people may be unaware of the extent of their symptoms. This is why we need specific sleep studies, as just asking how well someone slept does not always give a complete picture.

Beyond improving quality of life, sleep seems to directly impact many signs and symptoms of HD, at a molecular level and at a clinical level. So treating sleep issues could help people think more clearly and even help slow down symptoms of HD.

The Cambridge HD-Sleep study has now been running for 12 years! They have collected all sorts of data from more than 40 people, with and without HD to see how HD impacts sleep over the course of the disease. They confirmed that poor sleep tracked with HD progression, and the scientists could even predict who was more likely to progress to the next stage of HD based on sleep symptoms.

Interestingly, they found that people with HD who had worse sleep had more trouble thinking and increased amounts of NfL, suggesting poor sleep is having a very real effect on the health of their brains.

Melatonin, a chemical that causes us to fall asleep and stay asleep, increases in deep sleep, but people even at the very early stages of HD were shown to have altered melatonin levels in this study. This indicates that sleep issues are an early sign and symptom of HD.

The good news is that there are now many options for treating sleep with a new series of drugs which target a molecule in the brain called orexin. These drugs seem to have very limited side effects and have shown great promise in different diseases, including Alzheimer’s. Zanna and her colleagues in Cambridge are keen to see if these drugs might help people with HD, and possibly even slow down disease. They’re setting up a clinical trial to measure these questions in a controlled way.

Excitingly, Zanna’s work shows us that there are things that people can do TODAY to help with signs and symptoms of HD. So grab your pillow and get to bed early!

Communication breakdown

Next up is Chiara Scaramuzzino who studies how molecules move along the long, thin branches of neurons. This process doesn’t work so well in HD so Chiara is trying to get into the details of exactly what is going wrong. Molecular messages travel throughout cells and between cells in little bubbles. The transfer of these bubbles and capture of them by neighboring cells doesn’t work as well as it should in cells affected by HD.

Chiara’s lab has made a cool way to study this in the lab. Using 3D printed micro structures, they grow neurons on a chip, where the nerve cells make connections with other cells in a similar way to how they do in the brain.

Using this system, they can do all kinds of imaging of the nerve cells. This includes measuring the transport of individual cargos in cells moving along the length of the nerve cell – Chiara is sharing super cool videos with the crowd!

Comparing regular and HD nerve cells on a chip, they can see that some of this transport is impaired in HD. They also looked at connections between different combinations of HD and regular cells, seeing that networks that start with HD cells are the most impacted in their function.

They followed up on these cargo transport issues by doing some experiments in mice. With some very cool imaging technologies, they were able to “see” the movement of the cargo in the mouse brain. Chiara is hoping that this work will help her and her team identify new targets to develop potential therapeutic targets that might help regulate communication within and between brain cells, which could help improve thinking, movement, and mood in HD.

Systematic screen for somatic instability

Our next speaker is Ricardo Mouro Pinto, who was awarded a $1,000,000 Transformative Research Award from the HDF in 2023 for his work on targeting somatic expansion using CRISPR to develop new drugs for HD.

Ricardo’s lab are some of the many talented folks investigating genetic modifiers that influence age of onset of HD symptoms and how they impact somatic instability of the CAG repeat in the HTT gene. Ricardo’s team systematically looked at every genetic modifier (60 in all!) in HD mice to see how they impacted somatic instability. This found many of the usual suspects, like FAN1 and MSH3, as some of the genes with the most influence on somatic instability.

They looked in different parts of the mice, including the liver and the striatum, the part of the brain most impacted by HD. This showed that some modifiers, like PMS1, seemed to have more of an impact in the brain than in the liver. Identifying genes, like PMS1, that have a stronger effect in one tissue over another suggests some tissue-specific effects with this process.

Other modifiers, like MLH3, seemed to have an impact at different timepoints of the life of the HD mouse. Together, this shows us that somatic instability is a complicated process that happens in different phases with many different proteins playing a role.

