Proteins are like molecular dancers, with the cell acting as their dance floor. Proteins pair up with various partners to perform elaborate dances. Depending on who they partner with, they can carry out different functions in the cell, just like
someone might prefer to do the waltz with one partner, but the salsa with another. Identifying key dance partners in health and disease can help us advance treatments for diseases like Huntington’s.

Pairing up for the molecular waltz

Scientists often focus on a protein’s dance partners when investigating a protein’s function. Knowing which proteins are pairing up sheds light on how that protein works and what it does inside the cell. Cells are like an extraordinarily crowded dance floor, with billions of interacting proteins, constantly interacting with and swapping partners in an elaborate rhythm.

Identifying protein interactions is critical to our understanding of disease. Diseases can alter who a protein likes to interact with, which can affect the functions that it carries out in the cell. If our once tango-loving protein refuses to dance with a certain partner, they may no longer like to do the tango. That could be an issue if that’s their signature dance.

Huntingtin on the dance floor

In the case of Huntington’s disease (HD), researchers are working to map the dance partners of the protein Huntingtin. A spelling mistake in the Huntingtin protein causes HD. Knowing the interaction partners of Huntingtin with and without the spelling mistake can help uncover cellular processes altered by HD. Scientists can use this knowledge of protein interactions to improve our understanding of disease mechanisms and, eventually, develop potential treatments to test in clinical trials.

In a recent publication, a team led by Dr. Cheryl Arrowsmith at the University of Toronto devised an experiment to see all the different dance partners that Huntingtin has, not just other proteins. This work showed that huntingtin also binds to a molecule called RNA.

RNA: A new Huntingtin dance partner

RNA, a cousin of DNA, is best known for its role in producing proteins. While DNA primarily serves as a genetic blueprint for building proteins, RNA has a much broader range of activities. The most studied type of RNA is messenger RNA, also called mRNA, which codes for protein.

However, up to 90% of RNA molecules don’t code for proteins and are not mRNA. Instead, they interact with proteins, coordinating important cellular processes. In this way, these so-called “non-coding” RNAs act like protein dancers themselves or are at least protein choreographers, helping proteins dance together. While most proteins don’t partner with RNA, the new work from Dr. Arrowsmith’s group suggests that Huntingtin appears to be one of the few that do. This raised the possibility that the spelling mistake in Huntingtin that causes HD could disrupt these interactions.

Scientists had a couple of reasons to suspect that Huntingtin might partner with RNA. For example, when they used powerful microscopes to closely examine the exact shape and physical structure of Huntingtin, they noticed a spot on the protein that could, in theory, fit an RNA molecule right into it.

In addition, previous experiments by Dr. Arrowsmith’s lab showed that RNA molecules strongly partnered with Huntingtin in certain experiments where they were trying to study Huntingtin’s protein interactions. In fact, so much RNA partnered with Huntingtin that they needed to perform additional steps to get rid of the RNA (because they were interested in proteins at the time). However, this led them to wonder, what ARE those RNA molecules that partner with Huntingtin and could they play a role in HD?

The dance between Huntingtin and RNA

Before diving into more complex techniques, the researchers conducted a simpler experiment. They mixed RNA into a kind of “science jello” and subjected it to an electrical current. Because RNA molecules have a negative charge, they migrate toward positive charges positioned on the opposite side of the jello. Scientists compared the speed that the RNA moved through the jello with, and without, Huntingtin mixed in.

They found that, in the presence of Huntingtin, RNA moved through the jello more slowly, suggesting that RNA was in fact partnering with Huntingtin. Importantly, this slowing effect was not observed when DNA was mixed with Huntingtin, suggesting that Huntingtin has a specificity for RNA. This is important because DNA and RNA are chemically quite similar, but functionally very different. This experiment showed that Huntingtin is specifically interested in dancing with RNA, not DNA.

Encouraged by this result, the scientists decided to dig deeper by analyzing all the RNA that partnered with Huntingtin in living cells grown in a dish. As expected, they found that Huntingtin parternerd with many different RNA molecules. They next narrowed their investigation by focusing on some of those RNA partners to learn more.

A NEAT dance sequence

While reviewing Huntingtin’s RNA partners, the researchers noticed some interesting patterns. Many of these RNA molecules were involved in activities that are critical for cell survival. Because these activities are so crucial, they are not the kinds of RNA you would want Huntingtin snubbing on the dance floor!

