On 25th June 2024, Wave Life Sciences shared the results of their SELECT-HD clinical trial. This trial tested a therapy called WVE-003, designed to only lower the expanded, harmful form of the huntingtin (HTT) protein found in people with Huntington’s disease (HD). The data released today give positive updates on the safety of this therapy as well as how well it is working. Let’s get into it!

Allele selective lowering – what’s that about?

HTT lowering therapies are one of the leading approaches being tested in clinical trials at present, with the aim that they might slow or halt the progression of HD. As the name suggests, all of these therapies aim to reduce the amount of the harmful HTT protein that is made in people who have HD.

Since we all inherit two copies of every gene – one from Mom and one from Dad – nearly everyone who has HD would have inherited a regular copy of the HTT gene, and an expanded copy of the HTT gene, which has more than 36 “CAG” DNA letter repeats. The expanded HTT gene makes an expanded form of the HTT protein which is thought to be harmful. By reducing the amount of this harmful protein, scientists hope this might improve signs and symptoms of HD.

There are lots of different approaches scientists are taking to try and lower the levels of the HTT protein in people with HD. Many of those currently in the clinic actually target the levels of both regular and expanded HTT, so both forms of the protein are lowered. This is the case for tominersen, developed by Roche; AMT-130, developed by uniQure; and PTC-518, developed by PTC Therapeutics.

Wave are taking a different approach to these companies as their therapy only targets the expanded form of HTT. WVE-003 is an antisense oligonucleotide which exploits very specific single letter changes in the genetic code which are only found in the expanded HTT gene. The scientists at Wave think that this is important as the regular HTT protein has lots of important jobs to do in the cells of our bodies. So by maintaining the level of the regular protein, and reducing the levels only of the expanded HTT, their drug might be safer and have fewer side effects.

This approach does have some drawbacks. Everyone who is interested in participating in a trial for this drug first needs to have a genetic test. Only folks who have the specific letter changes targeted by the drug, termed SNP3, are then eligible for this therapy. This means that only a portion of people with HD might be treated with WVE-003 at present. Based on current genetic data, scientists estimate this to be about 40% of the patient population.

WVE-003 is given to people participating in the SELECT-HD trial by spinal tap. This is the same way tominersen, another antisense oligonucleotides or ASO therapy, is administered. This does pose a bit of an extra burden on people receiving this drug over say a drug in tablet form, as it must be administered by a specialist in a clinic with a particular set up.

How was SELECT-HD designed?

There were two different arms to the study: a single dose arm and a multi-dose arm. The single dose arm tested a single shot of the drug at various doses and then tracked participants over the course of almost 90 days. The multi-dose arm tested three repetitions of the lowest dose given at 8 week intervals and participants were tracked for almost 200 days. Both arms of the study had a placebo control group who received spinal taps which did not administer the drug.

The trial enrolled 45 people in the single dose arm and 20 people in the multi-dose arm. In both arms, the majority of participants are either Stage 2 or 3, with just two Stage 0 folks in the single dose arm, as defined by the HD International Staging System. All folks in the trial were monitored in clinical evaluations, had MRI scans of their brains, and gave spinal fluid samples at regular intervals.

What were the findings of the trial?

Safety first

The most important thing for a Phase 1 / 2 trial like this, is to make sure that the therapy being tested is safe. In the single dose arm of the study, the side effects experienced by folks receiving drug or placebo were approximately the same, suggesting that this dosing regime is safe and the drug was well tolerated. In the multi-dose arm, more mild and moderate side effects were observed in participants who received the drug. No serious adverse events were seen for either arm.

Another measurement the trial looked at is neurofilament light, often called NfL, a biomarker of brain health. In people with HD, NfL levels tend to rise over time, as higher levels of NfL generally indicate that the brain is getting more sick. In this trial, Wave found that folks treated with the drug largely had similar changes to their levels of NfL as those who received the placebo.

There were a few folks whose NfL levels rose above that of the placebo control group but this data was not broken down by HD stage or dosing regimen in the data presented. In such a small trial it is difficult to say exactly what this might mean, but it’s something Wave and others will be keeping an eye on as this program moves forward.

