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

CAG expansion causes toxicity

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

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

Targeting modifiers to control toxicity

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

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

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

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

HTT-lowering drugs

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

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

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

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

Ability to target doesn’t equal specificity

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

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

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

Not all HTT-targeting splice modulators will work the same

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

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

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

Is PMS1 the new target to beat?

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

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

Does this mean a resurgence for branaplam?

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

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

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

If you’re a frequent reader of HDBuzz, you may have noticed that our articles increasingly thank Huntington’s disease (HD) families for their generous and selfless brain donations. That’s because more and more research is making use of human brains, leading to a better understanding of HD in people. All of that is only possible because of the fantastic HD community that supports HD researchers. So today, May 7th, on Brain Donation Awareness Day, we tip our hats to each and every HD family member who has very generously donated a brain to HD research. Serendipitously, this falls during HD awareness month!

Why is brain donation so important?

Humans are the only species that naturally get HD. We have lots of animals that model HD, but those have all been created in a lab. While they’re important for answering some types of questions about the disease, they can’t ever truly replicate every disease feature we see in people. To understand exactly what HD is doing, we need samples from people.

While researchers have some models from people, like skin cells that can be turned into brain cells in a dish, these still can’t tell us everything that’s going on inside the complex human brain. To get the clearest picture of how HD affects the human brain as a whole, human brain donations are needed.

Using scientific experiments to analyze human brains from people with HD allows researchers to dissect the interaction between distinct types of brain cells, understand how amounts of molecules change as HD progresses, and much more. As technology advances, researchers are using molecular mapping to determine what’s going on at a cell-by-cell level.

What are we learning about HD from donated brains?

Overall, researchers are learning lots from studying human brains generously donated by HD families! They are answering questions about why certain brain cells are more vulnerable in HD, what other types of cells in the brain are doing, and how somatic expansion plays a role in when and why nerve cells in the brain get sick. Below are some examples of how these precious materials are used to advance HD research, many from recent talks we heard at the CHDI therapeutics conference earlier this year.

Cell death and brain health

Tony Reiner from the University of Tennessee Health Science Center is using tools to visualize different forms of the huntingtin protein throughout the brain. The huntingtin protein comes in lots of different flavors – expanded, fragmented, clumped, and others. Tony and his group are mapping these different forms of huntingtin in the human brain to try and understand the cause and effect for how different huntingtin flavors may contribute to specific brain cells getting sick.

Osama Al-Dalahmah from Columbia University Irving Medical Center uses human HD brains to study a star-shaped cell called an astrocyte. Astrocytes help maintain health and function of nerve cells in the brain. Osama’s team found that the more sick brain cells there are, the more the astrocytes are trying to make things better again. Understanding how HD affects astrocytes may help us understand how to improve health of the whole brain.

Better understanding somatic expansion

Christopher Walsh from Boston Children’s Hospital and Harvard Medical School is using human HD brains to look at somatic expansion – the increase in the CAG number in some cell types over the course of someone’s lifetime. Because there seems to be a link between somatic expansion and disease progression, lots of scientists are trying to better understand it. Chris is identifying single letter changes in the DNA code that are linked to somatic instability. These specific changes define a genetic “signature” that can be used to track cells, which can help scientists understand how the brain changes over someone’s lifetime.

Matthew Baffuto from the lab of Nat Heintz at Rockefeller University is using human HD brains looking at epigenetics – inherited labels on the genetic code that make it easier or harder for a gene to be made into a message or protein. Matthew is mapping these labels on genes that control somatic expansion and mapping those in cells in the brain that have high or low amounts of expansion. His work will shine light on how epigenetics can be used to understand how HD affects drivers of disease, like somatic expansion.

Tracking CAG expansions on a cell-by-cell level

Nat Heintz from Rockefeller University has been using human HD brains to try and understand how somatic expansion is connected to cell death. Using fancy technology, Nat and his team are able to look at the number of CAGs in each cell in the brain. Because we know which cells are vulnerable in HD, this gives researchers an idea of the contribution that expansions play in cell death. Surprisingly, they found that it isn’t just the cells that die that have large CAG expansions, perhaps suggesting there’s more to the story for why brain cells are dying in HD.