Interestingly, some drugs that lower HTT also seem to hit somatic instability-related genes. We recently wrote about this idea. The drug branaplam not only lowers HTT, but it also targets PMS1 to reduce somatic instability.

Ricardo and his team are looking through all of the different modifiers to see which might make the most sense to target with drugs, to slow somatic instability, and potentially treat HD and possibly other repeat expansion diseases like SCA1.

They are looking into CRISPR tools to try and edit some of these modifiers, with the aim of slowing somatic expansion. A very exciting potential future treatment for HD. While they’re only in mice right now, their plan is to move toward the clinic, so we’ll keep you posted as Ricardo’s work moves forward!

Improving gene therapies for HD

The final talk of the conference is from Beverly Davidson, who also was also awarded with a $1,000,000 Transformative Research Award from the HDF in 2023 for her work advancing gene therapies for HD.

Bev’s lab works on the problem of gene therapy delivery and are working to optimize technology that will allow scientists to move from treating a mouse brain to a human brain. She doesn’t just work on HD, but many different genetic diseases, all in need of new drugs.

In current gene therapies under investigation right now, like that of uniQure, multiple injections of the drug are needed in brain surgery at relatively high doses. Bev’s team is trying to rethink this process, making it less laborious for surgeons and arduous for patients.

Gene therapies are generally packaged in harmless viruses called AAVs. Bev’s team is testing different AAVs in animal models to see which work best at getting into different regions of the brain. Bev’s team have identified AAVs which, at very low doses, are able to really get into the center of the brain. This will be a great tool for HD gene therapies which aim to target the striatum, which is right in the middle of the human brain.

She shared beautiful images of a monkey brain showing that her lead AAV candidate, with only one injection, gets to deep structures of the brain and lights up lots of cells there. They’re working on producing a very potent drug delivery system!

Bev is also sharing a story about developing a new technique that allows them to mix samples from different mice, barcode the different cells, then analyze them as a group. This has massive advantages – saving time, money, and resources in the lab!

After the data is analyzed, they can work out which genes and how much of each are expressed in every cell from each brain that they pooled together. It’s a very innovative approach called SPLiTseq.

Up next on Bev’s to-do list is to package HD-targeting drugs into their potent AAV. She promises an update at the next big HD conference!

That’s all from us for HDF’s 2024 conference! Thanks for following along. You can also find other updates in the near future about the conference from Ken Serbin, aka Gene Veritas at his blog. We’ll be back in Boston in 2026 to bring you more updates!

We’re back for Day 3 of the Hereditary Disease Foundation (HDF) conference! First up is a session on RNA dynamics – what’s that?! Read on to find out!

Different HTT forms have different effects

Up first is Gill Bates, who will tell us about her work in understanding how somatic expansion causes disease and investigating ideas targeting different forms of HTT, to help develop therapies for HD.

The HTT gene is very long! And sometimes only parts of it get turned into protein, particularly the beginning part. This happens more frequently in HD. It turns out that first little bit – called HTT1a – is quite toxic to cells. Gill’s team research HTT1a in mouse models of HD and they have studied a series of mice with different CAG repeat lengths, spanning mice with a low CAG repeat number to HD mice with very large CAG numbers. Then they measure which forms of the HTT protein are made in these mice.

Interestingly, they find that the longer the CAG repeat is, the more of the HTT1a fragment is produced. So, perhaps, at least some of the disease-associated toxicity is driven by increased expression of HTT1a. They also find more sticky protein clumps of HTT in mice with longer CAG repeats and more HTT1a bits, suggesting HTT1a primarily makes up these protein clumps. Much less of the really big full-size HTT is made in mice with longer CAGs. Together this points to longer CAGs making more of the toxic protein forms (like HTT1a) and less of other forms.

Next, Gill’s team looked at what happened to HTT if they altered the protein with mutations, not in the CAG repeat, but in the protein building blocks directly preceding this region. This changed where and how many protein clumps they could see in mouse models of HD.

