HDBuzz

A recent paper from a group at UMass Chan Medical School, spearheaded by Dr. Daniel O’Reilly and led by Dr. Anastasia Khvorova, used genetic strategies to lower a protein other than huntingtin. This time the researchers went after a gene called MSH3. This is a gene that’s been getting a lot of attention in Huntington’s disease research as of late. So what’s all the hype about? And does this mean we’ve abandoned huntingtin lowering?

CAG stutter

One of the most interesting findings in HD research in the past several years has been something called “somatic instability,” which is also sometimes called “somatic expansion.” It refers to the perpetual expansion of the CAG repeat in “somatic” cells, or cells of the body. You can think of it like a molecular stutter of the CAGs in the huntingtin gene.

This ongoing expansion doesn’t happen in all cells though. The CAG repeats appear to be quite stable in certain cells and tissues, like blood. So that means if someone has a genetic test on their blood at the age of 18, the number of CAG repeats will very likely be the same when they’re 50, and remain unchanged throughout life. However, certain cells appear to gain CAG repeats throughout one’s life. Those cells tend to be the exact ones that are most vulnerable in HD – brain cells.

In 2003, Dr. Peggy Shelbourne carried out ground-breaking work using brain samples generously donated by people who had died from HD. Her work showed that specific areas of the brain have massive CAG expansions – up to 1000 CAG repeats! Those people certainly weren’t born with CAG repeats that big, which means that they were acquired over their lifetimes.

Interestingly, the brain region that had those massive CAG repeat expansions was also the most vulnerable to HD – an area called the striatum. For many years after this discovery, it wasn’t clear how these CAG expansions were happening or what it meant for HD progression.

What controls age of onset?

Then, in 2015, another ground-breaking paper was published, this time by the Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. This was a huge study that looked at the entire genetic makeup of over 4,000 people with HD. This gave the researchers lots and lots of data, the richest sample of genetic information that the world had ever had from individuals with the gene for HD.

The GeM-HD Consortium was interested in trying to find small genetic changes that may contribute to how early or late someone started to get symptoms of HD – genes we call “genetic modifiers.” Identifying variants that modify the age of symptom onset could uncover targets for therapeutics.

What the Gem-HD Consortium found knocked everyone’s socks off. The modifier genes that changed the age of symptom onset were almost all involved in a single biological process! Finding modifiers that clustered together like this was completely unexpected, but was also incredibly telling. The genes were involved in a process called DNA repair.

Molecular proofreaders

Proteins are the molecular machines that run our cells, and they are made using genetic messengers, RNA, which in turn are created from our DNA. Every time a new protein needs to be produced or refreshed, there’s an opportunity for mistakes in the process. DNA repair molecules are the proofreaders that check for mistakes. To ensure that there are no mistakes in that translation process from DNA to protein, these molecular proofreaders (aka DNA repair molecules) check that message.

Sometimes there are small genetic changes in DNA repair genes that cause them to function better or worse. Really great DNA repair genes do an excellent job proofreading the huntingtin gene, so no mistakes are made when the protein is made, and CAG repeat sizes remain stable. But DNA repair genes that are prone to making mistakes while proofreading may lose track of how many CAGs should be translated. This can mean that errors slip through, increasing the CAG repeat length over time.

The GeM-HD Consortium study showed that some people had tiny genetic differences that likely made their DNA repair genes better proofreaders, leading to later symptom onset. This finding finally added some perspective to Dr. Peggy Shelbourne’s work, linking DNA repair genes to the somatic expansion observed in the brains of people who had died from HD. Researchers remain very excited by this because it suggests that if we can control expansion of the CAG repeat, we may be able to delay HD symptom onset.

Targeting MSH3 controls CAG stutters

Scientists are now targeting DNA repair genes in various animals that model HD. One gene of interest is called MSH3. HDBuzz recently wrote about MSH3, its molecular partners, and their involvement in CAG expansion, which you can read about here. MSH3 proofreads the type of genetic structure that is created by CAG repeats. Scientists have been successful in blocking CAG repeat expansion by lowering levels of MSH3. They’ve used genetic methods similar to those used for lowering huntingtin.