Overall, the news is largely positive with respect to safety. The data collected so far indicate that the WVE-003 is generally well tolerated with limited side effects at the doses tested.

Selective lowering of expanded HTT

The next critical thing to be assessed in this trial is whether WVE-003 does indeed selectively lower levels of the harmful, expanded HTT protein, whilst leaving the regular healthy protein intact. When looking at changes to the levels of expanded HTT in both the single and multi-dose arms of this trial, the protein levels were reduced in participants taking the drug compared to those taking placebo. In both arms, this effect was shown to be statistically significant which means we can be very confident in the changes to the levels of expanded HTT affected by this drug – good news!

In the single dose arm, whether the participant received 30, 60 or 90 mg of the drug didn’t seem to make too much difference, and they all led to a 20-30% reduction of expanded HTT compared to placebo. What is interesting to see is that this single shot of drug gave a sustained HTT lowering effect measured up to 90 days later, suggesting this drug sticks around and keeps working over a fairly long period of time. Similarly, in the multidose arm, a 40-50% reduction of expanded HTT levels was observed on Day 197 of the trial, a full 12 weeks after the last treatment with WVE-003. This kind of data is useful to help the scientists figure out what kind of dosing strategy they might use moving forward.

The data presented by Wave also show that levels of the normal HTT protein are largely unaffected, and possibly even increase a little bit with treatment. Again, this is good news. It shows that WVE-003 does seem to only be changing the levels of the expanded HTT protein, leaving regular HTT levels intact.

Other measures from the trial

This trial is not designed to measure whether WVE-003 impacts signs or symptoms of HD. Showing effective HTT lowering with a drug is very different from showing the drug is disease-modifying, a term used to describe a therapy which might slow or halt HD. Nonetheless, Wave conducted some exploratory studies in this trial to look at possible changes to brain structure as well as other clinical measurements.

MRI scans were taken of trial participants to measure how a region of the brain called the caudate changed over time. The caudate gets smaller over time in people with HD. People in the multidose arm of the trial seemed to maybe have slightly less change to the size of their caudate over time. Another region of the brain, called the ventricles, also tracked in size the same as the placebo group. Neither of these findings were statistically significant but if shown to hold true in a subsequent study, they could suggest WVE-003 is slowing down the death of cells in the brain. However, at present, the data are promising, but inconclusive.

The trial also assessed Total Motor Score (TMS), a clinical metric which assesses movement symptoms in people with HD. The higher the score, the more advanced the symptoms. Again, the data seem to point to a slight decrease in TMS for people in the trial receiving WVE-003 for just over six months, when compared to placebo. This would be good news if true, but we will need a much bigger study to figure this out for sure.

So what’s next for WVE-003?

Overall, the findings from the SELECT-HD trial are positive: the drug appears largely safe and works as intended to effectively lower just expanded HTT. This is the first time any drug has been shown to only impact the expanded harmful form of HTT, so a big milestone for the HD community. There are also some positive suggestions that the drug might be helping signs and symptoms of HD, but we need more data to be sure of that.

It should be noted that Phase 1 / 2 trials like this are, by design, very small: until we know the drug is safe, we don’t want to be testing it in lots of people. With this encouraging safety data in hand, the next step is to test this drug in a much larger cohort of people to find out whether WVE-003 might truly slow or halt the progression of HD.

Given the encouraging data, the team at Wave are thinking about a potential path for accelerated approval of WVE-003 for the treatment of HD. They have even started to draft the design of their next study which would be much larger (around 150 people) and focus on testing WVE-003 in people with stage 1 or 2 HD. We look forward to learning more from Wave in the coming months about their forthcoming study.

On June 20, 2024, we received an update from PTC Therapeutics about their ongoing trial, PIVOT-HD. PIVOT is testing PTC-518, a small molecule drug, taken as a pill, that lowers huntingtin (HTT) in people with Huntington’s disease (HD). Their most recent update shared data from people who had been on the drug for 12 months. Read on to learn what their new results tell us!

HTT lowering

Before we get into the juicy details of the data release, let’s cover some basics about why PTC is interested in lowering HTT and what they hope it will do.

