A new study led by researchers from the University of California Irvine gives us new clues as to how genetic message molecules are edited differently in the context of Huntington’s disease (HD). Let’s get into what the scientists found and why this matters for our understanding of HD.

The cellular editor

When watching our favorite movies, we don’t typically consider the extraordinary amount of editing required to make them flow seamlessly from scene to scene. Behind this movie magic are editors who work tirelessly to enhance the drama of key plot twists with clever and precise cuts, removing unnecessary scenes and bloopers, and eventually stitching everything together to create the polished films we love.

Cells use a similar editing process when creating proteins, the molecular machines that perform nearly all the activities inside cells. Proteins are like polished feature-length films in theater and, just as movies originate from a collection of unedited scenes, proteins are also made from an unedited version called mRNA.

mRNA is a long string-like molecule with multiple “scenes” containing the genetic instructions needed to make protein. Through an important process called splicing, cells remove segments of mRNA called introns (bloopers) and keep segments called exons (key plot twists). If everything runs smoothly, the initial unedited mRNA, containing a mix of introns and exons, will have its introns removed leaving it with only exons when it is used to make proteins.

However, this editing process malfunctions in people with HD, leading to serious problems in how some of the protein machines work inside brain cells.

Cells with bloopers and missing scenes

Scientists have long suspected that mRNA splicing is disrupted in the brains of people with HD. Previous research has found introns mistakenly included in the final mRNA molecule and exons mysteriously missing. This would be like publishing movies without removing bloopers and missing critical plot twists – not something cinema-goers would be happy with!

Recent experiments suggest that the protein encoded by the gene that causes HD, called Huntingtin (HTT), may play a key role in this confusion. HTT is an mRNA-binding protein and is known to interact with other proteins that also bind mRNA. This raises an interesting question: if splicing is disrupted in HD, HTT interacts with mRNA, and HTT interacts with proteins involved in splicing, could mutant HTT be interfering with the cell’s mRNA editing process?

Blockbuster bombs in the cell

Intrigued by this mystery, Dr. Leslie Thompson and her team at the University of California Irvine investigated the underlying cause of splicing errors. Using mouse models of HD and post-mortem human brains, they first confirmed that splicing is disrupted in the HD brain, discovering various types of mRNA with undeleted introns (bloopers) and missing exons (key scenes). These errors were most common in the medium spiny neurons, the type of brain cell that is most vulnerable in HD. In addition, the mRNA message molecules that were found to contain splicing errors were particularly important for activities like neural communication and brain development.

Splicing errors are harmful because a cell’s protein machines made from improperly spliced mRNA either function abnormally or fail to be produced altogether. This would be like a movie so poorly edited that the publisher decides to pull it before hitting theaters.

These findings are exciting for HD researchers because they may explain why some proteins don’t work very well or are less abundant in HD cells, despite having no mutation or known interaction with HTT. Although the consequences of splicing errors are complex and difficult to predict, they are undoubtedly harmful to overall brain function.

TDP43: A distracted editor

Leslie and her team scrutinized the proteins interacting with HTT in search of possible causes of the splicing errors. They focused on proteins that, like HTT, also interact with mRNA – like partners in crime.

One protein, TDP43, stood out because it not only interacts with HTT and mRNA but is also known as a kind of splicing editor-in-chief. TDP43 is an extensively studied protein because its mutation causes a different neurodegenerative disease, Amyotrophic Lateral Sclerosis (ALS), so researchers already have a great profile on it. Adding to their suspicion, the types of mRNA that TDP43 is known to edit closely overlap with the mRNA containing splicing errors in HD.

Beginning their investigation of TDP43, Leslie and her team first tested if TDP43 binds to the same mRNA that is spliced incorrectly in HD. Sure enough, they found that TDP43’s favorite mRNA largely overlapped with the abnormally spliced mRNA in HD. When researchers compared the splicing changes of cells missing TDP43 to cells containing mutant HTT, they observed remarkable similarities. This suggests that TDP43 dysfunction might be the root cause of splicing errors in HD.

How HTT spoils the show

The team hypothesized that HTT’s interaction with TDP43 could be “stealing” it from the studio, and preventing it from splicing mRNA. To test this, they first confirmed that HTT interacts with TDP43 in mouse brains. Next, they examined brain cells from people with HD to see if TDP43 was in its normal location, the nucleus, where splicing occurs. Like an absent movie editor, TDP43 was mostly located outside of the nucleus, a clear indication that something was wrong.

Scientists have long recognized changes in TDP43 location from the nucleus to the cytoplasm (outside the nucleus) as a hallmark of ALS, and this change in location is associated with errors in splicing. What’s worse, the small amount of TDP43 still in the nucleus appeared inactive because it was locked up in big protein clumps with HTT, like an editor buried by movie reels!

Another red flag the scientists noticed was the absence of special chemical markings on mRNA, called m6A, that guide TDP43 to splice sites, like sticky notes reminding the editor to delete certain scenes. These chemical markings on mRNA were significantly reduced in HD brains, particularly on mRNA prone to splicing errors. Without these marks, TDP43 is unable to identify the “bloopers” it needs to remove and likely contributes to TDP43’s dysfunction.

At this point, the researcher’s working hypothesis was that mutant HTT abnormally interacts with TDP43, keeping it out of the nucleus or trapping it in large clumps, distracting it from its splicing duties. On top of this, the sticky notes (m6A marks) that guide TDP43 to the bloopers (introns) were mostly missing in HD brains. Together, these issues prevent mRNA from being properly edited, resulting in broken or missing protein machines. Over time, these problems lead to sick brain cells that can’t communicate properly.