Bob Handsaker from the lab of Steve McCarroll at Harvard Medical School and the Broad Institute is mapping CAG lengths on a cell-by-cell basis. They’ve measured CAG numbers up to 1000 CAGs long in some cells! They’re mapping when in disease rapid CAG expansion happens. They find that when cells get 150 or more CAGs, genes that should be off are turned on and others that should be on are turned off. Bob thinks this leads to toxicity and eventually death of the brain cells that undergo this rapid CAG expansion.

Where can I go for more information?

We realize the thought of donating a brain – the organ that encompasses the essence of you or your loved ones – is a tricky topic. It’s also important to acknowledge that brain donation is not something that everyone might participate in due to religious, cultural, personal, or other reasons.

If you think brain donation might be right for you or is something you are interested in learning more about, it does need to be thought about in advance. The key for brain donations is to set them up before people pass. The sooner the brain is received after death, the more preserved cells and tissues will be and the more scientists can learn.

If this is something you’re interested in learning more about, you can find information from:

• The Brain Donor Project
• Huntington’s Disease Society of America
• Huntington Society of Canada
• HD organizations in your home country
• Local academic institutions

Our deepest gratitude to those who have donated

The past few years have brought a massive increase in the number of studies using human brains. The advent of fancy new techniques that allow researchers to examine brains at a cell-by-cell level has increased the amount of information gathered from these brains and has helped ask and answer complicated questions.

So much of the science that happens in the lab wouldn’t be possible without the HD community. That is particularly true for studies using human brains. The findings that come from those studies get us closer to understanding HD in people, and closer to a treatment. Science, particularly HD science, relies on a partnership between the researchers and the HD family community.

Today, on Brain Donation Awareness Day, we send our deepest gratitude to the amazing HD community for standing hand-in-hand with HD researchers so that we can cross the finish line together, treatment in hand.

We wrote in August of 2023 about the US approval of a new drug to treat chorea, the movement symptoms of HD. That drug, valbenazine, commercially known as INGREZZA, has just been approved in a new format, one that can be added to soft foods. This news deserves a brief HDBuzz mention.

Chorea control

Valbenazine is one of a few drugs known as VMAT2 inhibitors. These treatments act on a chemical messenger called dopamine in the brain to reduce the involuntary movements of HD (chorea). VMAT2 inhibitors used for HD include tetrabenazine, deutetrabenazine (AUSTEDO), and valbenazine (INGREZZA), but there are a variety of other treatments prescribed to people with HD who experience chorea. A doctor might prescribe one over another based on a number of factors, including availability, cost, side effects, and control of other mood and behavioral symptoms.

Solutions for swallowing

These drugs are taken by mouth, but as symptoms like chorea and changes in muscle control worsen, many people with HD can experience difficulties with swallowing. Therapy sessions with an experienced speech language pathologist (SLP) can provide best practices and safety guidance around eating for those in the later stages of HD. But sometimes it’s just too much of a challenge for someone to swallow a pill.

In these circumstances, common across many diseases, medical professionals might recommend that a person’s medication be crushed or dissolved. They’re not always designed to be delivered this way, but it’s a good solution for those who have an easier time with soft foods, liquids, or who use a feeding tube.

A sprinkling of good news from Neurocrine

Simply put, the news from Neurocrine Biosciences, the company that makes valbenazine is that they have created and received approval in the United States for a new formula called INGREZZA SPRINKLE, which comes in a capsule designed to be opened and added to soft foods. As we mentioned when we talked about the original FDA approval, this drug is currently only available in the USA, and Neurocrine has not yet made plans to seek approvals in other countries.