Work led by Dr. Khvorova in a recent publication has now taken the next step, seeing if silencing MSH3 with a drug in mice that model HD has the same effect as genetic manipulation. Their drug delivers a small piece of genetic material that targets and silences MSH3 in the brain. Excitingly, they find that a single dose of their MSH3-targeting drug delivered to the brain can block CAG repeat expansion for up to 4 months in various models of HD mice!

While the potential for a drug that blocks somatic expansion is exciting, the authors acknowledge the need for more safety studies before their drugs targeting MSH3 can move into people. This new study shows that their drug only targets the MSH3 messenger molecule, sparing other genes. However, additional studies are needed to determine if other DNA repair genes are affected at the protein level. They also note the importance of long term safety studies to ensure their drugs aren’t having damaging effects on brain cells. Follow up experiments will also be needed to determine if reducing somatic instability improves HD-like symptoms in mice.

Expanding our targets

While other targets, like MSH3, are welcome in our conquest against HD, it doesn’t mean that huntingtin is being abandoned as a target. We, without doubt, know the single cause of HD lies with the huntingtin gene. So it still makes sense to design drugs that go after the root cause of the disease. In that vein, trials by Roche, Wave Life Sciences, and Vico Therapeutics testing their huntingtin-lowering drugs march on.

If experiments in mice that target MSH3 are successful though, having combinatorial therapies that go after the root cause while also blocking CAG repeat expansion could be the one-two punch needed for HD. We’ll no doubt be hearing lots more about DNA repair genes (molecular proofreaders) in HD research, and will likely see trials in the near future that target CAG expansions.

Genetic modifiers can influence when HD symptoms begin. Some of these genes encode for different types of molecular machines whose normal job is to repair our DNA when it is broken or damaged. A recently published study from scientists at Thomas Jefferson University uncovers details of how these molecular machines help repair damaged DNA structures that can occur in HD, revealing a complicated balancing act.

In this article, we explore what the scientists found, how this can help us understand how different modifiers work to alter the path of HD, and ways these new insights might guide development of new therapies.

Genetic modifiers of HD change the age at which symptoms appear

Every case of HD is caused by the same genetic change, the extension of a long stretch of the letters “CAG” in the Huntingtin gene. An intriguing mystery in HD research has been the fact that folks with the exact same CAG number can often start to get symptoms at very different ages.

To better understand why this is the case, in a number of studies now, scientists looked at DNA samples from thousands of people with HD and looked to see what small letter changes in their DNA code tallied with symptoms starting earlier or later in life.

The genes they identified in these studies are called genetic modifiers as they modify the course of HD, from what we might expect based on the CAG number alone. Interestingly, many of the genes identified in these modifier studies encode molecular machines (proteins) whose normal role in the cell is to repair DNA when it is broken or damaged.

Two such modifiers are FAN1 and MSH3, which are the focus of this research study. However, MSH3 doesn’t work on its own, it has to be together with another molecule called MSH2. One way to think about this is to consider how we make bread; yeast on its own is not enough to make the bread rise, it needs to be together with water and flour to be active and work properly. Similarly, MSH3 needs MSH2 to work, and the assembly they form together is called MutS Beta which is what Pluciennek and colleagues studied in their experiments.

DNA repair is a double-edged sword

The huntingtin gene contains a long string of “C-A-G” DNA letters repeating over and over. In people without HD this CAG number is usually less than 35, but in people with HD, the CAG number is more than 35.

Long strings of the CAG letters in DNA code can make strange shapes and structures with mismatches in the DNA helix, some of which are called extrusions. DNA damage repair machines recognise and work on these mismatches and extrusions, to try and restore them back to regular looking DNA strands. If cells fail to repair their DNA correctly, a number of bad things can happen, including the development of cancer.

Sometimes, these molecular machines are rather sloppy and can actually make things worse, adding in more CAGs into the huntingtin gene, a process called somatic expansion. In particular, MutS Beta has been shown to jump onto CAG extrusions and can make long CAG repeats even longer over time. On the other hand, FAN1 does a much better job of chopping out the damaged bits of DNA and ensuring the DNA code is faithfully maintained with no additional CAGs.

The battle of the molecular machines!

In this new study, Pluciennek and colleagues investigated how different molecular machines, FAN1 and MutS Beta, get recruited to these CAG extrusions and how they repair them.

First, the team showed that FAN1 can work on the CAG extrusions, but not on its own; other DNA repair proteins need to be present too and the chemical conditions have to be just right. One of the most important partners for FAN1 is a cool looking star-shaped protein called PCNA which clamps onto the DNA strand and helps other proteins, like FAN1, climb on too.