Putting the editor back to work

Although the current study does not attempt to correct or reverse these splicing errors, its findings will help guide future therapeutics. The involvement of TDP43 is particularly interesting because TDP43 is already extensively studied in ALS, and hundreds of TDP43-targeting therapies are currently in development. This does not necessarily mean treatments designed for TDP43 will work for HD, but they may serve as promising starting points for new therapeutic strategies or to help us better understand what TDP43 is doing in HD.

Future research is critical to understanding how mutant HTT disrupts TDP43 activity, and whether restoring TDP43 activity can correct the splicing errors observed in HD. Like editing a movie, fixing these molecular errors could turn a blockbuster disaster into a beloved masterpiece we cherish for years to come.

A new paper led by researchers at the Massachusetts General Hospital and Harvard Medical School used CRISPR to work out which genes can influence how the genetic C-A-G repeat that causes Huntington’s disease (HD) can change over time. This exciting study helps us to better understand how HD works and uncovers some potential targets for therapies that could slow or halt the disease.

Genetic Stumbles Can Increase C-A-G Repeats

HD is a genetic brain disorder and everyone who has HD has an expansion of the C-A-G DNA letters in their HD gene, also called huntingtin or HTT. Over time, these C-A-G repeats can become even longer in some types of brain cells. This process is called somatic instability or more specifically somatic expansion. But somatic expansion doesn’t occur in all cells. This phenomenon appears to occur more so in medium spiny neurons, the type of cells that are most affected in HD.

The topic of somatic instability has been trending in the HD field, as it is suggested to be a key driver of disease that may accelerate the age at which symptoms first appear. This is supported by large genetic studies in people with HD, which suggest that genes responsible for proofreading the genetic code can affect somatic instability.

Billions of DNA Pieces: The Puzzle of Life

Every cell in the body carries a complete set of DNA instructions, which act like a blueprint for making everything the body needs to grow, function, and stay alive. You can think of DNA like a twisted ladder, and its two strands are the sides of the ladder. The rungs of the ladder are made up of building blocks, known as A (adenine), T (thymine), C (cytosine), and G (guanine). These act like puzzle pieces that pair up in a very specific way: A always pairs with T, and C always pairs with G.

The DNA in each of our cells contains billions of these letters, so as you can imagine, sometimes there are mistakes or mismatches in the DNA puzzle leading to two pieces being paired up that don’t fit together properly. Luckily our cells have repair systems that work like mini-puzzle masters, scanning for these mistakes, removing the wrong piece, and replacing it with the right one so the puzzle or DNA fits together perfectly again.

When it comes to long C-A-G repeats in the huntingtin gene, sometimes, the two DNA strands can shift or “slip”. DNA slips in C-A-G repeat regions are like buttoning your shirt but skipping a button—causing a bulge that disrupts the whole pattern. This happens because the C-A-G sections of DNA are like identical puzzle pieces that can stick together in the wrong way.

If this happens, a loop of extra CAGs can form in one strand DNA. Since the DNA repair systems are always checking for mistakes, when they notice the loop of extra CAGs, they try fix it. But instead of removing the extra CAGs, it sometimes “corrects” the strand by adding more repeats to make everything match. This leads to expansions of the CAG repeat in huntingtin.

Measure Twice, Cut Once: Using CRISPR To Uncover Genes Behind Genetic Stumbles

In this paper, the researchers used CRISPR to turn-off specific genes in a mouse model of HD. CRISPR is a powerful tool that acts like a tiny molecular Swiss Army knife in the cell to cut or edit any DNA as long as there is a “homing” signal (or PAM site) nearby. Luckily these homing signals are found nearly everywhere in the genome, so researchers are finding cool ways to use CRISPR to edit literally any gene in the cell!

This tool is being used to correct typos in genes, including the huntingtin gene in HD. It can also be used to turn-off certain genes, which reduces the amount of protein they make.

The researchers focused on genes involved in cell’s DNA repair systems, since prior studies have suggested that some of these genes play an important role in controlling the stability of C-A-G repeats, either by making them longer or shorter.

They used CRISPR to turn-off more than 50 of these genes in HD mice and then measured the effect on C-A-G repeat changes in the striatum, the part of the brain most affected in HD, as well as in the liver.

Expanding and Contracting: How DNA Repair Genes Play CAG Repeats Like an Accordion

The study confirmed that several genes in the DNA mismatch repair pathway, such as MSH2, MSH3, and MLH3, make proteins that can enhance expansion of the C-A-G repeat. When these genes were turned off, less of these proteins were made and the expansion slowed significantly. This emphasizes the potential of targeting these proteins as drug targets for HD.

On the other hand, switching off certain genes, like FAN1 and PMS2, made C-A-G repeats expand faster. This suggests that boosting the production of these proteins could help slow down C-A-G expansion.

Interestingly, turning off DNA repair genes had different effects depending on the tissue. For example, some genes caused more C-A-G repeat expansion in the liver than in the striatum. This shows why it’s important to study these changes in the tissues most affected by the disease.

This study shows how powerful CRISPR can be for testing genes that affect C-A-G repeat instability directly in living animals. It allows scientists to study dozens of genes at once, something that wasn’t possible before.

‘Harness’-ing C-A-G Expansions

The findings help us better understand what drives HD and point to new potential drug targets that could slow C-A-G expansion and delay symptoms. In fact, there are lots of folks doing exactly that right now!

Rgenta Therapeutics and LoQus23 Therapeutics are two companies developing pills that aim to turn off production of proteins that make the C-A-G repeat longer, which could help slow down somatic expansion in the brain.

Another company, Latus Bio, is planning to use harmless viruses to deliver DNA-like molecules, known as microRNA, that can lower levels of a protein that can increase somatic expansion.

Harness Therapeutics is working on developing specialized DNA molecules, known as antisense oligonucleotides or ASOs, that are designed to boost production of FAN1, a protein that can actually make the C-A-G repeat shorter.