So what effect does HTT1a and other HTT fragments have on somatic expansion? This is something Gill and her team are working on in mice. Her team recently published this work. In that work, they used a mouse model with 185 CAG repeats. When they lowered a gene that is linked to somatic expansion, called MSH3, they were able to halt somatic expansion, but the signs and symptoms of HD still developed in the mice.

This might suggest that somatic expansion has to be halted before the CAG repeat reaches these very extreme lengths, like 185. However, those findings are from a specific mouse model of HD. We need more data to understand this better and know if the same thing happens in humans. A limitation of many HD mouse models is that they have extreme CAG numbers from birth so that scientists can see things that mimic symptoms of HD. It’s possible these models mimic juvenile HD, not the more common adult onset form which might be why they don’t see a change in symptoms.

Gill’s team are working with other labs to specifically lower either the full-length version of HTT or the HTT1a fragment, which Gill’s team think might be an ultra toxic form of the protein. Interestingly, they only see an effect if they dose mice when they are young. When they look at the effect of lowering both forms on HTT protein clumping, they find the biggest effect when they specifically target HTT1a. They’re also able to reduce protein clumps more if they treat the mice earlier.

A theme from recent research seems to suggest treating HD early might be our best bet, but that doesn’t mean treatments won’t work for people later on. A great thing about the HD field is that many people are working on a variety of approaches. Our eggs are in many baskets!

Changes to the recipe

Up next is Anukur Jain, who will be telling us about his work on how the RNA message molecule folds within cells and how that process can go wrong.

A brief Bio101 lesson may be helpful here. DNA is made into a message called RNA before it’s turned into protein. Proteins are the functional molecules of a cell, like the product of a recipe. But they can’t get made without the RNA message, it’s the protein recipe molecule.

The RNA messages from genes that have repeat expansions, like the CAG repeat in HD, are prone to folding strangely, causing problems in how the protein is produced from that message. Like if you spill something on your recipe copy and add 1 egg instead of 2. Oops! Ankur is telling the crowd how altered RNA message folding causes the cell to produce different protein forms and fragments. Just like how the product from your recipe would turn out a bit different if the copy you were reading from was altered.

Using molecules that are designed to glow under microscopes, Akur can follow these misfolded RNA messages in cells in real time. So over a course of just 10 minutes, he can watch them form structures that look like droplets in the cell. Very cool!

Ankur is interested in understanding if the spelling code of the RNA message affects where these droplet-like structures form in the nucleus of the cell. Using cells making different RNA messages with CAG repeats, his team are trying to find answers to this question.

So far, Ankur has done this work only with messages of pure CAG repeats, not the HTT message itself. This allows him to track how CAG repeats affect droplet-like RNA messages, but it doesn’t answer questions about what’s happening with this process in HD.

Modifiers of expansion and symptom onset

Next up is Darren Monckton, who will be telling us about some cool details about HD genetics. Darren and his team look at the different flavors of the HD gene that people have, and how this affects the path of disease progression they experience.

Darren is able to look in blood samples from people with HD to look at somatic expansions, using very sensitive measurements. In blood, they often only see a single extra CAG, which is very different to the 10s to 100s of extra CAGs we see in some cells in the brain. Looking at thousands of samples from people in the Enroll-HD trial, they have tracked somatic expansion over time. The 2 biggest factors contributing to somatic expansion are age and longer starting CAG lengths.

Interestingly, this is also seen in folks with intermediate CAG numbers, corresponding to 27 to 39 repeats. These people are unlikely to present with clinical HD symptoms in their lifetimes, yet Darren’s team see that they also have somatic instability. Darren thinks that this means that somatic instability per se is not enough to trigger disease. Perhaps we need the more extreme somatic instability that we see in people with adult-onset HD, usually with 40-50 CAGs, to initiate signs and symptoms of disease.