Next, the scientists showed that MutS Beta can push FAN1 off the DNA extrusions and stop it from working properly. Interestingly, the team found that the precise balance of MutS Beta and FAN1 was very important as to which molecular machine got to work on the extrusions. If there is more FAN1 than MutS Beta, the FAN1 wins and can get to work to start repairing damage on the DNA.

But what does this mean for HD research?

While understanding the precise minutia of how these molecular machines work may seem a million miles away from finding a cure for HD, the impact of this type of science can be very important for drug discovery.

The identification of genetic modifiers of HD gives scientists some of the best clues for how to make new medicines. These gene lists provide crucial insight about which proteins could be switched on or off, in the hope of delaying HD symptoms.

It’s because of thousands of HD patients and their families that donated DNA to research efforts that scientists were able to discover that both FAN1 and MutS Beta can influence the age of onset of HD. This new paper by Pluciennek and colleagues shines a light on some of the cool details of two of these modifiers, and the delicate balancing act between FAN1 and MutS Beta during repair of CAG extrusions.

Studies like this will in turn help drug hunters focused on these pathways to conduct better experiments as they attempt to refine and develop new drugs for HD.

The vast majority of people with Huntington’s disease experience movement symptoms known as chorea. Valbenazine, also known as INGREZZA, has recently been approved by the United States Food and Drug Administration (FDA), allowing doctors in the USA to prescribe this medicine for Huntington’s disease (HD) chorea. In this article we go through the key points of this announcement and what it means for HD family members.

Background on valbenazine

INGREZZA is the trade name of valbenazine, a drug developed by the company Neurocrine Biosciences. It works similarly to tetrabenazine and deutetrabenazine (Austedo), drugs commonly prescribed to help control the involuntary twitching or jerking movements that people with HD experience.

Treatment with these drugs blocks a protein called VMAT2 that is responsible for packaging certain types of chemicals that brain cells use to communicate. VMAT2 helps to put the chemical messenger dopamine (among others) into bubbles that cross from cell to cell. Dopamine plays a role in the movement circuits of our brain, and it’s thought that blocking VMAT2 can quiet down the cross-talk. Exactly why this improves irregular and involuntary movements is not clear, but these drugs work for many people with HD chorea.

Valbenazine has been approved in the USA since 2017 for the treatment of tardive dyskinesia (TD), involuntary movements that stem from use of medications known as neuroleptics or antipsychotics. Antipsychotics are taken by many people worldwide to treat the psychiatric and behavioral symptoms of bipolar disorder, schizophrenia, and other diseases (including HD). After using these medications for a long time, some people develop TD, which often involves twitches in the muscles of the mouth and face. Valbenazine (INGREZZA) can be helpful to control those involuntary movements, so Neurocrine began studying whether it could also be effective for chorea caused by Huntington’s disease.

Testing and approval of valbenazine for people with HD

Because valbenazine had been tested in people with TD and prescribed for several years, we already knew that it was safe in humans. However, a clinical trial was still needed to understand if it could effectively treat Huntington’s disease chorea. In collaboration with the Huntington Study Group, Neurocrine ran a Phase 3 clinical trial called KINECT-HD, beginning in 2020. 128 people participated; half were given once-a-day capsules of valbenazine for 12 weeks, and half took a placebo (a pill with no drug). Participants were invited to continue in a longer, ongoing trial called KINECT-HD2, in which everyone receives valbenazine.

KINECT-HD was a success, reaching its primary endpoint, meaning that valbenazine decreased the severity of HD chorea compared to the placebo. It improved the Total Maximal Chorea (TMC) score, a metric clinicians use to monitor chorea symptoms. That “top-line” result was made public in 2021, and since then Neurocrine has continued its studies, analyzing, presenting, and preparing the data from the two HD trials of valbenazine. They presented it to the FDA in December of 2022, and on August 18th 2023, Neurocrine announced that INGREZZA had been FDA approved, meaning that it can now be officially prescribed to people in the USA to treat HD chorea.

It can take some time for drugs to go from approval to launch to common prescription, especially for a rare disease. Once they get the green light, companies can devote more energy to educating medical professionals and the community about a new therapy. By the end of September, awareness among US doctors is likely to have ramped up, but there are already resources for family members to learn more.