These treatment approaches are still in the research stages so be sure to check HDBuzz for updates as these programs move along.

When thinking about Huntington’s disease (HD) research participation, many of us picture white-coated physicians, forms and waiting rooms, tests and needles. In reality, that experience represents one of the many ways that scientists gather information about how best to care for people with HD. Impactful studies can take many forms, from cautiously investigating the safety of a new drug, to observing movements in a doctor’s office, to simply surveying people from HD families about their day-to-day experience.

Survey studies and what they can reveal

A survey is a form of observational study – one that simply collects information without intervening. HD researchers, healthcare professionals, advocacy groups, drug companies, and others invested in this community use surveys to understand the behaviors, experiences, and challenges faced by HD families. The results can be applied to enhance medical or support services, improve interventions, communicate needs to those in power, or create educational content that really resonates with the people it’s meant to reach.

Filling out a survey on your phone, tablet, or laptop is an anywhere, anytime-you’ve-got-internet activity that can build the worldwide HD knowledge base and shape how all sorts of providers and educators approach HD. Many organizations conduct research in this manner, or they may compile surveys on behalf of scientists. The Huntington’s Disease Youth Organization (HDYO) conducts surveys open to the global HD community – and periodically releases their findings to the public. This way, participants can understand how 10 or 20 minutes of their time led to valuable insights about HD.

HDYO’s Survey Series

In March of 2023 HDYO began releasing HD community surveys on their website. While HDYO provides information and services to kids and adults, with a focus on ages 18-35, participants in these surveys were aged 18+. Like all responsibly designed human research, surveys need to be reviewed by an ethics committee – these were vetted by an official board at Monash University in Australia. The data was analyzed by HDYO staff and members of their Research Committee.

HDYO’s latest release covers early data or upcoming plans for three community surveys about 1) how people with HD seek support and resources, 2) the educational and emotional barriers to research participation, and 3) milestones in the lives of young people with HD. Of these surveys, the first has closed (more than 400 people responded), the second remains open (you can still participate if you’re 18+) and the third is in development (keep an eye out for new opportunities!). The surveys are currently available in more than 10 languages, and more will be added in future.
Let’s dive into what they learned.

Breaking down demographic information

Surveys often begin by collecting demographic information – although identity is kept anonymous, the respondent is asked to answer questions about their connection to HD, how old they are or where they come from, their race or what language they prefer to speak. There’s always lots to break down within this data, but let’s use as an example the 425 people who completed the first survey that HDYO released (demographic findings are similar for the others). Here are some key pieces of info about the population they surveyed:

• The majority of participants speak English, Spanish, or Portuguese.

• Most respondents (77%) identified as female.

• People from all over the world found HDYO’s website and their survey, including North America (35%), Europe (40%), South/Central America (14%), Oceania (9%), Asia (4%), and Africa (2%).

• This type of information could help HDYO or other organizations/educators to prioritize particular new languages, prompt them to seek more gender balance in research or explore how gender contributes to aspects of life with HD, or connect with local communities in new places.

Survey 1: How the community seeks support

This survey’s main purpose was to ask about resource-seeking among people in HD families. In what ways and how often do people look for info about HD? What topics are they most familiar with, and what do they search for? What are their preferred ways to get support? Again, lots to digest, but some of the findings that stand out include:

• Most people are poking around for HD info on a weekly or monthly basis, but there are many who look daily, or just a few times a year.

• Young folks most often find info about HD on the websites of HD organizations, or on social media – Facebook, Instagram, and YouTube had the most engagement. (Don’t forget to follow HDBuzz on the socials!)

• They prefer info in written articles, videos, and conversations, versus graphs and charts (no surprise there!)

• Their searches were most often about HD research, followed by personal stories and medical topics.

There were also opportunities to write in responses and opinions, and people shared their desires for in-person connection, an HD app, emphasis on thinking and behavioral symptoms, and more. Overall, HDYO concludes that community needs are unique and differ across regions, and that these responses can help them (and others!) to make decisions about what new and improved resources will best serve youth in HD families.

Survey 2: Educational and emotional barriers to research

This ongoing survey explores how young people feel about research participation (focused on in-person opportunities) and what their knowledge base is. What types of research do they participate in? What prevents them from participating, and how do they overcome these barriers? What terminology around research are they familiar with? How can they feel more supported around participating in research?

This study is still seeking participants (they’ve got over 100 so far but the more the better). From their early analysis they have found:

• Travel, work, financial burden, and site access are the biggest reported barriers to participation.

• More people reported that online information seeking and speaking with study coordinators helped them to overcome perceived barriers compared to any other category of support. However, participants overcame barriers in many different ways, like finding help with traveling, bringing a loved one along, or talking to someone who had already been part of the study.

• Understanding of terminology varies a lot: many people are familiar with definitions of study types (observational/interventional), clinical trial phases, and what different types of participants are called. Specific study terms like cohort, endpoint, and monitoring committee were less familiar to most.

• HDYO still needs to analyze more of the data from this study, and one of their priorities is to break down some of the write-in questions. These were centered on participant expectations, suggestions for better support from study sites and community organizations, and what people may have gained through participation.

Individual quotes from participants have revealed so far that folks would appreciate financial and logistical support like booking accommodations, counseling or support after participating, regular updates on opportunities, and education about the impact of participating in research. There are all sorts of organizations and individuals who could change their course of action once they better understand such community needs.

Survey 3: Mapping milestones

This survey aims to better understand different milestones in the life of a person from an HD family and at what age people experienced those events. The survey hasn’t been launched just yet, but HDYO shared their goals and plans:

• Examples of potential “milestones” include learning about HD in the family, making genetic testing decisions, identifying as a caregiver, and participating in research (among many others).