Huntingtin also prefers to partner with a specific type of RNA containing lots of guanine, a building block of RNA. To confirm this, the scientists made an artificial “lab-made” RNA strand with lots of guanines and, sure enough, Huntingtin sidled right up to it.

The researchers decided to shine the spotlight on one RNA that consistently partnered with Huntingtin and contained lots of guanine: NEAT1. NEAT1 is an RNA that plays a key role in forming something called paraspeckles – tiny structures inside the nucleus of cells that control RNA production. You can think of paraspeckles like the VIP lounge on the molecular dance floor. NEAT1 is the RNA choreographer specifically for the VIP lounge, dancing with partners there and regulating the dances of others. Huntingtin will join the VIP area, but has no problem dancing in other areas of the cell. The researchers found that when Huntingtin joins the VIP lounge paraspeckles, it likes to partner with NEAT1.

Next, the team wanted to know if levels of NEAT1 were changed by the spelling mistake in Huntingtin that causes HD. Although they found levels of NEAT1 were lower in brain cells grown in a dish and mouse brain tissue containing the Huntingtin spelling mistake, the results from human brain tissue were less clear. During the early stages of HD, NEAT1 levels were lower, but NEAT1 levels were higher in later stages of the disease. The scientists suggested this could be caused by the loss of brain cells as the disease progresses. Regardless, these results suggest that NEAT1 levels are changed in Huntington’s disease.

The VIP lounge

To see if there is a direct connection between NEAT1 and Huntingtin, the scientists tested whether changes in Huntingtin levels could affect NEAT1 levels or the paraspeckles that NEAT1 organizes. Afterall, if you know your favorite dance partner will be a no-show, you might not show up either! The researchers found that when Huntingtin levels were lowered, NEAT1 levels rapidly decreased afterward, suggesting that Huntingtin stabilizes NEAT1. So NEAT1 really only wants to be around if Huntingtin is around too. Because NEAT1 is crucial to forming paraspeckles, reducing Huntingtin also led to smaller and fewer paraspeckles in the nucleus. So without Huntingtin, NEAT1 doesn’t even bother organizing the VIP lounge. That’s a serious commitment to your dance partner!

Next, the researchers asked if the spelling error that causes HD effects NEAT1’s role in organizing paraspeckles. They found that brain cells grown in a dish that have HD-causing Huntingtin had fewer paraspeckles, and those that remained were smaller. This suggests that both the loss of Huntingtin and the presence of HD-causing Huntingtin disrupt paraspeckle formation, possibly by destabilizing NEAT1.

These findings are significant because they show that Huntingtin interacts with NEAT1, an RNA crucial for paraspeckle formation, and this interaction is disrupted in HD – potentially causing serious problems in the brain. However, there are still some important unanswered questions. For one, most of these experiments were done in cells grown in a dish, so we don’t know if the same interactions occur in the human brain. Additionally, the consequences of reduced NEAT1 and paraspeckle formation in the brain remain unclear. Previous studies in mice suggest that NEAT1 is not essential for brain development or brain cell survival. Still, the consequences of disrupting NEAT1 or paraspeckles in humans, or during human disease, are unknown.

Zooming out on the dance floor

While most of this work focuses on NEAT1 and paraspeckles, let’s not lose sight of the big picture: Huntingtin interacts with RNA! NEAT1 was just one of up to 571 RNAs the researchers found that may interact with Huntingtin, many of which were involved in important activities like producing energy. Future studies are needed to examine how Huntingtin might affect these other RNAs just as this study analysed NEAT1. For example, if Huntingtin is important for NEAT1 stability, could Huntingtin stabilize other important RNAs?

Let’s think therapeutics – where does this research get us? First of all, this study will certainly motivate additional research into Huntingtin’s RNA connection. And, if an interaction between any specific RNA and Huntingtin were found to be harmful or beneficial, then small molecules that influence that partnership could be designed. In the elaborate choreography of cellular processes, finding the right molecular dance partners is like playing the perfect song – it can set the stage for a harmonious performance or prevent a misstep that disrupts the entire routine.

Research led by Dr. Peg Nopoulos from the University of Iowa used the Enroll-HD database to answer a key question: “How does beta-blocker use influence motor-diagnosis onset and progression rates in premanifest and early motor-manifest Huntington’s disease (HD)?”. They found beta-blocker use was associated with positive effects!

Subtle changes because of HD

While HD primarily affects the brain, people with HD have subtle changes to their nervous system that can also affect heart rate and blood pressure. The scientists who worked on this paper had previously shown that these subtle nervous system changes happen early in life, which could cause their effects to build over time.