Some people experience more or less somatic expansion than we might expect on average. Using data from 1000s of people with HD, Darren’s team can pull out the genetic modifiers which affect the rate of somatic expansion. In this dataset, we can see many of the same genes previously identified as modifiers of HD symptom onset – many of which are genes critical for repairing DNA, in particular the little loop out structures that scientists think are commonly formed in repeating CAG DNA strands.

This is relevant because it suggests the very genes that control somatic expansion might be the same ones that control age of symptom onset. Something that has piqued the interest of many in the field recently! BUT, not all genes associated with DNA repair come up as modifiers of both age of symptom onset and somatic expansion. Why is that? That’s something Darren is interested in understanding.

Darren postulates that this may be related to the amount of each of the DNA repair proteins that are present. The cell can only use so much of some molecules, so more doesn’t always mean a stronger effect. Like a glass can only hold so much water, pouring into an overflowing cup doesn’t mean you’re adding more water.

Many of the hits are helper proteins which assist in DNA repair and processing, so their role is perhaps more subtle in somatic instability. Clearly this is a complex process, so HD scientists are going to be busy figuring this all out.

Darren’s also told us that the HTT gene itself modifies somatic instability! This is not caused by the CAG repeat, but by other changes in the HTT gene letter code, and in the DNA regions which surround the HTT gene in the genetic code. Altogether, this suggests that there are likely different mechanisms all working at the same time to alter the rate of somatic expansion and the onset of clinical symptoms. HD is often called the most complicated single gene disease – we believe that is probably true!

Darren’s team also looked at another CAG repeat disease, called SCA3. They see somatic instability in samples from these people too at the affected gene, ATXN3, but the effect is not as strong as it is in people with HD, at the HTT gene. So, like we’ve heard from several other talks, defining these processes in one disease will have implications for other diseases.

Big data to solve big problems

Next up is X. William Yang. His lab creates mouse models of HD that he shares with researchers across the globe to study the disease. In his talk today he is going to be talking to us about why he thinks some cells seem to be sicker than others in HD.

William is showing a super cool movie that moves through a mouse’s brain with markers that glow to show where the sticky HTT protein clumps are. They’re primarily in the center of the brain, in the striatum, and at the outer wrinkly edges, in the cortex. They are looking to see how the clumps match up with where they see somatic expansion in different parts of the mouse brain, and how this impacts which genes get turned on and off. This way they can try to unpick why some cells might get more sick in HD.

William’s team did a massive experiment where they switched off 100+ different genes in their mouse model. Wow! This is a ton of work that will generate lots of useful data for everyone in the field. They focused on switching off genes that they think could be controlling the global changes of genes that get turned on and off in HD.

Once they did this, they looked to see how each gene being switched off affected signs and symptoms of HD. When they switched off many of the DNA repair genes from modifier studies, this made things better – good news for folks working on these as drug targets!

And if that experiment wasn’t big enough, William and his team then looked at those mice using a single cell analysis, looking how each cell in the mouse brains was affected. In line with what others have shown, the striatum was the most affected area of the brain.

William is highlighting data from a specific experiment where they switched off expression of MSH3, a popular target since it influences somatic expansion in HD. When MSH3 was lowered, sticky HTT protein clumps were reduced in his mouse model.

Connecting all of this together to work out exactly what is going on in HD and which events happen in which order is still a tough task for HD scientists to tackle. There is not a clear consensus… yet! But there are lots of smart folks, like those in William’s team, all on the case.

Working together

Up next is Anna Pluciennik, who studies DNA and is looking into a gene called FAN1, which has been shown to modify when HD symptoms might begin. People who have higher amounts of FAN1 get symptoms of HD later than those with lower levels. But why is that and how does that happen? That’s what Anna is interested in finding out!