• The survey will also examine what was happening in people’s lives when they reached these milestones and what types of support they could/did access.

• The survey questions were selected with the help of a committee of youth from HD families and rated for importance.

HDYO hopes that the conclusions from this survey and others will help to inform professionals about how they can best support youth and young adults with HD in their families, and how best to educate so that people can make informed decisions about the future.

Takeaways

The preliminary data we’ve discussed today (and lots more) is available to view in detail through HDYO’s website. It’s also worth noting that professionals who conduct HD surveys, like psychologists, genetic counseling students, social workers, and other researchers, often publish their results in academic journals – though it can sometimes take some outreach or a literature search to access these.

The conclusions and individual suggestions generated from these studies, like the need for specific supports for people with HD who participate in research, are likely to resonate with a lot of HDBuzz readers. A lot of this may already seem obvious to people within the HD community, but scientists and people in power need data to take action. Graphs and percentages drawn from the responses of hundreds or thousands of people with HD help to define, for both insiders and outsiders, what this community really needs.

The hope is that studies reporting those needs could guide decision making: for example, data from people with HD could empower a company to include that concierge service in their clinical trial, or prompt a study site to devote more of their social worker’s hours to supporting patients with HD. Gathering this data and making it available is the first step. If you’re presented with a survey that’s got ethics approval and clear goals, consider taking a few minutes to add your voice!

The HDBuzz editorial team had a virtual sit-down with HDBuzz founder, editor emeritus, Huntington’s disease (HD) researcher, and neurologist Professor Ed Wild. We laughed, we cried… actually we just laughed. But we also talked about HD research, the deluge of positive clinical trial news from 2024, and Ed’s outlook for 2025. Spoiler alert: it’s a hopeful one!

Big Picture

HDBuzz: 2024 was a big year for HD research, particularly in the clinical space. Which breakthroughs or advances in HD research from the past year are you particularly excited about?

Ed: Honestly, I feel a bit spoiled for choice. In the middle of last year, there was a series of update announcements from trials that came more or less back-to-back, and it felt like drinking from a fire hose of good news.

One of the updates I was most excited about, because it’s really moved the needle in my opinion, is the uniQure gene therapy trial. It’s a surgically injected gene therapy, made of a genetically engineered virus that is programmed to inject its cargo into neurons. The virus turns those neurons into a factory for making a drug that lowers the production of huntingtin protein. The neurosurgical procedure is a substantial undertaking, but if it works, it will be worth it, because it should only need to be done once. It’s a high risk, high reward approach, and the first gene therapy that’s been tried in HD.

The uniQure program announced that two years in, in a couple of dozen participants treated with the gene therapy, the people who have received the drug appear to be doing significantly better than controls. The team asked if the uniQure-treated patients look better than we would expect them to based on what we know about the history of HD. There appeared to be a significant reduction in the rate of progression! Particularly on functional scores, the patients appeared to be stable over two years. The placebo effect is a powerful thing, but that combination is a really good starting point for the kind of thing that turns into a success.

HDBuzz: Wow, that’s encouraging! What about other data and measures that have been shared so far from this clinical trial?

Ed: Another piece of information that came from that announcement in the summer was that the level of neurofilament light (NfL) protein in spinal fluid was lower at the two year time point on average, than it was at the start of the trial for those patients. NfL is released into the spinal fluid when nerve cells are damaged. If NfL goes up, which it does in HD, that’s a sign of something bad happening. If NfL goes down, that is generally seen as a sign that we’ve actually rescued neurons, which is our aim with HD treatments. The combination of clinical signals moving in the right direction and NfL below baseline is what I’ve been looking for for the past 20 years, and never seen until last year in the uniQure data update.

It’s been said that I am sometimes unduly optimistic, and I might be being unduly optimistic here, but I do think this is the best set of results we’ve seen so far from a clinical trial. It’s small numbers and needs to be replicated, but the other good thing about a gene therapy trial is it’s kind of automatic – it basically carries on as long as the patients are alive. We just need to keep track of what happens to these patients.

HDBuzz: There was some other exciting news from uniQure last year. Can you tell us more about that?

Ed: In December, uniQure announced that they’d had a really productive discussion with the FDA, and in my opinion, this produced two pieces of information that I think are really important for the field, with some caveats.

The first is the use of NfL as a biomarker. In other words, an objective measurement that tells us whether a drug is doing what it’s supposed to do or not in HD. The use of NfL as a biomarker was given a big thumbs up by the FDA, and the agency said its use would support potential approval of the drug.

The second was the use of a clinical score called the composite UHDRS (cUHDRS). This score is the combination of scores from different tests, namely Total Functional Capacity (TFC), Total Motor Score (TMS), Symbol Digit Modalities Test (SDMT), and Stroop Word Reading (SWR). Previously, the FDA was very reluctant to consider cUHDRS because it was new and hadn’t been fully tested. But this time around, in 2024, the FDA seemed to endorse cUHDRS as an endpoint, without any hesitation or reservations.

This is important because each person with HD is very different from one another. One person might have a lot of motor and movement problems. Another person might have a lot of cognitive problems. cUHDRS helps capture the diversity of HD and it actually reduces the number of participants needed to complete every trial, by about 40%.

HDBuzz: Can you explain a bit further why cUHDRS might be used over a single measure, such as TFC, when we want to know if a drug is disease-modifying?

Ed: This is an important point. As an example, imagine someone with HD who’s depressed: this might mean they can’t work anymore. Then they are treated with an antidepressant, the depression gets better and they may be able to go back to work. However, you haven’t dealt with the underlying damage that’s ongoing every day in the brain caused by HD. All you’ve done is reduce the symptoms of depression. But this would move a score like TFC in a favourable direction.