They thought that medications used to treat these subtle changes, like those recommended for minor heart problems and small elevations in blood pressure, could potentially have global benefits for the nervous system, perhaps having a larger influence on HD symptoms overall.

LOLs for a calmer heart

The researchers were specifically interested in a class of medications called beta-blockers. You’ve likely heard of many of these medications – propranolol, metoprolol, and atenolol are 3 commonly prescribed beta-blockers. A trick for identifying them is that they end in the suffix -lol.

Beta-blockers are a routinely prescribed pill for managing various conditions, like high blood pressure, irregular heart rhythms, and anxiety. They work by blocking the effects of adrenaline and other stress hormones on the heart and blood vessels, helping to slow heart rate and reduce overall cardiovascular strain.

Beta-blockers have been widely used in clinical practice for over 50 years, with the first drug in this class, propranolol, approved by regulatory agencies in the 1960s. Since then, they have become a mainstay treatment for a range of cardiovascular conditions due to their proven safety and effectiveness.

Over decades of use, beta-blockers have demonstrated a strong safety profile, with side effects that are well understood and manageable in most patients, making them one of the most trusted types of drugs in medicine.

Enroll in action

To answer questions about the effect of beta-blockers on the onset and progression of HD, the researchers turned to the Enroll-HD database. Enroll-HD is the largest global observational study focused on HD, involving people from around the world. Over 20,000 people are currently part of Enroll-HD! No drug is given during the study; it’s designed to simply watch people with HD as they live and age and see how that differs from people without HD.

During clinical visits for Enroll-HD, participants are asked questions by their neurologists, including current medication use. This information is then de-identified so no one can match clinical information to a specific person, and researchers across the globe are given access to that data. This allows leaders in HD research from around the world to dig into this data and ask and answer questions that will get us closer to a treatment.

Delay and decrease

Dr. Nopoulos’ group used the Enroll-HD dataset to analyze the use of beta-blockers in people with the gene for HD who were not yet experiencing symptoms (premanifest HD) and those with early motor symptoms. The most common reasons people took these meds was because of high blood pressure, anxiety, depression, and heart problems like irregular heart rhythm or coronary artery disease.

For people in the premanifest HD group who were taking beta-blockers, the chance of being diagnosed with disease onset was decreased by 19% to 38%, depending on the specific medication. That’s quite a bit! (The 38% decrease was seen for those taking propranolol.)

People with early motor symptoms who were taking beta-blockers showed improvements in several tests used to measure progression of HD symptoms, compared to people not taking beta-blockers. The beta-blocker users had slower progression in motor symptoms, slower decline in their ability to carry out day-to-day tasks, and a slower decline in thinking and memory tests.

However, when they got into the nitty gritty of the data for the early motor group, the type of medication seemed to matter. In looking at the 3 most common beta-blockers that were used in Enroll-HD – metoprolol, propranolol, and bisoprolol – only some of the meds influenced some of the tests. Only metoprolol affected motor symptoms, and only bisoprolol affected the ability to carry out day-to-day tasks and thinking and memory.

Process or prescription?

These results beg the question – is it the medication that’s having the benefit or treatment of the underlying condition? To answer that question, the group also looked at another medication commonly prescribed for cardiovascular issues – ACE inhibitors.

While ACE inhibitors are frequently prescribed for similar health issues for which beta-blockers are given, ACE inhibitors did not have the same positive effect in this study. ACE inhibitors showed no positive association with HD onset and symptom progression. This suggests that there’s something specific about beta-blockers, and not just treating these heart-related issues, that is having this beneficial effect.

Limitations

The largest limitation of this study, which is noted by the authors, is that they’re looking at correlation, not causation. They can’t say for sure if the positive changes in onset and progression are caused by beta-blockers. They can only say these positive changes are associated with beta-blockers.

Studies like Enroll-HD allow researchers to dig through lots of data and are very helpful for pulling out this type of association. But clinical trials are needed to draw firm conclusions about the effects drugs are having. However, once scientists know about positive associations, they can then do specific experiments to get at exactly what is driving the association, which can lead to the development of other drugs, and future clinical trials.

The data is also limited in that the Enroll-HD database has limitations for collecting data from disease progression biomarkers, like neurofilament light (NfL). NfL is a molecule that’s released from damaged and dying brain cells. We know that NfL levels rise as HD progresses. However, we don’t know if NfL levels change with beta-blocker use. The second iteration of Enroll, which is currently being rolled out, is designed to expand in ways that will improve collection of biomarkers, including NfL.

