HDBuzz

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.

Welcome to the third and final day of HD science, live from Dubrovnik, Croatia!

Our Twitter updates are compiled below. Continue to follow live updates for the final day of the conference with the hashtag #HDTC2023.
Check out our coverage of Day 1 here: https://en.hdbuzz.net/343 and day 2 here: https://en.hdbuzz.net/344.

Biomarkers

This morning’s session will focus on biomarkers, things we can measure to get a picture of a person’s health or their response to a drug. Different types of biomarker measurements might focus on predicting onset, monitoring a person’s HD, or checking drug safety. As we heard last night, NfL levels can help us get a better picture of brain health, but there are other proteins also being studied for this purpose.

HD Clarity

First up is Dr. Niels Henning Skotte from the University of Copenhagen who will be telling us about his work studying biomarkers from HD patient samples. He uses samples from a large spinal fluid collection study called HDClarity https://hdclarity.net/. Niels is first talking about the importance of “quality control” in the spinal fluid samples – tests they do to ensure that they are uncontaminated and properly stored. He also presented some statistics to show how many are needed to answer different types of questions about HD. Many of the proteins which are potential biomarkers are only present in tiny amounts in patient samples.

There are special graphs called “volcano plots” that allow researchers to see which proteins found in spinal fluid differ the most between people with and without the HD gene. Some of the potential biomarkers even show differences between gene-negative and pre-symptomatic gene carriers, which could be helpful in the hunt for treatments that could be administered before symptom onset. When certain protein levels differ between people with and without HD in both blood and spinal fluid, researchers look more closely at them to understand how, and possibly why, their levels shift at different stages of HD. When a protein change is consistent across many people, then it may be considered as a useful biomarker of HD. The role of different proteins in the body is considered, and how they interact with one another, which can give us clues about biological processes affected in HD.

In this age of artificial intelligence or AI, scientists can feed large datasets to computer systems and ask them to consider complex sets of factors to determine which proteins would make the best biomarkers. Niels is using machine learning approaches to do just this. In the future, measuring changes across groups of many proteins prior to the development of symptoms might be used to better track exactly where a person is in disease progression or to decide when they should begin an HD treatment.

Fat molecules as a biomarker for HD

The next speaker is Dr. William Griffiths from Swansea University who will be telling us about how cholesterol and other fat molecules could be used as possible biomarkers for HD. William reminds us that about 25% of the body’s cholesterol is in the brain, and a lot of this is made on site. Some types are able to exit the brain, so we might be able to measure their levels to gain an understanding of brain health. Disruption of the cholesterol-making process and changes in levels of cholesterol have been observed in HD, and in fact there are drug development efforts focused on correcting these changes.

William’s work focuses on measuring the differences between cholesterol levels in people with HD and without HD to see if these molecules could be used as a biomarker. Measuring and analyzing cholesterols requires fancy biochemistry techniques. The specific molecules they are looking for are hard to detect even with top end equipment available, so they had to tweak the system using a cool technique called “click chemistry”. This boosts the signal of the cholesterol from grass-size to tree-size, as William explains. William’s group has found that one form of cholesterol, which is only generated in neurons, is diminished in blood samples from HD patients, making it a potential biomarker.

Somatic instability as a biomarker of HD

Up now is Dr. Darren Monckton from the University of Glasgow who will be telling us about his group’s research on whether some aspects of somatic instability could be a biomarker of HD.

Scientists can measure the levels of somatic instability of the CAG repeat part of the HD gene in all types of different patient samples. Darren uses fancy sequencing techniques to do this as accurately as possible in the DNA from blood donated by people with HD. The Monckton group has mapped out how the expansion of CAG repeats over time (somatic instability) changes at different rates in blood samples depending on the age of the person and their original CAG number.

They have also looked at blood samples from the same individual collected 7 years apart. This gives clues about how somatic instability increases in each person over time. Even over this huge timeframe, the changes are generally very subtle and happen slowly. Being able to measure these small changes is very important, because potential drugs which will alter the rate of somatic instability will also likely have very subtle effects.

These techniques will probably prove to be very useful in some of the clinical trials in the pipeline. HD is not the only disease that has somatic instability, and the techniques in development by the Monckton lab for measuring subtle DNA changes over time will be useful to apply to the study of other genetic diseases and corresponding treatments outside the field of HD.