So valbenazine is not new, and the idea of opening or crushing a capsule to help someone with HD continue taking a helpful treatment isn’t new either. But US government approval of a new formulation of an HD drug is a good reason to celebrate – and we’ll take any excuse we can to eat ice cream.

HDBuzz strives to be an honest and neutral source of information that Huntington’s disease (HD) families can turn to for trusted, unbiased reporting on research and clinical trial news. We’re honored to have become a global resource for the HD community over the years (14!) and we look forward to building upon the original mission of HDBuzz as we head into a new era. Read on to learn more about the new editors-in-chief and our plans for the transition.

The need for information

While we know it’s hard to fathom at this point, there once was a world before Google. In those dark ages, information was harder to come by. This was especially true for HD.

Often, the most people heard about HD was restricted to short blurb in a textbook, distilling HD down to a disease passed from generation to generation that one had a 50% chance of inheriting if their parent was affected. This limited picture was particularly disheartening for HD families seeking information. Seeking answers. Wondering what research was being done to find a treatment for this devastating disease.

The broad establishment of the internet changed the way information could be shared. It promised greater accessibility of cutting-edge research. It provided a platform that could be used to immediately share information from one corner of the globe to another – from the lab bench to HD families. But what was out there was often hard to find, full of jargon, and interspersed with misinformation.

The advent of HDBuzz

Two HD researchers saw the gap in getting accurate information from researchers to the people most eager for scientific updates on HD – HD families. In 2010, Dr. Ed Wild and Dr. Jeff Carroll established HDBuzz to rapidly disseminate high-quality HD research news to the global community, written in plain and accessible language, by HD clinicians and scientists.

HDBuzz has gone to great lengths to be impartial in our reporting.

• We don’t accept funding from any drug company or organization with a vested interest in a particular treatment or technology
• No funding organization gets any editorial control over HDBuzz content
• Independent external advisors provide input on content to ensure that it is impartial, scientifically accurate, and understandable
• All our authors make disclosure statements, which they review whenever they contribute new content to ensure any possible conflicts are clearly declared

New HDBuzz Editors

As Ed and Jeff advanced in their careers, their research and consulting responsibilities increased. This left them with less time to support the vital mission of HDBuzz. To ensure HD families could continue to rely on HDBuzz as a trusted resource for HD news, the team grew.

A decade after HDBuzz’s creation, in 2020, Ed and Jeff folded in 3 new editors: Dr. Rachel Harding, Dr. Sarah Hernandez, and Dr. Leora Fox. If you’ve been reading HDBuzz articles over the past 4 years, you’ve likely seen these names in the by-line.

After 4 years of having Rachel, Sarah, and Leora on team HDBuzz, Ed and Jeff are officially passing the baton and stepping back to an emeritus role. This will allow them to focus their efforts on HD research and care, advancing promising ideas and experimental treatments for HD toward the clinic and give the new team the opportunity to grow and develop HDBuzz even further.

Meet your “new” Editors-in-Chief

So who exactly are the new names behind HDBuzz and why should you look forward to hearing their take on HD research in the years to come?

DR. RACHEL HARDING

What got you into HD research?

I have always been interested in understanding the precise molecular details of how biology and disease work; how do different proteins work together to perform a specific biological function and what molecular changes happen in disease for things to stop working properly? I was intrigued by HD as we know the exact molecular change which causes disease, an increase in the CAG number of the huntingtin gene DNA, but even with this knowledge, unpicking the molecular details or exactly what goes wrong has proved very challenging for the field.

In 2018, I was fortunate enough to be awarded a Huntington’s Disease Society of America Berman Topper Family Career Development Fellowship, which helped fund my research looking into the HD protein and how this molecule is changed in disease. I became hooked on trying to answer this question, and it has become the focus of my research ever since.

It very quickly became apparent just how welcoming and collaborative the HD research community is, and I feel lucky to be able to work with so many fantastic folks. The impressive way HD meetings and conferences span patient viewpoints, clinical trial updates, cutting-edge breakthroughs in the lab and everything in between, is just super.

What’s your “real” job?