The fine print

In studies like this that can only generate associations, there’s always some fine print. While we can’t say for sure if beta-blockers are the cause of these improvements, we can call out a few of the confounding variables to try and understand what else could be at play here.

We know that beta-blockers are frequently prescribed for anxiety. We also know that unchecked anxiety can impact motor symptoms in people with HD and have major effects on one’s ability to carry out day-to-day tasks. It’s possible that beta-blockers used to suppress anxiety had a positive effect simply because they reduced overall worry and unease, leading to improved daily life.

We know that HD causes vascular changes, particularly in the brain. We also know that treating low level hypertension with beta-blockers could have long-term benefits for vascular effects. So it’s possible that managing vascular changes early could be leading to some of the positive changes noted in this study.

We also know, for sure, that living a healthy lifestyle is correlated with later disease onset and slower progression. It’s likely that people going to the doctor for medical problems that would be treated by beta-blockers are more health forward, so they may exercise more frequently or eat healthier foods too. So it’s possible that at least some of the positive benefits noted in this study could be because those taking beta-blockers are, overall, more health conscious people.

Prescription for change

The major take home from this new study is that the use of beta-blockers is associated with delayed motor diagnosis in people with premanifest HD and delayed disease progression in people with early motor symptoms. However the most effective beta-blocker is unclear since the exact drug that showed benefit varied by experiment. And notably, dose was not examined since it varies wildly based on medication and indication for which it is prescribed.

If this study has you wondering if you or a loved one should start taking a beta-blocker for HD, please reach out to your primary care physician or neurologist. While beta-blockers are generally safe, there are contraindications for these medications, such as low blood pressure, COPD, and circulatory problems.

One thing that we learned unequivocally from this study is that the people participating in Enroll-HD are changing the face of HD research. With their help, scientists are uncovering critical information to generate ideas that will lead to future clinical trials. The strength of the HD community and their participation in these large observational studies is the real prescription for change.

Vico Therapeutics recently presented at several conferences to share an interim update on their Phase 1/2a clinical trial testing their drug called VO659, which targets the repeating C-A-Gs in people with Huntington’s disease (HD). These data suggest that VO659 may be able to reduce levels of the toxic HD protein in the small group of participants tested so far and gives insights into safety. But how does VO659 work and how is Vico’s approach different to that of other companies? Let’s get into it.

Too many C-A-G repeats are the cause of HD

In everyone’s genetic code, there are 2 copies of a gene called Huntingtin, often shortened to HTT. Near the start of the HTT gene code, there are repeating C-A-G DNA letters. In folks who don’t have HD, both gene copies will have less than 35 C-A-G’s repeating in a row.

However, people with HD will have more than 35 C-A-G repeats, typically in just one of the copies of their HTT gene. This expansion of the C-A-G’s in the DNA is the genetic cause of HD.

Our DNA is like a recipe book for the molecules that make up the cells of our bodies. Our cell’s machinery carefully copies down each recipe into a message molecule which can then be used as a template to make the protein molecule it encodes.

The HTT gene is the DNA recipe that encodes the HTT protein molecule. So if the DNA encodes a C-A-G expansion, we will also see this expansion in the copy of the message molecule and in the protein.

VO659 – a drug to target repeats

VO659 is a type of drug called an antisense oligonucleotide or ASO, developed by the Dutch company, Vico Therapeutics. VO659 is delivered by spinal injection so that it can spread through the nervous system and into the brain.

ASO’s are designed to specifically bind onto certain types of genetic message molecules, which results in them being sent to the cell’s trash can. Without the message molecule, the protein molecule they encode cannot be made, so the level of this protein will decrease.

VO659 is designed to target long strings of repeating C-A-Gs in genetic message molecules, like the one found in the expanded HTT message in people with HD. This means that treatment with VO659 should specifically decrease the levels of the expanded HTT in the cell.

Expanding C-A-G repeats cause disease beyond HD

HD is not the only disease caused by expansion of C-A-Gs, there are in fact a total of 10 diseases which have similar genetics. In addition to HD, these include other rare diseases such spinocerebellar ataxias 1 and 3, often called SCA1 and SCA3.

Like HD, SCA1 and SCA3 are also caused by genetic mutations which increase the number of C-A-Gs over a specific threshold and result in neurological disease. These C-A-G increases occur in genes called Ataxin-1 and Ataxin-3 for SCA1 and SCA3 respectively. The expanded proteins encoded by C-A-G expanded Ataxin-1 and Ataxin-3 are thought to be toxic and a key driver of SCA1 and SCA3 disease.