What else do we know about valbenazine?

It is important to note that INGREZZA does not slow or halt the progression of HD. However, taking medication to improve involuntary movements and other HD symptoms can have a major impact on quality of life. For some people with HD and their loved ones, chorea isn’t bothersome, but for others, it can interfere with day-to-day activities and even safety, and treatment can make a big difference.

INGREZZA is taken as a single capsule which is swallowed once a day. This is a positive feature of this medication, as for many people with HD, remembering to take a complex array of tablets throughout the course of the day can be difficult. Similar to valbenazine’s “chemical cousins,” there may be ways to modify delivery for people who have swallowing issues or use a feeding tube.
The dose can also be altered over time depending on how well someone responds to the drug and any side effects they might experience. Neurocrine hopes that this means side effects will be more manageable for a larger number of people taking this medication compared to other VMAT2 targeting drugs.

Balancing side effects, cost, and other factors

Like all drugs, valbenazine has some downsides. VMAT2 inhibitors have common side effects, like sleepiness. They can also have very serious side effects which include depression as well as suicidal thoughts or actions. Therefore, it is very important that people with HD who are considering INGREZZA accurately relay their past medical history to their healthcare provider and alert them as soon as possible if they experience any side effects.

In addition to VMAT2 inhibitors, there are a variety of drugs that doctors prescribe to treat chorea alongside other symptoms. For example, some antipsychotics used for mental health and behavior in HD can also have the effect of calming movements. There are also considerations around cost, especially in countries like the US, where insurance coverage can differ or be absent entirely due to a lack of universal healthcare. Companies like Neurocrine with new drugs on the market aim to alleviate this issue through different channels including assistance programs.

It should be noted that a once-daily version of deutetrabenazine (Austedo XR) was introduced by Teva in the USA this May, which is likely not a coincidence – companies with drugs that treat the same disorder will often tailor their research strategies around public knowledge, like another company’s impending FDA approval. The reasons for prescribing or taking one medication over another diverge from doctor to doctor and patient to patient. Everyone responds to drugs differently, and coverage and approvals vary wildly from place to place.

Take home message

While we wait for treatments that can slow disease progression, drugs like INGREZZA can improve quality of life, and it is a welcome addition to our arsenal of tools to battle HD. The approval of valbenazine in the USA is good news for the HD community. It raises public awareness of Huntington’s disease, and creates healthy competition to keep costs low. Most importantly, the availability of multiple treatments for chorea increases choice for HD family members in their healthcare decisions.

That said, outside of the USA, only study participants of KINECT-HD trials will be able to get access to this drug, and Neurocrine has not yet confirmed their commitment to seeking regulatory approval in other countries. They do plan to address the community directly in the near future via a public webinar aimed at HD family members. HDBuzz hopes that all companies developing HD therapies will work towards global access to drugs that can improve quality of life for people with HD.

When you lose something, an easy solution can be to just replace it. But what if the something you’ve lost are cells in the brain? Can they simply be replaced? Some researchers have been working toward this for Huntington’s disease (HD) by injecting new cells into the brains of animal models. A recent publication that has garnered a lot of press looked at the effects of replacing cells in the brains of mice that model HD – with surprising findings. The work draws attention to a less well-known type of cell and could inform future studies.

The brain’s supporting cast

Neurons are one of many types of cells in the brain. They get a lot of attention in Huntington’s disease (HD), and rightfully so! Neurons are the cell type most affected by HD. They’re the ones that are shaped like a tree, with branches coming out the top, a long trunk, and roots at the bottom. This cell type transmits signals to help us think, feel, and move. We see neurons die over time in HD. But they’re not the only type of cell in the brain affected by HD.

Researchers are increasingly finding that other types of cells in the brain, called “glia”, contribute to HD. Glia are a support system for neurons in the brain, providing them with an environment that keeps them happy. We recently wrote about new findings related to the contribution of glia to HD.

Replace and improve

Back in 2016, researchers from New York and Copenhagen, Denmark did a series of experiments in which they replaced glia in the brains of mice that model HD. Excitingly, they showed that this improved the ability of the mice to function and delayed the onset of their HD-like symptoms. So even though glia aren’t the primary cell type affected by HD, replacing HD glia with healthy cells – ones that don’t carry the disease-causing mutation – led to a big improvement in mice that model HD!