We know that the genetic cause of HD is an expansion of the genetic code within the HTT gene. There’s an extra bit of genetic message that repeats the letters C, A, and G more times than it should. When someone has 40 or more CAG repeats in their HTT gene, they’ll go on to develop HD, unless researchers can find some way to intervene.

With such a conclusive test for determining if someone will develop HD, researchers have narrowed in on the HTT gene itself to develop potential treatments. We now have the technology to target HTT and reduce the amount of protein that’s produced. The thought is, with less of this nefarious player, progression of the disease itself would be slowed, or possibly stopped. Lowering HTT in the lab in animal models of HD has had success, and it’s now being tested in people.

PTC’s approach for lowering HTT

There are several companies testing HTT lowering in trials, and many of them are taking different approaches. We’ve covered ongoing HTT lowering trials from Roche, uniQure, and Wave Therapeutics. Currently, PTC Therapeutics is one of two companies testing a pill that can lower HTT in clinical trials. (The other is Skyhawk Therapeutics, who are advancing their HTT lowering small molecule SKY-0515.) PTC’s drug, PTC-518, works by rearranging the HTT message molecule.

Like stories, all genetic messages have a beginning, a middle, and an end. The end is the part of the code that tells molecules that the genetic story is over, like the last page in a storybook that reads, “The End”. PTC-518 works placing “The End” into the middle of the message. So rather than a logical story, the message is interrupted by “The End”. The cell realizes that the message doesn’t make any sense, and doesn’t bother making that protein.

After encouraging results in animal studies, PTC Therapeutics moved their drug into clinical trials. PIVOT-HD is a Phase 2 trial primarily designed to test the safety and tolerability of PTC-518. It tests 2 doses (5 mg and 10 mg) over the course of 12 months in people in Stage 2 and early Stage 3 of HD according to the HD-ISS.These are people who have begun to show clinical signs of HD and have just started showing difficulties with daily functioning. After the 12 months, all participants can continue taking the drug in an open label extension.

PIVOT-HD is a very small and relatively short trial, with just 32 people enrolled for the 12 month study – we don’t want to give too many folks the drug for too long until we know for sure it is safe. Although safety is one of the key goals of the study, lots of other measurements are taken to see how the drug might be working. These provide exciting hints but we really need a Phase 3 trial, which would test the drug in a lot more people for a longer timeframe, to see whether PTC-518 actually slows or halts HD.

What we learned a year ago

The last update we received about PTC-518 was exactly a year ago. That update released 12 week data from people with HD taking PTC-518. In the summer of 2023 we learned that PTC-518 did seem to lower HTT levels in blood. This may seem like an obvious point, but checking that the drug working as expected is important so that we know things are on the right track.

We also learned that PTC-518 was well tolerated overall, it got to the brain, and biomarker levels seemed to remain stable over the 12 week timeframe. The specific biomarker that was measured was neurofilament light (NfL), which measures the breakdown of brain cells, and is used as a measure of overall brain health. NfL steadily increases in people with HD as the disease progresses. NfL is becoming one of the field’s most reliable biomarkers to track HD progression. Last year’s data release suggested that PTC-518 seemed to be on the right path, so the study continued.

12 months later – biomarkers moving in the right direction!

People in the PIVOT-HD trial have now been taking PTC-518 for 12 months. The key objectives for the 12 month time point are to: 1) show that the drug is still getting to the brain and lowering HTT, 2) examine disease biomarkers, and 3) measure any changes in participant functionality. Cutting to the chase – things look positive for all of their 12 month objectives!

To determine if PTC-518 is lowering HTT in the brain, they take a sample of the cerebrospinal fluid (CSF) that bathes the brain. Since they can’t directly sample brain cells, this is the next best option to measure what’s going on with HTT levels in the brain. PTC reported that 5 mg of PTC-518 lowers HTT in the CSF by ~20%, and 10 mg by ~40%. Similar decreases were also seen in blood samples taken.

At 12 months, one of the biomarkers that they examined was NfL levels in blood. Natural history studies, like Enroll-HD, have shown us that NfL levels in blood typically increase by about 10-12% per year in people with Stage 2 HD.