However, if you have really modified the course of the disease, you would expect one or more of the components of cUHDRS to move in the favorable direction. But even that might not mean that the drug is disease modifying. In my opinion, it comes down to two things. One, is mechanism: what do you know about the drug and how it was designed to slow the progression of HD, does it have a proven ability to alter a known mechanism of HD, and in doing so, does it change the cUHDRS in the expected way? And number two, is supporting evidence that you have rescued neurons. That would come under the realm of biomarkers which could be something like an imaging test, which tells you that the brain is shrinking less, or NfL, which I talked about earlier, which is essentially a protein which tells you whether, on average, neurons are dying more quickly or more slowly than before.

NfL is very widely accepted as a biomarker of brain health throughout different brain diseases. If you lower NfL, it’s essentially proof that you’ve rescued neurons. It’s really great that all of these new drugs are in the clinic around the time when we’re getting the biomarkers that we need. It’s been a big focus for me, and it’s really nice and gratifying to see these biomarkers actually being used and being given a thumbs up by the regulators.

HDBuzz: So how can we ensure that when we are looking at biomarkers, we are seeing disease modification, not symptom modification?

Ed: The first thing to say is that we actually want both kinds of drugs. We want drugs to slow the disease, and we want drugs that are better at controlling symptoms, particularly something like cognitive symptoms. If I could help improve my patient’s cognition, even if we’re not slowing the progression of the underlying disease, that would be a big win.

My view is, this is why we need multiple biomarkers, and we need to never lose sight of the chain of evidence connecting the disease, to the drug, to the biomarker, and what could be messing up along the way. I think when a drug works, all of the biomarkers and the clinical scores will probably move in the same direction, and that then becomes just much more difficult to have happened by mistake.

For instance, if a drug inflames the brain of a patient, it might cause swelling, and that could look like slowing brain shrinkage. However, that would also probably cause an increase in NfL, because inflammation could damage neurons. We would conclude that we have an imaging marker going in the right direction, but a chemical biomarker going in the wrong direction. Therefore we shouldn’t conclude that that was a success. We need to get to the bottom of which of those two measures is telling us the truth. When everything moves in the same direction, it’s just much more likely that we’ve hit the target in the way that we want to.

At the Lab Bench

HDBuzz: You’re well known for your research in HD biomarkers. Can you talk to us a little bit about ideas that you’re interested in exploring in biomarkers as we move into 2025?

Ed: I think that the biggest gap in our biomarker toolkit is an imaging marker that shows us huntingtin protein in the brain. PET (Positron Emission Tomography) scans give us a picture of the brain that lights up where a particular molecule is, and the more of that molecule there is, the brighter it lights up, essentially. These really transformed other fields like Alzheimer’s disease, where you can do a PET scan for amyloid and Tau, the main proteins thought to be involved in Alzheimer’s disease. You can give a drug and see the amount of these proteins in the brain reducing, and this has given huge support to some of the early therapeutics for Alzheimer’s disease. We’d love that in HD!

The uniQure trial is a brilliant example of where that might be particularly useful. Even though the results look good with this drug, one of the reservations is that it’s treating a tiny part of the brain called the striatum, which has a volume of about 5 to 10 millilitres, compared to the whole brain, which is over 1,000. Even if you completely save that part of the brain, it’s possible that the way the rest of the brain is behaving might obscure the detection of that benefit when you look at scans or even molecular biomarkers.

Certainly, we haven’t seen evidence in the uniQure trial that the huntingtin level in spinal fluid has been lowered. We have to assume that that’s happening. If we had a PET scan that worked, that was able to show us where the huntingtin is in the brain, we’d be able to see that the gene therapy had actually lowered the production of huntingtin. That would be solid evidence of target engagement, as we call it. I’d love a huntingtin PET ligand.

I think the next big thing in therapeutic approaches for HD is going to be treatments that prevent the number of CAGs from expanding. And you’ll start to hear more and more about drugs targeting things like MSH3, which is a DNA repair protein. But basically, if we change the behavior of those DNA repair proteins, we should be able to keep the CAG count stable, or more stable than it is in the brain.

What we don’t have at the moment are any solid markers of whether those drugs are working and changing the CAG count in the brain, except by biopsy which we don’t want to do because it injures the brain. Is the CAG getting bigger? Is it stable? How quickly is it increasing? Biomarkers for the process of CAG expansion would be huge for HD.

The closest we can get to the brain realistically is by collecting spinal fluid. But the detection of DNA in spinal fluid is really difficult. We’re hoping to combine new DNA sequencing technologies with ways of focusing on stuff in spinal fluid that comes from neurons. We think we might be able to do that with microscopic bubbles called vesicles. Those extracellular vesicles, or EVs, could turn out to be the kind of secret sauce that we need to figure out as quickly as possible, whether CAG stabilizing drugs are actually working in HD.

Clinical Trials

HDBuzz: From which companies should we be expecting updates in 2025?

Ed: This is the first year where I feel like we might get to the end of the year with a good chance of a new drug licensed to slow the progression of HD. I don’t know which it will be, but my top two predictions will be either uniQure or PTC.

uniQure is expected to give an update in June, which will be the three year update on the same group of patients that we had the two year update from last summer, plus a bunch of new patients. The company has been told that if the three year update is good enough, they will be given accelerated approval by the FDA, a completely unprecedented promise. We just hope that the data delivers and that the agency still takes the same view.

PTC Therapeutics has a drug, now called votoplam, taken as a pill to lower production of huntingtin in the brain and body. We heard last summer that the drug seemed safe and well tolerated, and in contrast to other similar things that have been attempted, there was no sign that it was damaging neurons. On the contrary, it seemed really clean in terms of its safety signal. We expect to hear from PTC, probably late spring, early summer. That’s not just an update, that’s the full results. The top line results from the first in human trial. I think it’s something like 150 participants. It’s quite big for a first in human trial, and it’s been designed to be big so that if the drug is doing really well, they can go straight to the regulatory agencies and ask for conditional approval.