Younger crowd taking over

Those same researchers, led by Dr. Steve Goldman, recently published follow up experiments to see if the same is true in human cells. But there was a twist – the experiments with human cells were done entirely in the brains of mice! They did this by creating a “chimera” – a single organism made from two genetically distinct populations. In this case, the brains of these mice had human glia containing the gene that causes HD.

The researchers wanted to know if they could replace the human HD-affected glia in the brains of mice by injecting unaffected glia. And they found that they could! When human glia without the mutation that causes HD were injected into the brain, they outcompeted the local human glia that had HD. The new healthy glia population took over, ousting the HD glia.

Out with the old

But did the new glia take over in the mouse brain because they were healthy, while the resident glia had HD? Apparently not! The researchers also found the same results in the control counterparts for this experiment. In a surprise twist, the injected glia also replaced local glia that didn’t have HD. This suggests the replacement wasn’t related to the glia being sick with HD, but rather because the existing cells were older. The researchers found that the newly implanted glia were replacing the native glia simply because they were younger than the native cells.

The authors went on to perform molecular experiments to find out exactly what was going on. It turns out the new, young glia were just better at dividing, making it easier for them to take up space. Their presence also started a biological chain reaction that caused the older glia to die off. So it was really a one-two punch that allowed the young glia to outcompete the old – they were better at dividing, and they triggered the death of older glia.

What’s next?

The overall findings suggest that age was the primary factor for new glia taking over rather than HD itself. Even still, findings from this paper can help inform directions for HD research, particularly in relation to potential cell replacement therapies, like stem cell transplants.

Replacing lost cells could be beneficial for diseases like HD where we see a loss of brain cells that serve important roles in mood, movement, and behavior. However, we want to make sure the treatment itself doesn’t reduce the brain cell population that remains. In this publication, introducing new glia caused the widespread loss of native cells. While it may be good to have new glia, it could also be detrimental to lose glia that are already there.

Another point of caution for using this type of therapeutic approach for HD is that glia were replacing glia, not necessarily neurons. Since neurons are the primary cell type lost in HD, an effective treatment that replaces cells would also ideally increase the population of neurons in the brain. Future work should explore how a new and improved population of glia affects and influences neurons in the brain.

Researchers will also want to make sure that any treatment, whether it uses cell replacement or not, actually improves the symptoms of HD. Work described in this paper didn’t examine the behavior or overall health of the mice that model HD. So while they may have revamped their brains, we’re still not sure what, if any, effect this has on HD-like symptoms.

Overall, this paper brought us some cool science that shows that, in the case of human glia cell injections, cell replacement in the brain is possible. In the end, it was age that mattered more than disease. We’ll have to stay tuned to see if the fresh, young human glia improve the HD-like symptoms in mice, like the mouse glia did in the researchers’ 2016 paper.

On 21st June, both PTC Therapeutics and uniQure shared data from their respective clinical trials, both testing huntingtin-lowering as an approach to treat HD, but with different types of therapies. In this article we go through the data they each presented, what it all means and the next steps the companies will be taking.

Treating HD with huntingtin-lowering

Both PTC and uniQure’s approaches to treating Huntington’s disease draw on the basics of HD genetics. A gene called huntingtin becomes expanded, leading to an extra-long protein that is thought to damage brain cells. Dozens of pharmaceutical and biotech companies are working on therapies that try to decrease the amount of that long, faulty huntingtin protein, an approach known as huntingtin lowering. PTC and uniQure are two such companies which have ongoing clinical trials in this area although their approaches are quite different.

PTC: getting at genes by popping a pill?

Most huntingtin lowering drugs in development are aimed at the middle-man between the gene and the protein, a genetic messenger known as RNA. PTC’s drug, PTC-518, performs an intricate cut-and-paste step, so that now the middle-man is holding a stop sign. The cell’s machinery sees the stop sign and decides not to move forward with making the protein.

This type of drug is known as a splice modulator, and one major benefit of this approach is that it can be given by mouth. Based on data from animals we know that PTC-518 taken orally can reach many parts of brain and body without invasive procedures like a spinal injection or a brain surgery. PTC-518 targets both the expanded and regular forms of huntingtin so both versions of the protein are lowered following treatment with this drug.

uniQure: one shot therapy to lower huntingtin, forever?