In people taking PTC-518 for 12 months, the increase seemed to slow down and was 3% on 5 mg of PTC-518 and 4% in people taking 10 mg. These results show that taking PTC-518 does not seem to cause the brain any harm, and in fact, may even slow the damage to brain cells that occurs in HD.

12 months later – improved clinical scores!

For clinical metrics to determine how PTC-518 affects functionality of people with HD, they examined Total Motor Score (TMS), the Composite Unified Huntington’s Disease Rating Scale (cUHDRS), and Total Functional Capacity (TFC). What a mouthful! Let’s break down what they found.

The TMS scale measures movement symptoms in people with HD. For people taking PTC-518, there was a reduced progression on the TMS by over 70%! In the webcast update, PTC Therapeutics noted that the TMS is one of the most reliable metrics for determining disease progression in people with Stage 2 HD. So reducing progression of TMS is very encouraging as it suggests there might be a slowing of disease progression.

The cUHDRS is one of the most comprehensive clinical measures for assessing HD progression. It looks at changes in movement, thinking, behavior, and functioning. Typically, people with HD progress by 1 point on this scale per year. In people taking PTC-518, this progression seems to be cut in about half.

TFC measures the ability of a person to function on day-to-day tasks and looks at the ability of someone to hold a job, do their own finances, and carry out activities of daily living. In people taking PTC-518, this also looks to have moved in a positive direction. Together, these improvements in clinical scores suggest that taking PTC-518 could have a chance at slowing the progression of HD – very big news!

FDA hold lifted

While the most exciting updates were related to biomarkers and clinical scores (understandably!), PTC also looked at safety. At the end of the day, this Phase 2 trial is ultimately designed to test the safety and tolerability of PTC-518. Thankfully, all safety metrics suggest that PTC-518 is also checking this box. The most common symptoms reported were headache, falls, and flu-like symptoms, which were also reported in the placebo group.

Another important note, especially for the very astute readers, is that the FDA has lifted their hold on PTC-518. We previously reported that the FDA was pausing the PTC-518 clinical trial in the U.S. This wasn’t related to the safety of the drug, but rather the amount of data that had been produced to that point and shared with the FDA. The regulatory agency likes to see animal data extending past the time point being tested in the trial in people, and PTC only had data out to 3 months at that point. Excitingly, the new 12 month data has convinced the FDA to lift their previous hold in the U.S.

What’s next for PTC-518?

Overall, this is GOOD news! And we realize the HD community is very thirsty for a tall glass of good news at this point. However, we do need to temper expectations on all this excitement a bit. While these results are encouraging, they can’t be used to conclusively say if PTC-518 will be effective in modifying disease course of HD.

The ultimate goal of this Phase 2 trial is to work out if PTC-518 is safe enough to move into a larger Phase 3 study. The number of people in the trial is very small, at a total of 32 participants, so any conclusions drawn about the biomarker and clinical data need to be taken with a pinch of salt.

To conclusively determine if PTC-518 is effective in treating HD, a Phase 3 trial will need to be performed. Thankfully, PTC announced in their update that they’re in the midst of planning that Phase 3 trial. This trial will specifically be designed to test how well PTC-518 works in slowing or stopping progression of HD. They hope that this trial will serve to land them close to regulatory approval in what would be the first ever disease modifying treatment for HD, a drug for which we’re all eagerly waiting!

Sage Therapeutics released a press statement on June 11th that focuses on the main results of a study called SURVEYOR, aimed at studying cognition (thinking) in Huntinton’s disease (HD) and testing the safety of a drug called dalzanemdor (previously SAGE-718). Let’s talk about what we know and what’s next!

Amplifying nerve cell messages to improve thinking

Sage Therapeutics works on brain health across a variety of diseases. One of their areas of focus is cognition (thinking) and executive function – the ability to make decisions, plan, and act on new information. This area of research is particularly relevant to the HD field, because cognitive changes have a huge impact for people living with HD.

Sage has been working on an experimental therapy called dalzanemdor. The drug acts on NMDA receptors, which help to transmit chemical messages between nerve cells. There is an imbalance in this messenger system across many diseases, which causes changes in thinking and memory. Dalzanemdor is a type of drug designed to boost the messages passed by NMDA receptors – it’s a bit like giving your brain cells a megaphone.