As VO659 is designed to target long C-A-Gs, this means that it could be a useful drug to help reduce the toxic proteins made by any C-A-G expansion disease, including HD, SCA1, and SCA3.

Preferential lowering of the toxic copy

Runs of repeating C-A-Gs are found in many different genetic message molecules. Indeed, the regular healthy HTT gene typically has ~18 C-A-Gs. So how does VO659 work to target disease message molecules?

Data previously presented by Vico at the 2023 CHDI Therapeutics Meeting, reported on by HDBuzz, showed that the drug prefers very long C-A-G’s so it mainly seems to target disease message molecules, like the expanded HTT message. This is a preference though, as the regular HTT message is still targeted by VO659, just to a lesser extent.

This is a completely different approach from other ASOs being tested in the clinic to treat HD. Some target total HTT (unexpanded and C-A-G expanded) such as tominersen developed by Roche, while others target only the disease-form of HTT, such as WVE-003 from Wave Therapeutics. Unlike Vico who are targeting the C-A-Gs that are present on both the expanded and unexpanded copies of HTT, [Wave’s approach uses a unique genetic signature] (https://en.hdbuzz.net/371 that’s only present on the expanded copy.

Basket trials can help us find new drugs for rare diseases more quickly

Given the promise that VO659 has for HD and other C-A-G repeat diseases like SCA1 and SCA3, the scientists at Vico Therapeutics designed a “basket trial” to test it out. A basket trial is where people with different diseases which have a similar kind of molecular alteration are grouped together into one trial.

The basket trial approach can help to more quickly assess the safety of a drug, as well as how well it works, in more people. HD is considered a rare disease with ~1 in 4000 people affected. SCA1 and SCA3 are even more uncommon, both with ~1 in 100,000 people affected.

With so few people, it can be very challenging to recruit enough participants for a trial exclusively for just one of these diseases. By grouping people with different types of C-A-G repeat diseases, it can help scientists more quickly and efficiently test a drug in the clinic which might work for all of them.

In this case, Vico enrolled people with SCA1, SCA3, or HD, all of whom have an increased C-A-G repeat in their Ataxin-1, Ataxin-3, or HTT genes, respectively, into their Phase 1/2a clinical trial.

Designing a trial to test VO659 in people with C-A-G repeat diseases

To be enrolled in the trial, participants must be 25-60 years old and have a genetic diagnosis of SCA1, SCA3, or HD. These tests report back a C-A-G number and to qualify for the trial, people with SCA1 need 41+, SCA3 need 61+, and HD need 36+.

Participants of the trial also need to be in the early stages of SCA1, SCA3, or HD. For people with SCA1 and SCA3, this was defined as mild to moderate disease with a Scale for Assessment Rating of Ataxia (SARA) score of 3-18. For people with HD this is defined as Stage I disease with a Total Functional Capacity (TFC) Score of 11-13 and a Unified Huntington’s Disease Rating Scale (UHDRS) Diagnostic Confidence Level (DCL) of 4. All of these acronyms stand for different clinical metrics which can help doctors measure how far along in disease someone is.

The data presented so far are from a total of 23 people enrolled into the trial; 6 with HD, 3 with SCA1, and 14 with SCA3. The trial seeks to test 3 different doses of VO659 (10, 20, and 40 mg) to work out which dose is safe and also effective at targeting the disease-causing message molecules. All of the people with HD in the trial are receiving the top 40 mg dose of the drug.

Everyone in the trial is receiving four doses of the drug given once every 4 weeks. However the trial is continuing for 23 weeks after dosing has ended, allowing measurements to be made of folks who have taken the drug, to see how well it may be working and how safe it is after dosing has stopped.

Interim update results – what do we know about VO659 so far?

This interim update was shared via a press release and also through presentations at the recent EHDN and ENROLL-HD 2024 meeting in Strasbourg in September, and at the International Congress of Ataxia Research (ICAR) in London in November. Let’s get into the new data…

Safety

In a Phase 1/2a trial, one of the most important things to be determined about a new drug is how safe it is in people. The recent press release from Vico states that the drug is generally safe and tolerated which seems like good news. However, when data from the interim update were presented at the recent EHDN and ICAR meetings, we learned that this wasn’t the full picture.

Of the 6 people with HD who were given the drug, 4 people experienced radiculitis, a painful condition related to nerve damage. All individuals who experienced this serious side effect, termed a serious adverse event (SAE) in clinical trial speak, received at least three doses of the highest amount of the drug tested (40 mg).