We’ve written several times before about uniQure’s unique approach to treating HD – the first of its kind. Gene therapies create a fundamental change to a person’s genetics to try and treat or cure a disease. Although still targeting the genetic message molecule, uniQure’s approach with their drug, AMT-130, is quite different to PTC’s.

AMT-130 is a piece of man-made genetic material, packaged inside an empty, harmless virus, delivered to the deep parts of the brain via a surgery. The idea is that this one-time procedure will allow the therapy to spread into many brain cells, setting up little factories that continue to produce a genetic “antidote” for many years to come. This should prevent the huntingtin RNA message from producing so much huntingtin protein, in each brain cell that AMT-130 enters.

Updates from PTC

A pivot for PIVOT-HD

HDBuzz reported on the start as well as updates to the ongoing trial of PTC-518, so let’s recap. This roughly 3-month trial was planned to involve around 160 participants at sites throughout the US, Canada, Europe, and Australia. Participants would receive placebo or PTC-518 by mouth at a few different doses (5 mg or 10 mg), and visit study sites for evaluations related to safety, side effects, huntingtin levels in blood, and tests related to their movement, mood, and thinking abilities. Those who completed the study would have the option to enroll in an “open-label extension,” in which everyone receives PTC-518 and continues to have study visits periodically.

One unique aspect of this trial is that it was designed for people with very early signs of HD, potentially even before they are experiencing movement symptoms or major changes in their day-to-day abilities. But partway through, PTC announced a few changes. They decided to expand the study to include people with measurable movement symptoms and early difficulties with daily tasks, sometimes known as “manifest HD”. Additionally, they extended the drug trial period from 3 months to 12 months. Because of this lengthening, there were delays in getting approval to move forward from the USA’s Federal Drug Administration, so recruitment for the trial was paused in the United States but continued as planned elsewhere. We wrote more about these announcements in November of 2022.

Data shared from PIVOT-HD shows PTC-518 lowers huntingtin levels

At the same time that PTC shared these changes to the trial, they announced that they’d share data from the first, 3-month portion of the study in the first half of 2023. A helpful tidbit: when a company announces their intention to deliver news during a particular time window, it’s usually the case that they share in the latest part of that time window – in this case, late June 2023.

PTC held a meeting with investors and issued a statement sharing their findings from the PIVOT-HD trial to date. One of the key findings at this stage was huntingtin levels were reduced in people who received PTC-518, and that the group who received a higher dose of the drug, had a greater reduction in their huntingtin levels. This is positive news as it suggests that the effect on huntingtin levels is dose-dependent, i.e. the more drug you give, the greater the effect, so this will help guide future dosing strategies if this might need tweaking in subsequent phases of clinical testing.

The trial measured levels both of the genetic message and of the huntingtin protein molecule itself in blood samples from the participants. There was good agreement between these two measures which is what we would expect based on how the drug works by targeting the genetic message so this was an encouraging finding.

PTC-518 can move from the blood into the central nervous system

One common worry with drugs which are taken by mouth that are designed to treat brain disorders, is that it can be very difficult for these molecules to pass from the bloodstream to the central nervous system.
In the study data presented, PTC measured levels of the drug in the bloodstream and spinal fluid and showed that PTC-518 does indeed make its way into the spinal fluid that surrounds the brain. The balance of drug levels in the blood and spinal fluid was fairly equal which is good news although it doesn’t give us information about whether the drug is able to get to the regions of the brain important in HD, such as the striatum, that PTC hope to target.

Treatment with PTC-518 appears to be well tolerated

Following the disappointing news from the Novartis VIBRANT-HD clinical trial which tested branaplam, a drug similar to PTC-518, which was halted due to bad side effects, everyone was very keen to learn how the PIVOT-HD trial might fare in terms of safety.

The data PTC presented from this small study was encouraging, showing that no treatment-related serious adverse events occurred and that any minor side effects experienced by participants in the trial (e.g. headache) were found at equal levels in both treatment groups as well as the placebo group, suggesting they’re not related to the drug itself.

Another readout of brain health are the levels of a protein called NfL. Levels of NfL increase when the brain is sick and it is well documented that NfL levels increase in people with HD over time as their disease progresses. PTC measured the levels of NfL in the spinal fluid of trial participants and saw small decreases for people who were treated with each dose of the drug compared to placebo. This is good news as other huntingtin-lowering trials have actually seen spikes or increased levels of NfL. However, the data are fairly variable, and only come from a short duration of treatment, so it’s not yet clear how significant this decrease is until more people are treated for longer.