Sage has applied this approach to HD, but also to diseases like Parkinson’s and Alzheimer’s, which also involve changes in executive function over time.

Treating the cognitive symptoms of HD

There are some challenges when developing drugs to treat the cognitive symptoms of HD. Since HD was traditionally defined as a movement disorder, and is still officially diagnosed once movement symptoms develop, clinical trials have historically been designed to show changes in movement symptoms.

Our understanding of HD has evolved more recently through important observational studies like PREDICT-HD, TRACK-HD, and Enroll-HD. Clinical researchers are also developing new tools to better measure subtle changes in thinking symptoms, and scientists are developing new biomarkers to follow changes over time and responses to drugs. This has led to a shift in how informed families, scientists, and medical professionals think about HD, but systemic change happens more slowly.

Newer types of cognitive tests can show that cognitive changes are happening over time in a measurable way in people with HD. One group of tests, developed about a decade ago, is called the Huntington’s disease cognitive assessment battery (HD-CAB). It involves separate tests around problem solving, matching, language, and other aspects of thought and executive function. More data in this realm will ultimately help to convince regulatory agencies (those that approve drugs, like the FDA in the U.S. and EMA in Europe), that a new treatment can move the needle for people with HD, especially when it comes to early changes in thinking.

The PERSPECTIVE Program and the SURVEYOR trial

Previously, Sage has conducted a number of (small) trials of dalzanemdor in healthy volunteers, people with HD, and people with Parkinson’s and Alzheimer’s. Currently, they are working on a series of trials that are designed both to confirm cognitive changes in HD and test the safety of their experimental therapy, dalzanemdor. The overall program is called PERSPECTIVE. It involves the following:

• The SURVEYOR study, a small, 28-day study to look at cognitive changes and safety.

• The DIMENSION study, a larger, 3-month study to look more closely at the safety of dalzanemdor and how the body processes the drug, as well as its potential impact on cognitive symptoms of HD.

• The PURVIEW study, a longer study known as an open-label extension, in which everyone involved receives the drug. Participants with HD in SURVEYOR and DIMENSION could choose to join this study and continue receiving dalzanemdor.

Recent news from the SURVEYOR study

The SURVEYOR study is the focus of the June 11th 2024 press release. The main goals of the study were to measure cognitive impairment in HD compared to healthy participants and to look at the safety of dalzanemdor in participants with HD. Sage also wanted to better understand the relationship between changes in thinking and changes in function in people with HD.

The study involved 40 people with HD and 29 people who did not have HD. The first step was to have all the participants take the HD-CAB cognitive tests, and compare those with and without HD. Next, those with HD were divided into two groups. One group took dalzanemdor (a daily pill) for 28 days, and the other took a placebo (a sugar pill). Before, during, and after the drug period and up to a few weeks later, the participants completed the HD-CAB again, had other physical and safety tests, and reported on side effects.

The press release from Sage shared a couple of key pieces of information about the trial:

1. The HD-CAB tests confirmed cognitive changes between people with and without HD. This is important because it will help advance trial metrics beyond those that currently focus on movements associated with HD, like chorea. Objective evidence for the impact that HD has on cognitive changes shows that these metrics can be used in a meaningful way for larger clinical trials.

2. Dalzanemdor overall appears to be safe and well tolerated. While some participants reported “mild to moderate” side effects because of the drug, no one left the trial because of those effects. However, we don’t yet know what those effects were. Additionally, there were no new safety issues reported. This is good news considering that dalzanemdor has been given to many people across several clinical trials.

3. There may have been a slight improvement in cognition for people on dalzanemdor, compared to those on placebo, as measured by some individual tests within the HD-CAB. However, it’s important to note that this short study wasn’t designed to test this, so no conclusions can be drawn at this time about the ability of dalzanemdor to treat HD symptoms. Sage will look more closely at the data to understand what this means, but the preliminary results support moving forward with the program.

More to come for dalzanemdor

Overall, Sage’s recent press release about the SURVEYOR trial suggests dalzanemdor is generally safe. And perhaps more importantly, it suggests we have a robust way to measure cognition in HD with the HD-CAB. This piece will be critical for moving drugs forward that are designed to treat cognitive issues associated with HD.