Alynlam Pharmaceuticals is another company that’s doing a huntingtin lowering trial that just started in the last few months. What we hope for from Alnylam is actually a period of silence for a while, because they need to start getting patients in. For this kind of first in human program, no news is very much good news. But with a bit of luck, towards the end of the year, we should start to get some top line results.

Slightly below the radar is a drug that we used to hear about a lot, tominersen, which is the Roche drug. Following the negative results in 2021, the drug is actually in another trial, now targeting younger people with smaller CAG repeats and using lower doses, in the hope of finding a dose and a group of patients where the drug produces more benefit than harm. We just heard that that trial is fully recruited, but it will be 18 months from that point. We won’t hear about anything until probably mid-2026 although it’s possible that they will do an interim analysis, and we might hear something this year.

There’s been a lot of talk and excitement about these CAG-stabilizing drugs, essentially MSH3 inhibitors that are likely to be the first ones that we see reach trials. And there’s a couple of approaches we may well see before the end of this year; patients dosed with either a pill or injections into the spine of an MSH3-lowering drug. That will be super exciting, because it’s a completely new angle, but it’s an angle that came to us directly from the HD community. DNA from the 20,000+ people that are involved in Enroll HD was used to identify these DNA repair proteins as something that is important in the progression of HD. We’d be crazy if we didn’t take that evidence from mother nature and make drugs to replicate its benefits.

HDBuzz: Despite all of these exciting approaches and encouraging data from the clinic, the community has been disappointed before with things not panning out as we had hoped. What is your advice for managing expectations whilst remaining hopeful?

Ed: I think the reality that’s dawned on me is that this is a really difficult problem. We knew it was difficult, and we’ve had some lucky breaks, but we’ve also had more than our fair share of bad luck. Things that have gone well for other diseases have turned out to be much more difficult for HD. I’ve always talked about substantive hope. This was the kind of founding principle behind HDBuzz – that basically, hope is good, and to squander hope, or to let hope go unused or unfulfilled is a tragedy. HDBuzz was always kind of a machine for turning hope into action.

Everyone in the HD community hopes the scientists will develop treatments that work for HD, and we hope that it will happen as soon as possible. That’s a great starting point that I recommend for everyone in the HD community. But it’s the kind of hope that can be dashed if you hear a couple of pieces of bad news, which is what happened in 2021 with back-to-back disappointing updates from huntingtin lowering trials. Certainly that was very sad and depressing. But for me, because I knew what else was coming through the pipeline and was looking behind the headlines, yes, this was a disappointing result, but what can we learn from it? And the answer in both cases was a ton of stuff. What we learned from the negative tominersen result has been super important in setting us up for a much better probability of success in 2025 and beyond.

I always think of HD as a journey up a mountain. We’re trying to climb to the top and when we get there, that’s when we’ve cured HD. But if you just think about that whole journey, it’s incredibly daunting, and you’d be crazy to set off up a mountain without a clear plan or a plan of what to do at each stage if something goes wrong. I think the magic ingredient is being informed about what’s happening and why we’re doing what we’re doing. Why are we lowering huntingtin? Why do we care about DNA repair? What does that have to do with CAG repeats? And what does CAG repeats have to do with the disease?

At some point, a doctor is going to be sitting opposite you in a clinic room and is going to slide a consent form across the desk to you, saying, “Do you want to take part in this trial? Here are the risks and here are the potential benefits.” If that’s your first time hearing about that drug, fair enough, but if you already knew about that drug and why it’s been developed and what the history of it is before you entered the room, you’re in a much better position to make an informed decision. Breaking down the journey into steps means that if you miss a step, you’re only going to be on the one step down. You’re not going to be right back at the foot of the mountain.

Taking Action Now

HDBuzz: Recently we covered a paper showing an association between beta blocker use and delayed onset and decreased progression of HD. What are your thoughts on their use for HD based solely on the paper that came out?

Ed: What I will say about beta blockers is it’s an intriguing mystery. This was one of the largest studies that’s been done of these drugs and their effect on HD, and the results are pretty robust. Does it mean that people should start beta blockers? Not necessarily, because it’s possible that the kind of person that is prescribed a beta blocker happens to be the kind of person whose HD is going to progress more slowly anyway. If there is a direct mechanism, it might be something kind of super boring, like stuff that’s good for your blood vessels, is good for your brain, and that is good for HD.

This could be an extension of the best advice we’ve been able to give so far, which is, again, quite boring. Don’t smoke, don’t hit your head against a brick wall, do exercise regularly, have a balanced diet, and look after your cardiovascular health. One of the big things I emphasize is that just because you’ve got the HD gene expansion doesn’t mean that you should stop going to those annoying appointments with your GP, where they measure your blood pressure, cholesterol, and other stuff. Look after your general health.

One thing I do know about HD is that it is very difficult to slow the progression, but it’s very easy to accelerate the progression. If you take a bunch of harmful recreational drugs, drink too much, become a professional boxer, neglect your general health, and smoke 40 a day… Don’t do any of those things. Do the other things.

Looking Ahead

HDBuzz: What challenges do you foresee for the HD community in 2025?

Ed: Science is amazing at producing breakthroughs and treatments that work. And the nature of science is that it just doesn’t give up. If we have a problem, we’re going to keep coming up with new ideas, refining them and testing them until something works, and all you have to do is wait, and sooner or later, there will be drugs that work for HD.

Unfortunately, science and healthcare operate in the real world. I think the biggest challenges, which we’ve thought of as largely relating to places like Latin America, will turn out to be challenges everywhere in 2025 and beyond. I think about the United States, which is a beautiful, brilliant country that I love, but there are lots of Americans that don’t have access to health care, and certainly would really struggle to get new, innovative drugs like gene therapies, or genetic therapies, which are likely to be quite expensive.