Updates from uniQure

The HD-Gene-TRX trials so far

Given the novelty of HD gene therapy, current clinical trials of AMT-130 are in the early stages and are focused on ensuring safety. Across multiple small trials in the USA and Europe, only around 40 people with early HD symptoms have undergone the surgery, up to 26 in the USA and 15 in Europe.

A low and a high dose of AMT-130 are being tested in this trial. A few of those were “sham” surgeries, with no drug delivered, as a comparison group. Participants are very carefully monitored for a couple of weeks after the surgery, and then followed closely for a year with less frequent visits up to 5 years. They go to study visits and complete blood work, neurological exams, and assessments of their HD, like thinking and movement tests.

Last June 2022, uniQure shared some early data from the first cohort of ten people in the low-dose group – they didn’t observe any major safety issues, and huntingtin levels, though only measurable in a very small group, were trending down.

Then, in August, some dangerous neurological side effects were reported following 3 of the high dose surgeries, leading to a short pause. These were resolved for all the participants, such that in November, new surgeries could again move forward with some extra monitoring in place.

What we learned today about AMT-130

Since last November, we’ve been waiting for more data from uniQure about the ongoing trial of AMT-130, expected in June. This release involves two years of data from the first, low-dose cohort of ten, and one year of data from the second, high dose cohort of sixteen US participants.

The good news from uniQure is that the NfL spike which occurs after the surgery to deliver the drug does seem to return close to baseline by about 18 months and no further increases are observed. The change in NfL levels compared to controls in the long run are not really clear just yet though. No significant changes were observed in total brain volume either which is positive.

In terms of symptoms, uniQure reported several measurements made in treated patients. This includes a set of assessments that takes into account many aspects of a persons movement, called the total motor score. Compared to the expected trajectory of these changes in movements, patients treated with AMT-130 seemed to be doing a little bit better over 18 months.

A measure called total functional capacity encompasses how people are doing in their tasks of daily life. Patients treated with AMT-130 appeared to show a stabilization of this measurement, which includes milestones such as continued work, ability to do household finances, etc. Consistent with that, formal tests of people’s ability to think flexibly also seemed to stabilize, compared to the expected trajectory for HD patients.

However, some of the data shared by uniQure are a bit confusing to make sense of. When they looked at levels of huntingtin in the spinal fluid, this was decreased in the low dose cohort but increased in the high dose cohort when looking at the cohort averages. This could be due to a highly noisy dataset across just a small number of participants, or perhaps some technical issue with the huntingtin level measurements, but that isn’t known just yet.

It’s worth remembering that with AMT-130, in particular, that extreme caution is required, and we in the field are straddling a tricky divide. On the one hand, we want to have larger numbers of people treated with AMT-130 so that we can see robust changes in the measurements being done on the subjects. But remember, this is a very novel gene therapy with a virus that cannot be shut off! And so uniQure and regulators have to walk a tightrope between enrolling enough people to generate robust data and patient safety.

The bottom line and what’s next

Following many disappointing trial outcomes from other companies testing huntingtin-lowering therapies in the clinic, it’s encouraging to see progress from two different approaches.

The data presented by PTC are broadly encouraging and show that the drug appears to be working to lower huntingtin levels, as intended, with minimal side effects. It’s important to note that this trial is currently very small – data from a total of just 22 people were reported in this particular update. How these findings might change in a study with a larger cohort remains to be seen. We also don’t yet know if the observed huntingtin-lowering will lead to a halting or slowing of symptoms in people with HD. PTC stated in this update that they will use the data presented in this update to argue to the FDA for the trial enrollment to be recommenced at the US sites where it was previously paused. They will also now continue enrollment in their European sites.

Whilst the uniQure data are not necessarily discouraging, they are frankly not clear cut either. This is often the case with small trials where variability is high between participants so trying to work out if a drug is having a desired effect can be challenging. uniQure plan to continue recruitment of their trial in both the US and Europe, the former of which will also investigate treatment of AMT-130 and steroids at the same time, to hopefully reduce some of the side effects they have seen with this drug.

We will keep you posted on all fronts as things develop.