I am a Principal Investigator at a research institute called the Structural Genomics Consortium (SGC) in Toronto. I wear a second hat as I am also an Assistant Professor in the Department of Pharmacology and Toxicology at the University of Toronto, Canada.

What this all means is that I run a research group who are primarily focussed on studying the HD protein, to better understand how it works, and what goes wrong in disease. As part of the SGC, we are also involved in many early-stage drug discovery research programs, in HD and other diseases.

The work we do is highly collaborative and we have partnerships with lots of different HD labs and other specialists around the world. Open science is a key part of our ethos and we share both our results and the materials we make and study in the lab, including the HD protein, with different labs that span all continents.

Why are you excited about bringing HDBuzz forward?

It has been such an honour to write, edit, present, and report for HDBuzz in the past few years. I have learnt so much about the HD community and it has reinforced my beliefs that science should be for everyone, and that it is critical that everyone has access to the latest research findings in plain language.

In this next phase, I am excited to build upon the great foundation created by Ed and Jeff, and push HDBuzz further. I am especially keen to connect with even more HD communities from around the world and further increase the accessibility of HD research to everyone who needs it.

DR. SARAH HERNANDEZ

What got you into HD research?

“Huntington’s disease” has been a household phrase for me since I was about 12 years old. That’s when I found out my maternal grandmother died from HD. I grew up watching family members suffer with HD, knowing what it meant for the next generations if something wasn’t done. That really lit my curiosity. From then on, I wanted to learn as much as possible about HD and how we could solve this problem so that we could get a treatment.

It turns out I had a whole lot more questions than there were answers! Ultimately this led to me getting a PhD in Biology with the hopes of helping to find a treatment. I did my postdoc with Dr. Leslie Thompson at the University of California, Irvine. She’s a pioneer in HD research – she was a member of the team that went to Venezuela to identify the gene that causes HD.

With Leslie, I used stem cells to model HD. We’re able to turn those cells into brain cells and ask and answer all sorts of questions about how the gene that causes HD is specifically affecting brain cells. I also worked with fruit flies that carried the HD gene to do genetic experiments.

What’s your “real” job?

About 2 years ago I started working at the Hereditary Disease Foundation (HDF) as the Director of Research Programs. The HDF was started by the Wexler Family, who is also affected by HD. Dr. Nancy Wexler has really changed the face of HD research, instilling collaboration into the field that has moved mountains. She led the missions to Venezuela to find the gene that causes HD.

At the HDF, I coordinate our scientific programming through webinars, workshops, and conferences. I also manage the grants program. Finding a treatment for HD is the primary mission of the HDF, and we believe that will happen through research. In 2023 we spent 85% of all donations on research. In 7 years, we’ve given over $13M in grants and fellowships to over 100 recipients!

I love the work that I get to do at HDF because I get to help support amazing researchers and see all the latest HD research as scientists are coming up with it. It’s the perfect job for me! My 12-year-old self would be pumped to see where I am.

Why are you excited about bringing HDBuzz forward?

The mission of HDBuzz really speaks to how I felt when I first found out HD runs in my family. When I was a kid, I just wanted answers about HD. I wanted to know about the latest research. I wanted to know what people were doing out there to get us closer to a treatment. If HDBuzz had been around back then, it could have saved me a lot of time (like, a whole PhD’s worth!).

I’m excited to bring HDBuzz forward because I know how HD families feel that just want to know what’s going on. I feel like scientists have a duty to get the information they find to the people that are affected by that information. The research project isn’t over until information gets where it needs to go. HDBuzz has been a fantastic resource for the HD community in ensuring that happens.

I spent 22 years in classrooms and at the lab bench developing the tools and skills that enable me to help people understand the science behind what’s going on in HD. I’m honored to be the conduit to get information about the research to the HD families who need it most.

DR. LEORA FOX

What got you into HD research?