Tracking Huntington with PET tracing

We are back from our coffee break and now we will be hearing from Dr. Mette Skinbjerg about a huntingtin PET tracer which allows tracking of the toxic clumps of protein in the brain which accumulate over time. We wrote about this previously here. Without a tracer, the only way we can see how huntingtin protein accumulates in the human brain is to look at samples after someone has died. Tracers are a safe way to look in living people and could be a great way to see how drugs might be working.

CHDI has been working with academic partners to make a tracer for HD which they have extensively characterised in many different HD animal models including mice and monkeys which allows tracking of the build up of protein clumps over time. Now they are moving beyond the animal models to test their tracer in people. Tracers are labelled with radioactivity so scientists can measure where they stick to the target – in this case the clumps. It’s important tracers leave the body after dosing so exposure to radioactivity is in the safe range.

Although the tracer seems to be safe to use in people, unfortunately the signal in the brain didn’t track with what the scientists expected. This is disappointing but this program taught us a lot about making a tracer for HD which can be used for making better ones in the future. Now the team is working on a new generation of tracers which they are hoping will perform much better. Things are progressing forward in the lab with lots of testing in HD animals so hopefully this next round will work better.

Biomarkers and machine learning

The next speaker is Dr. Peter Wijeratne from the University of Sussex. Peter’s group aims to use biomarkers and machine learning to characterise and predict HD progression in individuals. Very cool!

As researchers continue to identify all sorts of different biomarkers from biofluids, imaging, etc, many biomarkers for one person could be combined for better predictions. But combining and understanding all of this data together is hard for people to do, this is where AI can help us out!

Peter used a fun ChatGPT example to explain machine learning – an algorithm that can adapt and make inferences from patterns in data. He showed how quickly these systems can learn new information and make informed decisions – very cool! To “train” the AI system, you need lots and lots of high quality training data where scientists already know the answers. The AI system can then learn to spot patterns in this data, enabling it to spot similar and related patterns in test data where the answers aren’t known yet.

Peter’s group are looking at brain imaging data from three different studies which looked at how different brain structures change in HD over time. Training AI on these complex and rich datasets, they hope that they will be able to make robust predictions of disease. Turns out, good predictions for disease onset could be made, and the results agreed well with the HD-ISS staging system. They hope this will prove useful for making predictions at the individual level in the future.

HTT levels and tominersen

In the next talk, Dr. Blair Leavitt, a clinician/researcher from the University of British Columbia, will speak about his study of samples from the GENERATION HD1 trial of tominersen. He is diving deeper into how huntingtin levels change with tominersen treatment.

Blair starts by thanking HD family members who so generously and selflessly share biological samples with scientists to create a biobank resource. This is invaluable to scientists to understand HD and how drugs may change the path of this disease. Blair is focusing on one individual in particular, who felt very strongly about donating his brain when he passed. A rich data set and many samples are available from the tominersen trials he participated in, along with his brain tissue, which offers a rare window into drug effects.

Looking at the brain, scientists on Blair’s team were able to measure levels of the drug in different regions and compare this to the exposure levels predicted by earlier monkey experiments. Generally these showed the predictions were pretty good. Next they looked at huntingtin levels in different regions of the brain and how these compare with control brains. As expected for a huntingtin-lowering treatment, the levels in this individual were much lower than in controls. Disappointingly, the levels of huntingtin in the spinal fluid were too low to be quantified for this individual. This means we don’t know how well the brain and spinal fluid levels of huntingtin correlate, for this trial participant at least.

It’s hard to overstate how precious this tissue is for scientists to be able to truly examine in depth how a treatment has affected the brain. Collaborators in the audience will ask additional questions using this tissue so generously donated by this one trial participant.

Clinical trials

After a lunch break, we are back for the last scientific session of the #HDTC2023 conference. This afternoon’s session will be focused on clinical trials, and we’ll be hearing about study design and progress in human research.

Classifying HD stages

Dr. Jeff Long of the University of Iowa is speaking about the HD-ISS, a staging system for HD. It’s a clinical research tool that allows researchers to better classify people in the early stages of HD for more efficient trial design and recruitment.