Anna’s lab doesn’t work with cells in a dish or with mouse models of HD, but only with the precise molecules they are interrogating. In this type of reduced system, they can get into the nitty gritty of exactly how all these molecular machines are working. It turns out that in order for FAN1 to do its job repairing DNA, it needs to work together with other protein molecules. Anna’s team have elegantly defined exactly which proteins are needed for FAN1 to work. We previously wrote about Anna’s work.

Anna’s team used powerful microscopes to look at FAN1 bound onto DNA and one of its partners, called PCNA. By collecting lots of images, they were able to generate a detailed 3D model of the complex of molecules, and so can work out exactly how they work together. She shows that the CAG repeat extrudes out from the DNA helix, and bends awkwardly when it binds proteins like FAN1 and PCNA. This allows FAN1 to precisely chop the DNA nearby the extrusion to begin the DNA repair process and fix the funny looking extrusion.

Anna is teasing out exactly which letter in the genetic code of FAN1 allows it to bind and chop these extrusions – a very high level of detail! She can map some of the variations identified in large genetic studies to her model and test these forms of FAN1 in a test tube. This is cool as her team are able to work out exactly why some genetic variations affect the FAN1 protein, providing great evidence for why these variations impact HD progression.

Learning from others

Our last talk of Day 3 is from Alice Davidson, who studies another repeat expansion disease which affects the eye, called Fuchs dystrophy. This is one of the leading underlying reasons for why some people might need a cornea transplant. Alice and her team have been researching the underlying genetics of this condition to figure out what is going on. In a gene called TCF4, there is a CTG repeat. If this is expanded beyond 50 repeats, then people are at much higher risk of developing Fuchs.

Alice believes that Fuchs could be a good system to test drugs that generally target repeat diseases, given its late onset and the ease of delivering drugs to the eye compared to the brain or muscle for example.

There are a lot of parallels between Fuchs and other repeat diseases, like HD, including toxicities observed with RNA message molecules, sticky protein clumping, and other features, like somatic expansion. Similar to the findings of Darren’s team that we covered earlier, Alice shows us that there is more instability in people who inherit a longer repeat. They next looked to see what might be causing repeat instability.

Alice and her team are interested in defining some of the underpinning mechanisms that lead to Fuchs. And perhaps the underlying theme of the conference so far has been that there are lots of similar mechanisms across diseases that could help inform treatments for many disorders.

That’s all for the research updates for Day 3 – we’ll be back tomorrow for updates from the last day of the conference!

The HDBuzz team was back in Boston this year to livetweet updates from the Milton Wexler Biennial Symposium hosted by the Hereditary Disease Foundation (HDF), the first of which was held in 1998! This is a 4-day event that brings together almost 300 world leaders in Huntington’s disease (HD) research to share their current data, generate new ideas, and get us closer to a treatment for HD.

”I’m glad you’re sitting down for this”

Our first talk is by Fyodor Urnov, who will give us an update on editing the brain with CRISPR for therapeutics. Interesting! Dr. Urnov starts by reminding us how far things have come in brain research in the last few years, stating that he can give us a “healthy dose of optimism”.

He started by showing us a timeline of data that has led to medicines for editing DNA. It’s been an explosion over the past few decades! All culminating in the development of a regulatory approved drug, for blood-based diseases. HDBuzz wrote about that drug, called Casgevy, recently.

Fyodor will tell us about drivers of CRISPR progress, the revolutionary gene editing technology, and how they build on each other. Let’s go!

Fyodor works with Jennifer Doudna, one of the inventors of CRISPR. Who better to have on team HD to help us develop medicines!? He very excitingly is showing data about a company he works with, Intellia Therapeutics, and how they’re moving forward with CRISPR-based treatments for other brain diseases with over 700 participants. Unthinkable just a few years ago!

And all of this has spurred from a scientific discovery that was made only 12 years ago for which Jennifer was awarded a Nobel prize. Quite amazing! Fyodor keeps stating, “I’m glad you’re sitting down for this” as he tells us about more stellar science that is knocking our socks off.