This is a side effect observed in studies investigating other ASO therapies. Vico plan to mitigate this issue moving forward by lowering the amount of drug given to people in the trial. Fortunately, 3 of the 4 people experiencing this side effect are showing signs of recovering.

All other side effects were minor, including headaches, dizziness, and nausea, and were in line with what was expected for this type of clinical trial.

NfL

Neurofilament light, also called NfL, is a biomarker of brain health. Measured in the spinal fluid, if NfL levels go up, it is generally an indicator that brain health is declining. (So, for NfL levels, up is bad and down is good.)

The data presented at ICAR and EHDN suggest that NfL might go up a bit after dosing in some people, which could be reasonably expected after a lumbar puncture. Looking at all the data collected so far for folks who have reached their 4th dose, the good news is that in nearly everyone who received the drug so far, the levels didn’t go up significantly in the long run.

In more recent data from the ICAR presentation, it actually looks like there might be a 2.5% decrease in 5 people with HD who received the 40 mg dose after 120 days, 5 weeks after their last dose. This is encouraging, but we should be cautious with data from such a small number of people.

HTT lowering

Vico looked at how the levels of the expanded HTT protein changed in people with HD who received the drug. As this expanded form of HTT is only made in people with HD, they had samples from just 6 people to look at. Two people in this group of the trial have very early HD so the levels of expanded HTT in their spinal fluid were actually too low to measure with confidence.

In the press release and presentation at EHDN, a 28% reduction in expanded HTT levels was seen for folks with HD receiving 40mg of the drug after their 4th dose. This shows that the drug is working as expected and lowering HTT levels.

In more recent data presented at ICAR, HTT levels were shown to be reduced by 38% in 3 people. This data was collected at 120 days, 5 weeks after these folks received their last dose. This seems to suggest that the effect of the drug is long lasting, and expanded HTT levels remain low even after dosing with the drug has stopped.

What about people with SCAs?

Data have been shared for folks in the trial with SCA3, to see how their expanded Ataxin-3 levels changed in both spinal fluid and blood samples. No change was seen in spinal fluid but it does look like the levels seem to go down in blood samples in some people.

There doesn’t seem to be a dose-dependent effect in these changes i.e., more lowering in people who got more drug. However, it’s very early days with very few people, so we might need to wait for more data from more people to know for sure.

What’s next for VO659?

More data

This Phase 1/2a study is ongoing and there is a lot more data to be collected. Until we have those final and complete datasets, we won’t quite know the outlook of this therapeutic approach for the different diseases being investigated.

Dosing strategy

Something we knew from the preclinical data (aka data gathered in the lab from cells in a dish or animals that model HD) shared by Vico is that this drug really seems to hang around and keep working for a long time after it is administered. The fancy science term for this is that the drug has a long half life. This can have potential issues if too much drug accumulates in specific tissues in the body over time, but can also have the benefit of meaning that you don’t need to dose people quite so often.

The radiculitis in 4 folks who received the highest dose of the drug could well be linked to the fact that the drug sticks around for a long time but we don’t yet know the exact cause. Moving forward, Vico have stated that they are planning to dose people with VO659 much less frequently, between 1-3 times a year, in future studies of this drug.

Another trial?

Vico believes that VO659 appears to be a promising treatment for people with SCA3 and HD. They are already in discussions with regulators on a plan for a phase 2 trial of this drug in people with HD.

At the end of the day, these early stage clinical trials are designed to test safety and tolerability of new drugs, which is exactly what Vico are working out with this trial. While there do seem to be a few potential safety issues with the highest dose of VO659 being tested, Vico are following up on those and evolving their strategy to address the issues they’ve seen. We’ll be sure to keep you updated as VO659 advances.

On December 3, 2024 we received word that the very first person received a new drug, called ALN-HTT02, as part of a Phase 1 trial aiming to treat Huntington’s disease (HD). Going boldly as the first human ever to receive this drug, they’re charting a course that we all hope will one day lead to a disease-modifying drug for HD. Let’s dig into the details of this new trial!

Who is behind this new trial?

In early November, Alnylam Pharmaceuticals announced that they were launching a clinical trial to test their huntingtin-lowering drug. A spelling error in the gene huntingtin, called HTT for short, is what causes HD. Those who inherit this spelling mistake in HTT will go on to develop changes with mood, movement, and memory as HD progresses. Lowering levels of the HTT molecule with the spelling mistake is one strategy being tested in the clinic to potentially treat HD.

