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

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

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

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

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

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

VO659 – a drug to target repeats

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

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

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

Expanding C-A-G repeats cause disease beyond HD

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

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

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

Preferential lowering of the toxic copy

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Safety

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

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

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

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

NfL

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

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

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

HTT lowering

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

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

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

What about people with SCAs?

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

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

What’s next for VO659?

More data

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

Dosing strategy

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

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

Another trial?

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

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

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

Who is behind this new trial?

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

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

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

Molecular Mars Rovers

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

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

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

Same twinkle, different star

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

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

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

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

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

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

Details about the trial

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

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

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

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

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

Guided by the stars

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

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

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

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

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

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

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

What is Advanced Care Planning?

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

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

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

A roadmap for Advanced Care Planning

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

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

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

Putting it on the record

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

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

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

What can be done now?

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

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

More resources on ACP

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

In the spirit of gratitude, this Giving Tuesday, the HDBuzz editorial team would like to reflect on the unique and transformative role the Huntington’s disease (HD) family community plays in advancing scientific research. From their resilience in the face of this extremely challenging condition, to their extraordinary contributions to scientific studies, the HD family community continues to be an essential partner in driving progress toward treatments and, one day soon, a treatmentcure.

Participation in Research: A Commitment to Progress

One of the most inspiring aspects of the HD family community is their unwavering commitment to participating in research. Clinical trials, observational studies, and other data collection efforts all rely heavily on the active involvement of individuals with HD, their families, and at-risk individuals. These studies demand time, effort, and emotional resilience, yet the HD community consistently rises to the occasion, understanding that their participation is key to scientific progress.

This has been a long-standing theme in HD research. The Venezuela project began in 1979, a critical project in the history of HD research, enabled by the contributions of families from communities in this region. Their participation laid the groundwork for identifying the genetic mutation that causes HD, revolutionising the field and enabling genetic testing and targeted research.

Selfless contributions

Programs like Enroll-HD, a global observational study, owe much of their success to the dedication of HD families. More than 350 projects interrogating Enroll-HD data have been conducted, and more than 150 peer-reviewed manuscripts detailing their finds have been published – a huge achievement!

Additionally, genome-wide association studies (also called GWAS) have been made possible through the donation of DNA samples from HD families to a variety of different registries. GWAS look to try and find genetic modifiers of disease; other genetic factors which track with symptoms starting earlier or later in life than might be predicted based on CAG number alone. Many of these newly identified modifiers from GWAS of people with HD are now top priority targets for drug discovery by academic and industry researchers alike.

Biomarker identification and tracking studies, such as HD-Clarity and iNFLuence-HD, rely on the collection of cerebrospinal fluid (CSF) samples and blood samples to identify measurable indicators of disease progression. Similarly, many stem cell and brain cell studies, which transform donated skin cell samples into disease models, have been a direct result of the generosity of HD families.

More and more HD research studies are using donated human brain samples. This tracks with the advent of many fancy new techniques that allow researchers to examine post-mortem brains at a cell-by-cell level, increasing the amount of information gathered from these precious samples by orders of magnitude. The findings that come from those studies get us closer to understanding HD in people, and closer to a treatment.

Sharing Personal Stories: Humanising the Science

The HD family community has been instrumental in humanising the science behind the disease. By sharing personal stories through blogs, conference presentations, and other outlets, they provide researchers, policymakers, and the general public with a window into the real-life impact of HD. These narratives inspire scientists to work harder, inform the design of patient-centred clinical trials, and help ensure that new therapies address the true needs of those affected.

Projects like My HD Story and POWER-HD further enrich the research landscape by collecting HD family member-reported outcomes, details of peoples real-world lived experiences, and other vital data. Moreover, these stories foster empathy and understanding, breaking down barriers of stigma and isolation. They serve as a reminder that behind every dataset and lab experiment are real people – families who are fighting to ensure a better future for their loved ones and others.

The Power of Advocacy and Awareness

The HD community has been a relentless force in advocating for increased funding, research opportunities, more social supports, and greater public awareness. Many of the local HD organisations around the world are driven by families and caregivers, and have worked tirelessly to bring HD into the spotlight. These efforts have not only fostered public understanding but have also paved the way for governments and private entities to prioritise HD research initiatives. Without their advocacy, many breakthroughs in funding and resources would not have been possible.

Notably, HD advocates have brought their voices to regulatory bodies like the FDA, ensuring that the patient perspective is central in evaluating new therapies. This advocacy has been crucial in shaping guidelines for drug development and approval processes, making them more responsive to the needs of the HD community.

A Call for Continued Partnership

As we give thanks for the HD family community, it is also a call to action for researchers, policymakers, and society at large to continue prioritising their voices and contributions. Building on this partnership means:

• Designing studies that respect and prioritise the needs of participants.
• Ensuring that research findings are communicated back to the community in a timely and accessible manner.
• Advocating for continued investment in HD research and community resources.

Looking Ahead with Gratitude

Progress in HD research would not be possible without the courage, generosity, and perseverance of the HD family community. They are the heart and soul of the fight against Huntington’s disease, and their contributions illuminate the path toward a future free of this devastating condition.

As we reflect on all that has been achieved, let us reaffirm our gratitude to this remarkable community and recommit to working together toward our shared vision of hope, healing, and discovery. So this Giving Tuesday, we encourage everyone from the HD community, particularly those from HD families, to look inward, acknowledge your contributions, and give yourself some gratitude.

A new study led by researchers from Columbia University used postmortem brain samples to show that a special type of brain cell, called astrocytes, may play a role in how certain nerve cells are lost in Huntington’s disease (HD). This could have important implications for how we understand disease progression as well as for the development of new therapeutics that could target these cells specifically.