CRISPR is being used for other diseases, but what is learned from these diseases can be streamlined to be used for HD. This will take efforts from many companies, which they plan to “daisy-chain” into a platform of CRISPR cures, bringing everyone’s expertise together.

Fyodor is sharing a platform that could be a game changer for genetic diseases. He talks about a world where children that have a gene that can be edited could potentially have a cure in 4 years for $25-70 million dollars. Currently a dream which may soon become reality.

Now he moves on to the good stuff – therapeutics for Huntington’s disease! He’s sharing his research working to correct the expanded version of huntingtin (HTT), the molecule that causes HD. As the CRISPR technology quickly improves, so do the options for HD. There are lots of different flavors of CRISPR, so we have all sorts of tools in the toolbox to work out the best path forward to potentially make a HD gene therapy.

Foydor makes a bold prediction that there will be a CRISPR-based drug for cholesterol within 3 years. This will provide a regulatory track record for CRISPR-based drugs, making the path clearer for diseases like HD. Fyodor is telling us about the successes of CRISPR approaches in other diseases, since information from these clinical trials will help inform therapeutic strategies for HD.

For HD, Fyodor and his team is planning to use CRISPR to change the way the HTT gene is put together – something called splicing. They’ll specifically do this to target only the expanded, disease-causing copy of HTT.

Like an approach from a super villain movie, they’ll use something called a “poison exon”. Sinister sounding… All this means is that they’ll splice in a piece of genetic code that causes the expanded HTT copy to get sent to the cellular trash bin.

So far they’ve only done this in cells in a dish, but this approach seems quite promising. Using this technique, they can reduce the amount of the expanded HTT copy by ~70%. Impressive in the world of molecular biology!

Another challenge for HD gene therapies is getting the CRISPR drug into the brain, no mean feat. Instead of a harmless virus usually used to deliver these types of drugs to the brain, tiny carrier molecules called lipid nanoparticles seem to do the trick, at least in mice and cells grown in a dish.

Fyodor left the group with a swell of hope that the currently approved CRISPR drug, Casgevy, along with the massive amount of data moving forward for other diseases will be the rising tide to lift the ship for CRISPR therapeutics for HD.

A light at the end of the tunnel?

Our second and last talk for tonight is from the one and only Ed Wild, co-founder of HDBuzz. He’ll be sharing an exciting update on clinical trials in the HD space.

Ed starts by reminding us about the state of play the last time we gathered for this meeting in 2022 – we had just had a slew of sad and disappointing news about many HD clinical trials which HDBuzz readers will remember well.

Ed reminds us that everyone’s journey with HD starts with bad news, but we must get back up and come together to generate good news. Recently we’ve had a deluge of very much needed good news from many HD drug hunting companies that he will review for us now.

The first company and drug Ed talks about is tominersen from Roche. They’ve worked hard to comb through the data from the GENERATION-HD1 trial to determine if there is a way forward for this drug.

They’re currently moving forward with GENERATION-HD2, a Phase 2 trial to test tominersen in younger people with less pronounced symptoms of HD and a lower dose of the drug. Testing drugs in early HD was previously challenging, as it’s challenging to determine if the drug is working in someone who doesn’t have clear symptoms. This is now possible because expert HD scientists and doctors got together to work out a new staging system for HD to figure out what they could measure in younger people.

The fact that companies are shifting to testing drugs at earlier stages does not mean that it’s too late for people who have developed symptoms. Something that works to prevent or slow HD will likely also work in people at later stages.

You can learn more about the Roche GENERATION-HD2 trial from a recent HDBuzz article.

Ed then moved into talking about the recent good news from PTC Therapeutics, which was recently covered by HDBuzz. PTC Therapeutics are testing their HTT lowering drug PTC-518, which is a small molecule that is taken as a pill. PTC-518 lowers HTT levels in a dose-dependent manner i.e. the more drug you take, the more lowering that happens.

A new piece of data we learned from their recent update was that HTT lowering does not inevitably lead to high NfL levels, indicating damage to neurons. While this sounds obvious, we actually didn’t know this until recently.