Alnylam is a relative newcomer to the scene of HD therapeutics, but they’re not new to drug discovery. They’ve been around for 22 years and received commercial approval for their first drug 6 years ago. They also have experience with other brain disorders; they’re currently advancing towards a Phase 2 trial for a drug that they hope will treat Alzheimer’s disease.

The company is named for the bright center star in the constellation Orion’s belt, “Alnilam”. As that star has been used for thousands of years by navigators, it symbolizes Alnylam’s passion for discovery. For some, this star represents a bridge between earthly and celestial realms. Hopefully all these positive cosmic analogies are good luck and Alnylam’s drugs can bridge us to an HD-free future!

Molecular Mars Rovers

The drug that Alnylam developed in collaboration with Regeneron Pharmaceuticals that is being tested in this trial is called ALN-HTT02. It works through a mechanism called “RNA interference”, also known as RNAi. RNAi is unique because it takes advantage of molecular machinery that already exists inside cells for processing – like little Mars Rovers processing samples from the red planet. RNAi is Alnyam’s specialty. They developed the world’s first RNAi-based medicine! (A drug used to treat a nerve disease.)

ALN-HTT02 itself is a piece of synthetic genetic material that contains part of the code for HTT. Once it’s introduced to a cell, the cell’s own molecular machines are used to process the synthetic genetic material. This creates a fragment of the synthetic genetic material that binds to the HTT message to lower it.

ALN-HTT02 targets the first bit of the HTT gene called “exon 1”. This is the part of the genetic message that contains the spelling error that causes HD. Researchers think that exon 1 could be the key to driving toxicity that builds up over time, damaging brain cells. Hopefully by specifically targeting this area, that damage will be lessened, or stopped altogether.

Same twinkle, different star

Other ongoing clinical trials are taking a similar approach – targeting HTT to lower levels. While there are similarities to these other trials, there are also some subtle differences.

Like most other trials, ALN-HTT02 is what we call “total HTT” lowering. That means it targets both copies of the HTT gene, the one from mom and the other from dad. This means that both regular HTT and the HTT with the spelling mistake are lowered. Other companies, like Wave Life Sciences and Vico Therapeutics, are running trials that specifically or preferentially target only the copy of HTT with the disease-causing spelling mistake.

There are currently quite a few HTT lowering drugs being tested in clinical trials, but the way the drugs actually lower HTT levels differs. Companies like Wave, Vico, and Roche are using something called an antisense oligonucleotide, or an ASO. This is a short piece of genetic material that binds the HTT message molecule to lower levels. So it doesn’t use the cell’s molecular machinery to produce the message-binding fragment the way that RNAi does.

Companies like PTC Therapeutics and Skyhawk Therapeutics are using something called splice modulators that target HTT to lower levels. These are small molecules taken as a pill that target the way the HTT message molecule is processed, causing it to be sent to the cell’s trash can, like the waste containment units on the International Space Station. (Clearly there are only so many relevant space analogies…)

Similar to Alnylam, uniQure is using an RNAi-based approach. The difference between uniQure and Alynlaym though is that uniQure’s drug AMT-130 is carried in a harmless virus and delivered via brain surgery. Conversely, Alynalym’s ALN-HTT02 isn’t encapsulated in a virus and is delivered via spinal injection.

Overall though, all of the drugs being tested by these companies have the same goal – lower the HTT message to hopefully reduce the toxic effects of the protein with the goal of slowing or stopping HD.

Details about the trial

ALN-HTT02 is being tested in Phase 1 trial. As with all Phase 1 trials, the primary goal of this study will be to determine if it is safe. Phase 1 trials are the first time that drugs developed in the lab are ever given to humans! Knowing that they’re safe and well tolerated by people is the first step in advancing them in the clinic.

They’ll also look at how well the drug targets HTT and how levels change in the CSF, the fluid that bathes the brain. They’ll use clinical tests to measure symptoms, but would need a larger trial with different measures to understand if ALN-HTT02 works to change clinical features of HD.

Up to 54 people with Stage 2 or early Stage 3 HD between the ages of 25 and 70 are being recruited for this trial. Recruitment age is notable here, as most trials exclude those over the age of 65.

Currently, recruitment is only open at two sites in the UK, but the study is also being initiated in Canada and recruitment in additional countries is expected to follow.