Star-shaped astrocytes are important for brain health

Nerve cells are responsible for sending signals across the brain that control our behaviour, mood, and help with communication between brain and body. These cells are the most affected in HD and are slowly lost as the disease progresses.

Besides nerve cells, our brain is made up of several other types of cells, including astrocytes. Astrocytes play an important role supporting nerve cell health and help with information processing.

Like nerve cells, and actually most cell types in our bodies, astrocytes also have the huntingtin gene switched on. In people with HD, this means they make the toxic huntingtin protein.

Several studies have indicated that this might cause astrocytes to not work as well in HD brains, including changes in how they interact with nerve cells. These changes are thought to contribute to HD progression. This new study sought to figure out exactly what changes are happening in astrocytes in HD.

Astrocytes: one size does not fit all

Researchers have long known that in people with HD, nerve cells in specific areas of the brain are more vulnerable to dying, a process called neurodegeneration. In this study, the authors looked at how genes are switched on or off in different regions of the brain using postmortem tissue. They found that differences in gene levels from healthy and HD donors were linked to specific brain regions and certain nerve cell types.

Across different brain regions, astrocytes are also not one uniform cell type. They are named for their star-like shape, and like the stars in the sky, there are many distinct types of astrocytes. These differ in shape, structure, and the roles they play in the brain, including how they interact with other cells. The researchers in this study identified several astrocyte subgroups in brain regions that are either vulnerable or resilient to neurodegeneration in HD.

Interestingly, a subgroup of astrocytes were present in HD brains, but not unaffected control brains in a region called the caudate nucleus, an area where nerve cell death is especially high in HD. This highlights that not only nerve cells are affected in vulnerable brain regions, but also that astrocyte subgroups are changed.

The presence of this subgroup of astrocytes meant that astrocytes that have specific functions were replaced, which could change how they interact with nerve cells in this region. Looking at different stages of disease progression, certain clusters of astrocytes were either increased or reduced. This could affect how these astrocytes might support nerve cells or maybe even contribute to their loss.

How do changes in astrocyte functions affect nerve cells?

Astrocytes have many different roles, but one of the most important ones is in brain metabolism. These cells help manage and process nutrients that nerve cells need to stay healthy and to function properly. These nutrients include different types of sugars, cholesterols, and fats.

There are many different kinds of fats and fat-like substances, also called lipids, in the brain. Previous research studies have identified changes in the amount of specific types of fats in HD brains compared to controls. The researchers in this study found that the amount of several types of fats tracked with disease severity in HD brain tissue.

But how do different lipids affect nerve cells? To test this, healthy nerve cells were grown in a dish and exposed to a stressor alongside the specific lipids identified in the study. In the context of cell stress, these appeared to be toxic and caused nerve cells to die.

An outstanding question is whether and how astrocytes contribute to the changes in lipid expression. It is not yet known whether astrocytes play a role in regulating those specific lipids. However, as astrocytes are the cell type that takes up and secretes the majority of lipids, it is important that future research establishes whether astrocytes contribute to nerve cell loss through changes in lipid metabolism.

Astrocytes: good guy or bad guy?

This study found a specific type of astrocyte that there are lots of in brain regions less affected by HD but very little of in the most affected areas of the brain. They found that this type of astrocyte has a particular group of genes switched on more than normal. These genes encode a type of protein called metallotheioneins.

The metallotheionein proteins help to protect cells from a damaging type of stress, called oxidative stress. This type of stress is caused by an imbalance of ‘bad’ reactive molecules and ‘good’ antioxidants. Increased levels of oxidative stress have been reported in HD and are known to damage cells.

Astrocytes are thought to play a key role in protecting nerve cells from damage caused by oxidative stress. The researchers in this study identified a specific gene, metallotheionein-3, which was associated with a neuroprotective astrocyte subgroup. When nerve cells were exposed to toxins in the laboratory, astrocytes that expressed higher levels of this gene could protect these nerve cells from cell death.

A new modifier of HD?

In HD, the age of disease onset generally tracks with the number of CAG repeats in the huntingtin gene, where more CAG repeats lead to an earlier age of onset. However, folks with the same CAG number can get symptoms earlier or late in life. This is partly due to genetic modifiers; small changes to the DNA letter code in other genes that can also affect the age of onset of HD symptoms.

In this study, researchers looked across 390 people with HD to see whether they could find genetic signatures in the metallotheionein-3 gene that tracked with the age when symptoms first appear.

Three small genetic signatures appeared to be linked to a later onset of symptoms in people with HD, whilst two other genetic changes appeared to increase how much this gene is switched on in a specific brain region, the prefrontal cortex. This highlights the potential clinical relevance of this gene and may represent a new way to target astrocytes therapeutically by designing drugs to change the expression of the metallotheionein-3 protein.

Astrocytes – a potential therapeutic target in HD?

The majority of cells lost in HD are nerve cells, but from studies like this, we are learning more about how other cell types and their functions are affected in the HD brain. The brain is incredibly complex, and by understanding more about other cells like astrocytes, we also learn more about how changes in cell-cell interactions may lead to neurodegeneration.

Unravelling the intricate relationships between nerve cells and astrocytes could be essential for developing effective therapies for HD. I like to think of the brain as an orchestra, where all instruments need to play well together. As such, it’s not sufficient to just target one part such as nerve cells and therapeutics need to target all cells affected by HD.

A lot of the findings from this study rely on human postmortem brain tissue and would not have been possible without organ donation. It’s the generous and selfless contribution that individuals make, that allows research like this to be possible.