It’s in the nature of HD that it drains people’s resources, so the people who need the drugs most often end up being the people who can least afford to receive them. That needs to change, if all of this scientific progress is going to be translated into changing people’s lives for the better. For HD-impacted families even more than everyone else, it matters whom you vote for.

HDBuzz: If you could summarize the HD space from 2024 in three words, what would you say? What about 2025?

Ed: “Finally, good news” – is how I would summarise 2024 in 3 words. If I was going to do it in emojis, it would be: exclamation point, smiley face, dancing lady.

For 2025, I would say “imminent success (trepidation)”!

People who develop Huntington’s disease (HD) are born with the genetic change that causes the disease. So why does it take decades, usually around 40 to 50 years, for the symptoms of the disease to appear? And why are certain brain cells more vulnerable to death than others? These have always been key questions in HD research. A new paper from the lab of Dr. Steven McCarroll gives us new insights into these questions, and it points a finger at the CAG repeats that are the genetic basis for HD.

Genetic stutter

At the genetic level, HD is caused by repeating C-A-G letters in the genetic code within the gene huntingtin, or HTT. However, we all have the HTT gene. In fact, we all have a stretch of CAGs that repeat within our HTT gene. It’s just that people who go on to develop HD have extra CAGs within their HTT gene – 36 or more. You can think of it like a genetic stutter.

In one of the biggest breakthroughs in HD research, scientists found that this genetic stutter actually gets bigger in some cells over time. This is a biological phenomenon called “somatic instability”, which is also sometimes referred to as “somatic expansion”. It’s the perpetual expansion of the CAG repeat in some types of “somatic” cells, or cells of the body. Researchers have found that the number of CAGs balloon in some cells, at times reaching up to 1,000 repeats!

However, some cells are more vulnerable than others to these effects of HD. Even though the CAG expansion that causes HD is found in every cell type in a person’s body, molecular signs of the disease are much more apparent in some types of cells compared to others.

All cells aren’t equal

Brain cells are most affected by HD. However, there are lots of different types of cells in the brain, and they’re not all affected in the same way. When people think of brain cells, they typically think of neurons – the tree-shaped cells responsible for directing our thoughts, feelings, and movements.

But there are other types of cells in the brain too. Glia are support cells that provide structure, nutrients, and maintain a healthy brain. Endothelial cells help form the blood-brain barrier, keeping harmful substances like viruses and some medications out of the brain. There are even different subtypes of neurons!

Medium spiny neurons, or MSNs, are a type of brain cell found in a region of the brain called the striatum that is almost exactly in the middle of our heads. MSNs help to control movement and coordination, and are particularly vulnerable to dying off as HD progresses. While we’ve known this for decades, no one really knew why. However, new experimental techniques, like those used by the McCarroll group, are getting us closer to the answer.

The beach vs. a sand grain

McCarroll’s team used a technique called “single nucleus RNA sequencing”. This let them look at the individual genetic signatures of every single cell in the brain samples they analyzed. It’s incredibly impressive! New single nucleus techniques, like those used here, are advancing what researchers know about HD because it transforms how they analyze samples.

About a decade ago, if you wanted to look at molecular changes in a tissue sample, you would chop it up and analyze it. Pretty crude in hindsight. This would give you a decent idea of the levels of molecules within an entire sample, but you wouldn’t be able to tell which cells were producing what molecules. This is kind of like taking a picture of the sand on a beach. You could probably tell if it was tan, or rocky, but that’s about it.

Single nuclei techniques allow researchers to zoom in and look at every single cell within a tissue sample. This would be like taking a sample of that beach and putting it under the microscope. So now instead of a uniform tan sample, you might see that some grains of sand are actually white fragments of shell, or blue pieces of sea glass; you get a much deeper understanding of the composition of that sample.

Expansions in single cells

When the researchers used single nucleus sequencing on brains of people who had HD, they found that CAG expansions were profound in MSNs, but not in other types of brain cells, like glia or other kinds of neurons. The authors suggest that we should perhaps reframe our thinking – rather than asking why MSNs are particularly vulnerable to cell death in HD, maybe we should be asking why somatic expansion is more prevalent in certain cell types, like MSNs.

From there, they could pull out the exact number of CAG repeats within each MSN for each brain sample. They could then map that against all the other genetic changes within each cell. Hopefully you’re starting to appreciate that this is a lot of data!

Mapping the number of CAG repeats with genetic changes, allowed them to calculate disruptions in those cells. Interestingly, they found that certain CAG repeat lengths were linked to the amount of genetic disruptions in the MSNs. So cells with CAG expansions between 36 and 150 didn’t seem to show signs of genetic disturbances. But once the repeats expanded beyond 150 CAGs, the changes they measured were huge. This suggests that something is going on inside the MSNs once the CAG length reaches 150 or more to disrupt the genetic signatures of the cell. But what?

Identity eroded

They dug deeper into the molecular changes that were happening inside the MSNs that had ultra-long CAG repeats of 150 or more. They were involved in the identity of the MSN itself – genes that make an MSN an MSN, and not another type of nerve cell.

As we covered, there are different subtypes of neurons in the brain. What gives them their unique identity is the genes and molecules that they produce. Some neurons produce molecules that inhibit the activity of other neurons, ensuring controlled and accurate movements. These are known as ‘inhibitory neurons’. Others produce molecules that accelerate and excite signaling between brain cells, which defines them as ‘excitatory neurons’. These definitions help researchers to classify neurons with identities.