I grew up volunteering (singing and dancing, actually!) in long-term care facilities where I became aware of a lot of neurodegenerative diseases, including HD. I was also one of those high school science nerds who started working in a lab as soon as someone would let me. This combo led me to study neuroscience in college, work in an Alzheimer’s lab afterwards, and eventually to pursue a PhD in neuroscience at Columbia University in New York City.

I was lucky enough to land in the lab of Ai Yamamoto, who was one of the first scientists to show that “turning off” the HD gene could lead to improvements in HD mice. She introduced me to the HD research community and gave me opportunities to write and speak in addition to designing experiments.

What’s your “real” job?

I’ve been at HDSA since 2016, and since 2021 I’ve overseen research and patient engagement programs. HDSA funds research, communicates about research, and helps to bring family voices into the drug development process. We are the largest family-facing HD organization, and we primarily serve the US.

In addition to research we support more than 60 multidisciplinary HD care centers around the USA, and we have a variety of advocacy initiatives, educational programming at the local and national level including our yearly HDSA Convention, the largest global gathering of HD families. We provide many different types of social services through our network of 100+ social workers, support groups, disability services, and other national and local programs.

Research plays into many aspects of support and care and vice versa, and I am constantly learning from the community members I speak to and from my colleagues in social services.

Why are you excited about bringing HDBuzz forward?

I like to say that my passion is helping people understand science, and helping scientists understand people. Bridging community needs with stellar research and presenting it in a way that everyone can understand is key to perpetuating the search for treatments.

I did not enter this field with a personal connection to HD, but this community, the families and the scientists, have become very dear to me. I love to write and edit, to engage with all sorts of people, to enable cross-talk and access and inquiry, to see research progress and to communicate its importance.

To be able to apply a hard-won skillset to help make HD science accessible, even entertaining, within a global community I care about – what a dream!!

What we’re dreaming of doing

HDBuzz has a solid foundation thanks to Ed and Jeff, and we are building upon their efforts to strengthen and expand upon the HDBuzz mission. Here are some of the steps we are taking towards that goal:

• Get feedback from the global HD community about information needs, perceptions, and ideas for HDBuzz
• Increase our pool of scientist-writers to include a diversity of voices
• Integrate AI translation for global accessibility by having all articles available in as many languages as possible
• Plan site updates and ongoing content based on community feedback

Thank you to Ed and Jeff!

As the new editors-in-chief of HDBuzz, we give our warmest, most heartfelt thank you to Ed and Jeff for what they created in HDBuzz. You’ve created an invaluable resource for the community that has shaped the way HD families receive news about ongoing research and trials. We look forward to continuing your mission as we usher HDBuzz into the future!

Drug hunters have been particularly interested in the repeating C-A-G letters of genetic code that lead to Huntington’s disease (HD). The number of CAG repeats gets bigger in vulnerable brain cells over time and may hold the key for slowing or stopping HD. Many scientists have been asking what happens to HD symptoms if we stop this expansion. Recent work from a group in London led by Dr. Gill Bates examined exactly this, seeking to define the threshold of CAG repeats needed to cause disease. Let’s discuss what her team found!

We’re all just alphabet soup

The genetic code of every living organism is made up of only 4 letters – C, A, G, and T. They’re combined in different ways to make every gene in our body. That’s a lot of diversity for just 4 letters!

Within the huntingtin gene that leads to HD is a stretch of repeating C-A-G letters. People with HD are born with 36 or more CAG repeats in the huntingtin gene. As a person grows older, we know the number of CAG repeats can shift and wobble in some cells, getting bigger over time.

This ongoing CAG expansion is called “somatic instability”. This specifically happens in brain cells damaged by HD. It’s important to note that the CAG repeat size is relatively stable in blood. So a blood test showing 42 CAGs at the age of 18 will very likely still show 42 CAGs at age 50. But the brain cells of that person could have more than 100 CAG repeats, and a few may even have 200 repeats or more.

Expansions may be the key

Some scientists think that preventing CAG repeats from increasing in the brain may be key to stopping HD altogether. But no one knows how many CAGs are too many in the brain, or at what age CAG increases start to happen.