Sage recently shared at the 2024 HDSA Convention that recruitment for their PURVIEW open label extension study is ongoing. The DIMENSION study is still ongoing, though no longer recruiting, but Sage is expected to release data associated with that trial by the end of the year. Since this larger trial is specifically designed to test the ability of dalzanemdor to treat cognition in HD, we should have a good idea by the time we reach 2025 if dalzanemdor is effective for HD. Stay tuned!

Two separate research groups recently published work on the blood-brain barrier (BBB). You can think of the BBB like a bouncer that keeps the riffraff out of the VIP section that is your brain. One group advanced how the brain’s barrier is modeled in the lab using stem cells. Another group developed a harmless virus that can be delivered intravenously (by IV) and get past the brain’s barrier to deliver drugs. While Huntington’s disease (HD) wasn’t specifically studied in either publication, both can advance how we study HD in the lab and eventually treat the disease.

Your brain is a VIP

Your brain is like a VIP section – not everything floating around in your blood and body is allowed there. Bacteria and viruses that may make your stomach or lungs sick are kept out of the brain. Even certain medicines are excluded, like antibiotics.

The brain’s bouncer is called the blood-brain barrier, or BBB for short. The BBB is incredibly selective about what is allowed into our brains. It’s established very early during development, before we’re ever born. Because the brain is so delicate, the BBB ensures that only privileged molecules and substances can get in.

While many people envision a membrane that covers the outside of the brain, the BBB is actually created by the blood vessels that run throughout the brain. Think of velvet ropes that line streets with exclusive clubs rather than a glass dome that sits atop the city. The BBB is a tight meshwork of cells that line the brain’s blood vessels, carefully choosing which substances are allowed in and which are pumped along with each heartbeat, until they pass by the velvet ropes along the streets of the brain’s VIP entrance.

Pros and cons of the VIP bouncer

Being so selective about which substances are allowed in helps to keep our brains healthy. But it also poses an issue for developing medicines to treat brain diseases. The BBB works in our favor when it’s keeping out unwanted guests, but sometimes we want things in that get stopped at the gates!

Lots of people are working to create artificial BBB models in the lab. Modeling allows scientists to test how certain diseases affect the BBB, like if the barrier properties break down during the course of an illness. Models in dishes also let researchers test drugs before they go into people, and even before they’re tested in mice. Knowing if a drug will get stopped at the brain’s velvet ropes can go a long way in speeding up drug development.

Other researchers are working on ways to bypass the BBB for drug development. They’re devising ways to get drugs into the brain that would normally be kept out. This type of research is critical for improving the way drugs are given for brain diseases. Hopefully this could one day prevent the need for invasive delivery strategies, like brain surgery.

Velvet ropes, in a dish

A recent paper from the lab of Ziyuan Guo out of Cincinnati Children’s Hospital improved how researchers can model the BBB using stem cells. Stem cells have revolutionized the way scientists can study brain diseases. Because stem cells can be reprogrammed from skin samples and turned into brain cells in a dish, they allow researchers to study someone’s brain cells without a brain biopsy. A big win for people still using their brains!

While cells in the lab are typically grown flat on a dish, this doesn’t accurately represent the 3D nature of life. More recently, researchers have been growing nerve cells in 3D spheres, sometimes called organoids or mini-brains. While these 3D lab-grown structures can’t actually function like a brain, lacking the ability to transmit thoughts and feelings, they do give researchers a better idea of what happens when cells are grown in an environment that more closely matches the body.

Until now, these 3D spheres didn’t include the BBB. The Guo lab added to 3D brain models by including a network of blood vessels. These blood vessels adopted traits of the brain’s VIP bouncer, the BBB. While the authors of this paper didn’t test their new model using cells with HD, it opens the door for other researchers to do exactly that. This would allow them to learn how HD affects the BBB and test the ability of certain drugs to get past an HD BBB.

Party crashers, but the fun ones

While most of the time, we want the BBB to bounce out the riffraff, sometimes we want to let things in that the BBB keeps out – like potential HD treatments. Getting around the BBB is always the first challenge that drug makers have to consider when designing drugs for the brain, and for HD.