Previous trials testing HTT lowering had all shown a spike in NfL levels – a molecule that rises when brain cells are damaged. So scientists thought this was causing things like brain swelling because of the drug or brain surgery, but no one actually knew. Until now! People who were given PTC-518 had flat levels of NfL, suggesting that HTT lowering itself wasn’t the cause of a transient rise in NfL levels in previous clinical trials. Good news!

We also learned that this type of drug, called a splice modulator, appears to be safe in treating HD. This is the same type of therapeutic as the Novartis drug branaplam that was halted, so this is also very welcome good news.

PTC also showed that people taking PTC-518 had HD symptoms that seemed to advance more slowly, perhaps suggesting that the drug is doing what we hope. However, this is a small trial, so we have to take this information with a pinch of salt. Excitingly, PTC are making moves toward a Phase 3 trial for PTC-518.

Next Ed shared an update from Wave Life Sciences, which we also recently covered. Wave are testing a HTT lowering strategy that specifically targets the expanded copy of HTT. This leaves the unexpanded copy alone, left to work in the body and brain, to perform its normal functions. Again, it seems that WVE-003 seems to be doing just this!

Ed suggests we should keep tabs on the NfL data from this study, as the data does show somewhat of a spike for a few folks. Ed thinks that HD researchers need to put their heads together to figure this out before we test this drug in more people.

When things are all going in the right direction, they’re easy to interpret. But already confusing things can confound our interpretation. So proceeding cautiously is best.

Ed is now providing an update from the uniQure trial, which you can read more about here. This trial is testing yet another HTT lowering strategy; this one involving a single dose of a drug delivered by a harmless virus via brain surgery. With this kind of approach, things must move very slowly to ensure safety at every step of the way.

uniQure’s drug, AMT-130, caused an initial spike in NfL. This was expected since any brain surgery will at least temporarily harm some brain cells. However, it looks like NfL goes down back to baseline, and possibly drops below baseline – we’ll see if this trend holds!

While uniQure also shared data suggesting AMT-130 slowed disease progression, again, it’s important to note that this is a small number of people. So results here also have to be interpreted with caution. However, any movement of the needle is welcome news in our books!

Up next is an update on Skyhawk Therapeutics, who recently released data from their Phase 1 trial testing a HTT lowering drug, called SKY0515, that can be taken as a pill.

While they didn’t release much data with this update, they did show that they’re able to lower HTT in a dose dependent manner. So the drug does what they want! They’re now moving on to a third arm of the study that will test SKY0515 in people with HD.

Ed shared a quick update about Prilenia. Ed noted that pridopidine failed to meet its primary or secondary endpoints of their recent trial testing this drug. Despite this setback, you may have seen some news stories about how Prilenia plan to move things forward.

Ultimately, Prilenia sliced and diced the data after the trial was over to try and gain some insight. These aren’t conclusive since the study wasn’t designed to test this. Under this extremely distorted lens, Prilenia think that neuroleptics might affect how the drug works.

Neuroleptics are antipsychotic medications often prescribed to people with HD to manage psychiatric symptoms, like depression, that are sometimes associated with HD. This is a key part of treatment for many people with HD.

Ed is somewhat worried about the confusion generated around neuroleptics. Before we make decisions about which drugs people with HD should be taking, he believes we should be informed by clinical trial data.

Anyone who has been prescribed neuroleptics by their neurologist should not go off their medication without first speaking with their medical team. A blinded clinical trial would need to first be run to make any conclusions about how neuroleptics affect the severity of HD.

Ed then went into a long-winded explanation about the stars in London – apparently he’s gotten into astrophotography…. In a way that only Ed can, a moderately self-congratulatory departure was used to wrap and liken HD drugs to the stars in our sights.

That’s all for Day 1. The HDBuzz team will be back for Day 2 with some hot off the presses HD science updates!