Several important genetic studies in the past few years have suggested that longer CAG repeats could help explain why brain cells die in HD. For example, people who develop HD earlier or later than expected have changes in genes that impact somatic instability of the CAG repeat in huntingtin. These genes are called “modifiers” – they modify the age at which someone starts to show symptoms of HD.

What’s interesting is that modifier genes mostly participate in the same process in the body, called mismatch repair, which is known to affect somatic instability of the CAG repeat. Very suspicious! This suggests that somatic instability of the CAG repeat is pretty important in HD.

Since somatic instability in brain cells may contribute to how these cells die, and since mismatch repair genes impact somatic instability, HD researchers are now very interested in drugs that target mismatch repair genes. Perhaps by targeting the right mismatch repair gene, we can stop somatic instability of the CAG repeat in vulnerable brain cells. The hope is that a drug which does this could slow or stop HD.

A numbers game

It turns out that we can stop somatic instability in the brain! At least we can in mice, for right now. Several pharmaceutical companies are developing HD drugs targeting mismatch repair genes and somatic instability in HD (for example, LoQus23, Rgenta, and Voyager Pharmaceuticals).

But no one really knows how long a CAG repeat must be to damage brain cells, or how early you might need to stop somatic instability in people as a treatment for HD. Recent studies in HD mice have tried to help answer these questions by looking at the impact of stopping somatic instability in HD mice with different CAG repeat lengths.

What’s helpful about HD mice is that they are born with many more CAG repeats than people with HD – because HD researchers want mice to develop symptoms of HD much faster than people do. For example, a type of mouse that models HD called “Q111” has over 100 CAG repeats. Another HD mouse model called “Q175” has about 185 CAG repeats. Both the Q111 and Q175 HD mice show symptoms of HD in less than a year.

Defining the threshold

Researchers think this threshold of about 100 CAGs may be the number of repeats needed to kill brain cells in people with HD. So what happens if you stop somatic instability in these HD mice? Do the mice get better? The answer for mice born with 185 CAG repeats, surprisingly, is no. They still develop HD, even when somatic instability is halted.

In a newly published study from the lab of Dr. Gill Bates at University College London, Q175 mice having about 185 CAG repeats were altered so that they didn’t have the mismatch repair gene MSH3. MSH3 is a high priority target for HD drug hunters since somatic instability stops altogether when MSH3 is gone.

As expected, somatic instability stopped almost completely in the brains of Q175 mice when MSH3 was eliminated. But these mice still developed features of HD, even though MSH3 was eliminated and somatic instability of the CAG repeat was halted.

What could this mean? Shouldn’t stopping somatic instability prevent the mice from developing HD? Gill’s group reasons that mice born with 185 CAG repeats already have too many repeats in the brain, so stopping expansions below 185 CAG will probably be necessary to treat HD in people.

This parallels the conclusions of a previous study which eliminated MSH3 in Q111 mice that have 100 CAG repeats, fewer than the 185 CAG repeats studied by Gill. In this other study, Dr. Vanessa Wheeler showed that Q111 mice without MSH3 have no somatic instability and have improved cellular markers of HD. So stopping somatic instability in brain cells before they reach 100 CAG repeats may be necessary for this strategy to work in people.

When should we treat HD?

This begs the question many people are asking lately: when should we treat HD? How early would a person with HD need to be treated to stop their brain cells from expanding across the threshold of 100 CAG repeats? Some brain cells appear to have 100 CAG repeats before people start to show measurable symptoms of HD. So it may be necessary to treat people even before they start to develop symptoms.

Treating people before they develop symptoms of HD poses lots of difficult questions that no one quite has the answers to yet. However, many brilliant scientists are now looking at CAG repeats directly in brains of people with HD to find answers. These insights detailing the threshold of CAG toxicity will help scientists to design better drugs and upcoming clinical trials to target somatic instability as a potential HD therapy.