New work led by the lab of Ben Deverman at the Broad Institute of MIT and Harvard details their work on a special virus that can get its contents past the BBB into the brain. Ben has been a pioneer in this space, designing and improving different iterations of harmless viruses that can act as shuttles to deliver medicines to the brain.

This new virus works by attaching to a tag on cells that form the brain’s barrier. Once the harmless virus is attached, it can deliver its contents past the BBB. This is like slipping the bouncer some cash so you can sneak in some (fun!) party crashers. The team showed that their virus specifically recognizes brain cells of the human BBB. So even though there may be similar cells elsewhere in the body, the virus is specifically shuttled to the brain even when injected through an IV. It also means that their virus should work in humans, not just in laboratory mice.

Getting into the HD club

Having improved models for studying the BBB allows HD scientists to better understand how the disease affects the barrier, and consequently, what party crashers are mistakenly let in or kept out. It also is a powerful tool for determining drug doses. By first testing drugs on mini-brains in a dish, researchers can learn if the drug can get past the BBB. They can also learn how much drug is needed when the barrier is less selective, as seems to be the case for HD.

Developing and improving viruses that can carry medicines past the BBB can lead to a major leap forward in the way that drugs are delivered. In HD, uniQure is currently testing a virus that needs to be directly injected into the brain via surgery to deliver its contents. With newer iterations of viruses, the hope is that one day such gene therapies could be delivered by IV.

Together these studies advance studying the BBB in the lab and developing therapeutic tools for brain diseases. While neither paper specifically looked at HD, these types of approaches can easily be used for HD research – and they will be!

Huntingtin (HTT)-lowering and somatic expansion have been two of the hottest topics in Huntington’s disease (HD) research in the past decade. Recent work from a team at Massachusetts General Hospital detailed a serendipitous overlap between the two – certain HTT-lowering drugs can also help regulate the ongoing CAG repeat expansion. Seemingly, this could allow researchers to kill two birds with one stone using a single drug. But there’s more to this story.

CAG expansion causes toxicity

The CAG repeat within the HTT gene is the nefarious player leading to HD. This repeat can expand in some cells over time, which is the biological phenomenon known as somatic expansion. We’ve talked a lot about somatic expansion lately, which you can read more about in this recent article.

A current hypothesis for how the CAG expansion that causes HD makes people sick is a 2-step process. In this model, first, the inherited CAG length slowly expands in some cells over time. Second, once the CAG length reaches a threshold, toxicity in the cell is triggered, leading to death. This process doesn’t appear to occur in all cells, which is why some scientists think that only some cells, like brain cells, get sick and die in HD.

Targeting modifiers to control toxicity

In 2015, a large study was published by the Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium, a collective of scientists who pooled their ideas and resources to try and figure out why folks with the same CAG number might get symptoms of disease earlier or later in life. This study looked at the entire genetic makeup of over 4,000 people with HD. This study identified genes that can influence when symptoms of HD might begin. They dubbed the genes that alter age of onset “modifiers”, since they modify when someone will show signs of disease.

Lots of the modifier genes have links to how DNA is repaired and seem to influence expansion of the CAG repeat in the HD gene. A key idea that arose from the GeM-HD team and subsequent studies is that people who have changes in these modifiers that scientists predict will slow somatic expansion, seem to get HD later.

Some researchers think if we can control modifiers so that somatic expansion is slowed, we could prevent the second step in the process of HD – toxicity and cell death. For this reason, a lot of scientists have been studying modifier genes that control somatic expansion. One such group is led by Jim Gusella, who was one of the key people on the 2015 GeM-HD paper.

A recently published study, driven by Zach McLean from Jim’s group details something quite curious. They noticed that drugs that can lower the levels of HTT also have off-target effects on modifiers that control somatic instability.

HTT-lowering drugs

The HTT-lowering drugs tested in this current study are branaplam and risdiplam. These drugs are small molecules that can be taken orally. Both are a type of drug called splice modulators – they work by introducing a stop sign in the middle of the HTT message. The cell reads this stop sign, sees that it’s out of place and doesn’t make sense, and doesn’t bother turning the message into protein.