Now that this new tool is in wider use, Jeff’s team is developing a database of information from large observational trials, like IMAGE-HD, PREDICT-HD, TRACK-HD, and ENROLL-HD, to better understand the timecourse of progression through HD-ISS stages. Having built these tools, Jeff’s team is working to understand how they’d be useful in a clinical trial – how many HD patients at a particular disease stage would be needed to generate robust findings to convince us whether or not a drug worked.

Since the HD-ISS incorporates data from brain images, biomarkers, and genetics, many variables can be considered to define which clinical measurements are the best ones to use to show whether a new drug might be working. Using observational trial databases, researchers like Jeff can apply statistical techniques to better predict how many participants and what types of assessments are likely to be needed to show the benefit of a drug. This is complex and important math that illustrates the importance of participation in observational research.

The proof is in the pudding (or the data)

The next talk is a highly anticipated one sharing the very early results of the PROOF-HD Trial of Pridopidine. We learned from press on Tuesday that the trial did not meet its primary endpoints, but now we are seeing the data.

Dr. Michael Hayden, the CEO of Prilenia, is giving this presentation. He is first explaining the mechanism of how the drug is believed to affect nerve cells, in particular its action on a type of receptor that facilitates communication between neurons, known as sigma 1.

The PROOF-HD trial was designed to use certain clinical assessments, a combination of movement, behavior, and thinking tests, to see if pridopidine helped slow the worsening of HD symptoms over the course of about a year and a half. Trials are designed with “primary,” “secondary,” and “exploratory” endpoints. Showing that a drug affects primary endpoints is usually how decisions are made to continue developing the drug and eventually to get it approved. This trial recruited fast, and most participants stayed in it the entire time, a testament to the mobilization and commitment of HD patients. When the vast majority of people continue in a long trial, it can also speak to the safety and tolerability of the drug.

The main overall finding is that the trial’s primary endpoints were not met. In this case it was a measurement of people’s ability to function day-to-day. On average, people taking pridopidine and people taking placebo functioned similarly for the duration of the trial. Another important endpoint was a combination of different movement, behavioral, and thinking measures, and these also did not improve for people taking pridopidine. Pridopidine might have shown some benefits in one movement measurement, called the Q-motor, but this was not statistically significant.

When a trial is designed, but before it begins, the sponsor (in this case Prilenia) has to make decisions about what types of statistics and analyses it will perform once the results are in. In PROOF-HD, Prilenia decided they would separate groups of participants into those taking drugs called neuroleptics (also known as neuropsychotics) and those not taking neuroleptics. This is because pridopidine affects some of the same biological pathways as neuroleptics. When Prilenia looked at data just from people who weren’t taking neuroleptic drugs, the potential benefit was more obvious using some clinical measurements, especially in the first year. Ultimately this also was not statistically significant.

Michael is now showing data from a trial of pridopidine in people with ALS, a disease which has some shared biology with HD. This trial also showed some potential benefits on secondary outcomes.

Prilenia believes that there remains some promise for pridopidine for treating HD, and the company will now focus on delving deeper into the data. They especially need to understand how different neuroleptic treatments affect response to the drug.

Red light for branaplam

Up next, Dr. Beth Borowsky, of Novartis, describes the results of their trial with a drug called branaplam in HD patients. We wrote about this drug and its surprising mechanism of action here.

While branaplam was safe in children with another disease (spinal muscular atrophy), some animal studies had indicated there was a possibility of damage in the nerves that project from the brain to the skin and muscles of the body. Based on that concern, Novartis included specialized experts in that kind of nerve damage amongst treated HD patients, just in case such a symptom emerged during the trial.

Unfortunately, over a few weeks, some subtle movement and lab measurements started to suggest that the feared risks had actually emerged. In consultation with their independent expert safety monitors, Novartis decided to initially pause dosing. At the time of pause the patients had gotten treatment from between 5 and 22 weeks. After careful review, they found that 78% of the treated patients showed one or more signs that could indicate nerve damage, and also some changes in brain structures called ventricles.

Based on a very careful analysis of the benefit and the risk for patients, Novartis made the decision to halt the trial in December 2022. We covered this here. Currently, all the participants in the trial are continuing to be monitored for symptoms of nerve damage and to track how that may change over time after they stopped taking the drug.