As the CAG repeats stretched to 150 and beyond, the researchers found that MSNs began losing the genetic signatures of their cellular identity. Genes that should be off were on, and genes that should be on were off. The features that helped define them as MSNs were being eroded. Notably, in MSNs with ultra-long repeats, they found that the cells appeared to be turning on genes that cause cell death, perhaps providing a clue as to why this specific cell type is so vulnerable in HD.

Armadillo model

To explain their hypothesis, the authors describe their data as an armadillo-shaped curve. For our non-American readers, an armadillo is a small, armored mammal with a hard shell made of bony plates, native to the southern United States and South America. (Picture for reference.) They’re low to the ground, with a curved body, and long flat tail.

With the armadillo body shape in mind, the CAG lengths of most MSNs seem to fall under the curved body part of the animal during the initial decades of life. Once the cells get to about 80 CAGs, the expansions begin happening more rapidly, on the order of years. These few cells with increasingly longer CAG lengths fall under the long flat tail part of the armadillo. At 150 this process speeds up even further in this model, taking only months to acquire hundreds of more CAG repeats. It’s only when CAGs reach a length of 150 or more that they start to see detrimental effects on the cells.

Armadillo schmarmadillo, what about people?

To describe their model of a slow acceleration in CAG expansion, the authors detail a hypothetical situation for someone who inherited 40 CAGs. They postulate that the first phase of expansion occurs slowly in MSNs, taking about 50 years to go from 40 to 60 CAGs. The next phase occurs a bit faster, taking about 12 years to expand from 68 to 80 CAGs. From there, the cell reaches a tipping point, where expansion occurs more rapidly. In just a few years a cell could go from 80 to 150 CAGs. After that, the expansion to hundreds of CAG repeats could occur in a matter of months. During this last phase, genetic identity of the MSNs is lost, and the cell begins turning on genetic programs leading to its death.

It’s critical to note that this is a hypothetical situation. None of the time values stated here are set in stone and are only being used to describe this model. This does not depict an exact situation of what’s happening to the MSNs in the brain of someone with 40 CAG repeats.

It’s also important to know that this doesn’t happen inside every MSN in someone’s brain all at the same time. This is an asynchronous process, meaning MSNs will acquire additional CAG repeats at different rates, producing a mosaic of CAG repeat lengths. Timing here will also be highly dependent on environmental factors, lifestyle choices, and genetic modifiers, all known to contribute to the age of symptom onset.

Advancing what we know

This work challenges long-standing theories of some of the ways we think about HD. When protein aggregates were first discovered in the late 1990s, most researchers thought that those sticky protein clumps were causing the signs and symptoms of HD. Over the decades, the thought in the field has broadened, where many researchers now feel various molecular components contribute to disease, including a component that’s contributed by the genetic material itself.

This new paper stands firmly in the second camp – that “HD pathogenesis is a DNA process”, caused by instability in the genetic code brought about because of a tipping point in the number of CAGs in the HTT gene in certain types of cells.

This is the first paper to deeply analyze these ultra-long CAG repeat lengths. Previous work could really only sequence the CAGs out to about 150 repeats. While we’ve known since 2003 that these ultra-long repeats exist, we just haven’t been able to read the DNA sequence. It’s actually technically quite challenging to get accurate sequences of very long stretches of repeating DNA letters!

The best time to treat HD

There’s been rigorous debate about the best time to treat HD. Of course it’s always easier to preserve something rather than trying to restore it. So general consensus has become that treating HD before symptoms appear would be the best time. But does that mean treating HD after symptoms appear wouldn’t have any benefit?

Encouragingly, this new work suggests that approaches targeting somatic instability may be successful even after symptom onset. That’s because CAG repeat expansion happens in neurons asynchronously. So even if some MSNs have acquired so many CAGs that they’re already turning on genetic programs leading to their death, other MSNs haven’t. Those are the ones that could be targeted to slow or stop HD progression.

What does this mean for HTT lowering?

The first potential disease-modifying approach out of the gate was HTT lowering. Afterall, we know the genetic cause of HD is expanded HTT, so it’s a very logical approach to lower expanded HTT levels for therapeutic gain.

There’s also lots of hope with other approaches, including targeting somatic instability. Lots of people are focusing on this area, and we’ll undoubtedly see these approaches coming to the clinic soon. But this doesn’t mean we should abandon HTT lowering approaches!

HTT lowering approaches had a rocky start, but we’ve recently received positive updates from several clinical trials suggesting that HTT lowering as an approach may be having clinical benefit. These studies are the first evidence we’ve ever had that something could be working to slow clinical signs of HD. So we definitely don’t want to stop now!

Zooming out for clarity

For the HD community, it’s important to remember that this type of deep molecular work is looking at cellular and molecular changes in a particular cell type. While the striatum is the most affected area of the brain by HD with MSNs certainly being the most vulnerable cell type, other areas of the brain and body are also affected by HD. Since this paper specifically looked at the striatum, we don’t yet know if these same types of mechanisms related to somatic instability are also at play in other areas of the brain and body.

It would be nice if science were black and white, but unfortunately it’s not. Somatic instability does seem to be a key in understanding HD, but it’s likely not the only driver of disease. There are likely various biological mechanisms contributing. Other work suggests that ultra-long CAG repeats aren’t causing death of cells in the cortex (the wrinkly outer bit of the brain). Since this part of the brain is also affected by HD, it suggests that somatic instability isn’t the only thing we should focus on. So diversifying therapeutic approaches, like with HTT lowering as well as targeting somatic instability, is our best bet.

And finally, we’d be remiss if we didn’t mention the people and families who made the selfless and generous decision to donate their brains to advance this research – thank you! These types of findings that challenge current thinking in the field are what drive research forward and take us in new scientific directions, helping to define truth in this disease and discover new treatments. That all relies on the strong partnership we have between the researchers and the HD family community.