Participants will be given a single dose of ALN-HTT02 via spinal injection during the trial. A portion of the participants will be given a placebo, an injection that contains no active drug. After 12 months, those who received the placebo will be given the option to receive an injection that contains ALN-HTT02.

Guided by the stars

As our first trial participant steps boldly into a future unknown, guided by a company that is inspired by the stars, we hope this charts a new path for HD therapeutics. Phase 1 trial participants are incredibly brave, like astronauts walking courageously into the unknown.

We are profoundly grateful to these brave volunteers who help answer questions about new drugs, taking the first steps across the celestial bridge to a future without HD.

Here, we cover a report on Advanced Care Planning (ACP) prepared by clinical researchers at the University College London, reminding us there are things that can be done right now to improve the lives of people living with HD. Until we have drugs that slow the progression of HD, peace of mind can be some of the best medicine.

Facing the challenges of HD doesn’t have to be done alone

Anyone dealing with Huntington disease (HD) knows that it comes with many physical and mental challenges, and these can affect everyone differently. For some, symptoms may eventually call for life changes such as moving to a long-term care facility.

As the ability to make decisions can be lost in the later stages of HD, it can help to express care preferences early on to ensure that one’s wishes are respected. Because each person’s journey with HD is unique, individualized and tailored care plans are crucial.

The best way to navigate these challenges is by openly discussing preferences with loved ones and healthcare providers. To support this, a team of clinicians have published a guide to help individuals and families plan ahead, empowering people with HD to retain a sense of autonomy and extend their independence, even after they can no longer make decisions independently.

What is Advanced Care Planning?

ACP is a process that helps individuals reflect on, understand, and communicate their concerns, preferences, and wishes for future medical care. While thinking about future health decisions can feel overwhelming, many people find value in discussing these matters, once they are ready.

Although doctors might have concerns that these conversations may cause undue stress, studies have shown that many individuals appreciate the chance to talk about their future care, as long as it is done in a personalized and context-specific way.

ACP can empower people with HD and extend their autonomy by ensuring that their choices are respected even when they may no longer be able to communicate them. It also reassures healthcare providers that the care they deliver aligns with a person’s values and wishes. For caregivers, knowing a person’s preferences can reduce feelings of helplessness, as they can act in ways that truly honor the individual. Documenting these preferences can even support legal aspects of care, such as appointing a power of attorney.

A roadmap for Advanced Care Planning

Previous studies have found that ACP is often underutilized in clinical practice, despite its benefits. Doctors have to approach ACP with sensitivity, recognizing that not everyone may be ready or willing to discuss future care decisions, while balancing this sensitivity with the benefits gained from setting things up in advance.

Addressing these challenges, a team of clinical researchers at the Huntington’s Disease Centre at University College London have developed a system to offer ACP to all patients who express interest. Their approach ensures that each person with HD has the opportunity to initiate ACP discussions whenever they feel ready.

People don’t need to make every decision at once when beginning ACP. Initial conversations can focus on exploring goals and values, providing a foundation for more specific plans later on. ACP is an ongoing, flexible process that accommodates changing views–these discussions are documented and reviewed regularly to reflect any updates in a person’s preferences.

Putting it on the record

In the case of the Huntington’s Disease Centre at University College London, ACP can eventually lead to some key documents. An Advance Statement captures personal wishes and preferences for end-of-life care or when decision-making capacity is lost. While not legally binding, it guides future care decisions and can include things like religious beliefs, preferred care locations, opinions on certain treatments, and funeral preferences.

Another option is an Advance Decision to Refuse Treatment (ADRT), a legally binding document where an individual can specify refusal of certain treatments, like artificial ventilation or resuscitation, if they lose capacity.

A Lasting Power of Attorney (LPA) allows a trusted person to make decisions on the individual’s behalf if they become unable to do so themselves. Given that each country has different regulations, it is important to discuss options with a healthcare team. This report offers a framework for healthcare teams to support ACP, helping to personalize and honor people’s wishes across different countries and settings.

What can be done now?

A Chinese proverb goes, “The best time to plant a tree was 20 years ago. The second-best time is now.” Similarly, the report highlights that while many people delay starting ACP and can still benefit from it, starting earlier is also an option.

HD is a long journey, allowing people ample time to approach ACP thoughtfully, ensuring that they’re ready to engage in these discussions. Recognizing that decisions don’t have to be made all at once and progressing at a comfortable pace can offer peace of mind.

More resources on ACP

• HDA video on Advanced Care Planning
• Huntington’s Disease Society of America’s Family Guide Series
• Huntington Society of Canada’s guide on Future Planning