Beth has brought a snapshot of data that Novartis collected to bring the HD community up to speed on what they found. First – as hoped, branaplam lowered Huntingtin levels by around 25% in the spinal fluid, suggesting that branaplam was able to lower levels of Huntingtin in the brain.

Unfortunately, Novartis also found higher levels of a protein called neurofilament light, or NfL, a marker of unhappy brain cells. We’ve talked about NfL before, since it increases in the normal course of HD, and it was a big focus of the biomarkers session at this meeting. We’d hope that if an HD drug works, levels of NfL will go down over time. But in the branaplam study, Novartis discovered that NfL levels in the blood and spinal fluid increased with treatment. This is one of the findings that helped encourage Novartis to pause the study.

In parallel to these lab tests, physicians were carrying out careful nerve function studies in each participant. About 86% of participants had some kind of neurological symptom, and brain imaging showed larger fluid-filled cavities known as lateral ventricles.

All together, it seems like Novartis’s drug did what they thought it would do – reduce Huntingtin levels in the brain. Unfortunately, this was accompanied by serious side effects, so there is not a safe path forward for this drug. Importantly, Novartis is continuing to monitor the trial participants and to analyze data to inform drug development moving forward.

AMT-130 marches forward

Up next, Dr. Talaha Ali from uniQure is giving an update on their study of an HD gene therapy for HD called AMT-130. This relies on the injection of harmless viruses that carry instructions to teach brain cells how to reduce HTT levels.

The amazing thing about these viral gene therapies is that they theoretically require only a single injection, as the viruses persist in the brain for many years – perhaps forever. The downside of this is that it requires surgery to deliver the viruses into the brain. This surgical approach is being tested in two separate trials – one in the US and one in Europe. Because this is such cutting edge stuff, only small numbers of people are being included – around 40 patients in total.

Patients in the trial receive very careful, very slow, injection of the drug into different parts of the deep brain structures that are most impacted in HD. The trial is testing a low dose and a high dose of AMT-130, and closely monitoring participants for the first year and then more frequently for up to 5 years. uniQure will be sharing new data and updates soon, likely by the end of June 2023.

As previously covered, along the way uniQure had some concerning reactions in three patients. After careful examination, the independent doctors monitoring these symptoms decided that the risk seemed acceptable, and the trial was continued.

Excitingly, uniQure has some evidence that AMT-130 reduces brain levels of Huntingtin in the CSF – but to date, the number of treated patients is much too small to make accurate estimates. Hopefully more exciting data to come next time we hear from uniQure!

Narrowing the targets for tominersen

The next talk is by Dr. Peter McColgan from Roche, which is developing a drug called tominersen for HD. He’ll talk about the history of the program, what they’re learning from tominersen trials, and what’s happening with the ongoing GENERATION HD2 trial.

Ionis originally developed tominersen, a spinally delivered genetic drug called an ASO. In early, short safety trials, it was the first drug able to lower huntingtin levels in humans. This was followed by a very large trial to test effects on HD symptoms, known as GENERATION HD1. We learned in March of 2021 that GENERATION HD1 had been halted because of safety concerns – tominersen wasn’t helping HD patients, and at the highest dose it may even have been hurting.

Later, Roche dived deeper into the data, and found that some participants in GENERATION HD1 may have benefitted from tominersen, specifically those who started the trial at a younger age and with less severe symptoms. For this reason, Roche designed and launched the GENERATION HD2 trial, which is a smaller study testing tominersen in a younger population of people in the earliest stages of HD. This study is recruiting now and eventually there will be up to 75 sites in 15 countries.

Peter is now showing data on NfL, a protein that can serve as a marker of damage to nerve cells. New analyses of data from GENERATION HD1 show that giving tominersen at lower doses is likely safer based on lower levels of NfL. The GENERATION HD2 trial is testing two different, lower levels of tominersen, and mathematical modeling predicts that these lower doses will be safer because they will not lead to such large increases in NfL.

Now Peter is sharing new NfL data from the GENERATION HD1 trial. Towards the end of the trial, it actually looks as though NfL levels are going down with tominersen, which is further evidence that the lower doses being tested in GENERATION HD2 could have some promise.

Here’s Peter’s whole presentation on tominersen.

That concludes the research talks at the 2023 HD Therapeutics Conference. Thanks for following along, and visit http://hdbuzz.net to read summaries of Day 1, Day 2, and Day 3!