Your eyes may have widened when you saw the name branaplam. This is the same drug that was tested in the failed Phase 2 VIBRANT-HD trial by Novartis. We previously wrote about the halting of this trial for safety reasons.

Risdiplam is an agency-approved medication used for the treatment of spinal muscular atrophy (SMA). For that disease, it works by increasing the amounts of a protein that people with SMA are missing. Risdiplam, sold as Evrysdi, was approved by the FDA in August of 2020 and the European Medicines Agency (EMA) in March of 2021. Risdiplam has been approved for SMA in over 80 countries.

Interestingly, risdiplam also lowers HTT. That means that people have safely been taking a HTT-lowering drug for several years. However, those people don’t have HD, which could make a difference.

Ability to target doesn’t equal specificity

One thing to note about some oral splice modulators that lower HTT is that they’re not specific. They’re not designed to only and specifically target HTT. They work by including bits of message, like stop signs, for many different genes. These off-target effects have caused scientists to suspect that they could have unintended consequences.

To better understand these unintended consequences, the team added branaplam and risdiplam to cells in a dish. What they found was quite serendipitous! It turns out that branaplam and risdiplam both lower HTT and can also slow the rate of CAG expansion. This is because these drugs also target a gene called PMS1. PMS1 just so happens to be one of those modifiers that was identified in the GeM-HD study. It’s thought that the less PMS1 people have, the later they start to show symptoms of HD.

In cells in a dish, branaplam and risdiplam seem to slow HTT somatic expansion by including a premature stop sign in the PMS1 message. Because of this, the cell lowers the amounts of PMS1 in the same way that it lowers HTT. With less PMS1, there is less CAG expansion in HTT. Quite fortuitous!

Not all HTT-targeting splice modulators will work the same

The team behind this study note that there are differences between branaplam and risdiplam. While branaplam targets HTT more than PMS1, risdiplam does the opposite; risdiplam targets PMS1 more than HTT. Additionally, branaplam’s effects on somatic expansion seem to only occur through PMS1, but risdiplam has effects on expansion outside of PMS1.

So while both drugs target HTT and PMS1, they each have unique effects. This means they could also be targeting other genes differently. Adding to this complexity, these drugs work by recognizing spelling in the genetic code. Since we all have little changes in our genetic spelling that make us unique, they may work differently in different people. This study highlights the caution that needs to be taken because of this.

Another similar drug that wasn’t tested in this study is PTC-518. This drug works in a very similar way and is currently being tested in a Phase 2 trial by PTC Therapeutics. We can’t infer anything about PTC-518 from this new work because it wasn’t included in the current study. So we don’t know exactly how similar or different it is from branaplam or risdiplam.

Is PMS1 the new target to beat?

This new study bolsters PMS1 as a potential target to go after to treat HD to reduce somatic expansion. However researchers need to be cautious when targeting genes that control somatic expansion. These genes also regulate how our DNA is repaired, which is critical for maintaining integrity of our genetic sequence and preventing cancer.

Researchers also have to first work out how much to lower PMS1, or other genes that control somatic expansion. They need to find the sweet spot for lowering them enough to slow somatic expansion and provide therapeutic benefit. This study only assessed PMS1 in cells in a dish. This would have to move to mouse models next.

Does this mean a resurgence for branaplam?

You may be wondering if this new data means branaplam is coming back to clinical trials for HD. The short answer – no. While there are no immediate plans to test branaplam in the clinic for HD, other splice modulators are moving forward. We can still learn quite a bit about HTT lowering splice modulators that are moving forward by studying branaplam in the lab.

By studying branaplam and other drugs with similar mechanisms of action, we can get a better idea of how they’re similar and how they’re different. Knowing this, and studying which ones work better, can help identify other drugs with more specific effects on targets of choice. It can also help us understand how we can reduce unwanted side-effects.

So while this study identified a positive side-effect of a HTT-lowering splice modulator, that doesn’t mean it’s coming back to the clinic. However, knowing that HTT-lowering drugs can also target somatic expansion could inform ongoing and future trials using this class of drugs, perhaps leading to the development of drugs that target two birds with one stone.