Gratitude Day—Sunday, March 23rd—is a global initiative organized by Factor-H, celebrating the resilience and strength of Huntington’s disease (HD) families, particularly those in underserved communities—the same communities who have historically partnered with the medical and scientific community to advance research. In particular, the families from Venezuela, who did so much to help with our understanding of the disease.
It’s a day to reflect on the power of compassion, solidarity, and support, recognizing the contributions of caregivers, researchers, and advocates working to improve the lives of those affected by HD. For the HD community, Gratitude Day is an opportunity to amplify awareness, and inspire continued action toward a future with better care, resources, and ultimately, effective treatments, which must include families living in conditions of extreme vulnerability.
In honor of Gratitude Day, the HDBuzz editorial team interviewed Dr. Ignacio Muñoz-Sanjuán (aka Nacho), President and Founder of Factor-H, to learn more about their mission, help amplify their message and share in the meaning behind this inspiring day.
Factor-H is much more than just an organization; it’s a movement. The name itself stands for Huntington’s, Hope, and Humanity, reflecting its mission to shift the dominant factor in these families’ lives from the disease, to hope and the human connection.
Through its four key pillars—health, youth, community development, and data collection and advocacy—Factor-H is making a tangible impact in some of the most underserved HD communities in the world. Nacho describes the work Factor-H is doing as, “using Huntington’s disease to help communities that sit at the interface of neurodegenerative genetic disorders and poverty or conditions of extreme vulnerability.”
The Communities at the Heart of HD Research
Many people are unaware that some of the world’s largest clusters of HD are found in Latin America, particularly in Venezuela, Peru, and Colombia. In these regions, entire families, and sometimes entire villages, are devastated by the disease. In some communities, a staggering 10–20% of the families have a history of HD—a heartbreaking reality.
Adding to the challenge is the extreme poverty that these families face. In Venezuela, many HD families live in tin-roofed huts without running water or electricity. Basic necessities such as food, medicine, and education are often out of reach. Meanwhile, in Colombia, HD families may not experience the same level of economic hardship, but they endure severe isolation, completely cut off from care and resources.
Nacho shares that, “Overall, about 80 to 90% of all the families we have been supporting live either in poverty or extreme poverty by international standards. In many cases, families don’t eat more than once a day and the meals are not very nutritious. So, just trying to get regular support on nutritional supplements and adequate food is a problem with the numbers of families that we are supporting.”
These are the very communities that played a pivotal role in the discovery of the HD gene, published in 1993. Despite this monumental contribution to science, many of these families still lack access to the most basic needs. Factor-H exists to bridge this gap, offering immediate relief while also working toward long-term solutions.
Humanitarian aid: Factor-H provides essential supplies such as food, bedding, and medical care to families struggling with extreme poverty.
Medical aid: Factor-H promotes, facilitates, and provides access to specialists for symptomatic patients and at-risk children including neurology, pediatric neurology, vaccinations, dental and eye care, speech therapy, among other forms of support.
Housing improvements: Many HD families live in unsafe and unstable conditions. Factor-H helps renovate homes to provide safer, more comfortable living environments.
Education for children: The organization runs a scholarship program that has helped dozens of children stay in school, giving them hope for a better future despite their families’ struggles with HD.
Training caregivers: Local caregivers are trained to support people with HD, ensuring that families have access to knowledgeable and compassionate care.
Legal advocacy: Factor-H has successfully helped families in Colombia secure disability benefits and medical assistance, empowering them to navigate systems that might otherwise leave them behind.
The Balance Between Immediate Needs and Research
One of the more complex issues surrounding Factor-H’s work is the balance between direct support and research. While the organization prioritizes immediate needs—understandable given the level of suffering—there is also the question of how these communities might benefit from participation in ethically-designed research projects.
Nacho acknowledges this challenge. Even if new therapies are developed, ensuring accessibility in these regions will be a major hurdle. He has suggested advocating for free access programs, particularly for treatments that could be administered locally, such as oral medications. However, achieving this goal will require major shifts in healthcare policies and infrastructure, and will require the support of companies working to develop novel HD therapeutics.
Battling Stigma and Misconceptions
Beyond the physical and economic struggles, many HD families in Latin America also face deep-seated stigma and misinformation about the disease. This is further potentiated by a lack of education in these areas, often to the level that people can’t read or write.
Nacho highlighted the widespread misconceptions about HD, saying, “People who are not from HD families wonder whether the disease is contagious. That really affects a lot of children because they can’t maintain friendships in school the moment they start having symptoms, or when people know they come from an HD family.” These harmful beliefs contribute to social isolation and further hardship for affected families.
Education and awareness are crucial. Factor-H works to dispel myths and foster greater understanding, not only within HD communities but also in the broader society. This is where global initiatives like Gratitude Day come in.
HD Gratitude Day 2025: Honoring HD Families
March 23rd marks Gratitude Day, an annual event recognizing the contributions of HD families to research while also raising awareness of their ongoing struggles. This day was chosen because it marks the anniversary of the 1993 publication detailing the discovery of the HD gene—a discovery made possible in large part by families in Latin America.
Gratitude Day is not just about reflection; it’s a call to action. The 2025 celebration includes:
Kids Lab Day (March 18th): A virtual event connecting children from affected communities with a research lab in France, headed by HD researcher Dr. Christian Neri, inspiring them to engage with science.
Candlelight vigils (March 19th & 21st): Families in Venezuela will gather to honor those lost to HD.
Pediatric Medical Day (March 20th): A healthcare event dedicated to children in affected communities.
Live Stream from Venezuela (Sunday, March 23rd): A global event providing an intimate look into the lives of HD families.
The Gratitude Day live stream is not just a celebration; it’s an opportunity to challenge misconceptions around HD and shine a light on the strength and the resilience of these communities.
A Model for Sustainable Change
One of the most inspiring aspects of Factor-H’s work is its emphasis on sustainability. The organization is fostering self-sufficiency by empowering local communities. It does this by fully reinvesting into the communities they’re seeking to help—100% of all donations to Factor-H go to supporting these communities in South America.
A key part of this effort is the concept of social agents—local individuals who step up to provide companionship, support, and advocacy within their own communities, and who act as representatives of these families and to facilitate aid. These social agents aren’t necessarily medical professionals; they are trusted members of the community who understand its unique challenges. Their role is invaluable in providing both practical assistance and emotional support to families who might otherwise feel abandoned.
Factor-H is also working to strengthen healthcare infrastructure by training caregivers and advocating for better medical access. Their long-term vision is to create lasting change that extends beyond immediate relief and builds true resilience in HD-affected communities.
A Future of Hope and Humanity
Factor-H is a testament to the power of human connection and compassion. It demonstrates that even in the face of immense challenges, change is possible when people come together with a shared vision of hope and dignity.
For those of us in the HD community and beyond, Factor-H’s work serves as an urgent reminder that scientific progress must go hand-in-hand with social responsibility. While we continue striving for treatments and a cure, we must also ensure that the families who made these advancements possible are not left behind. Nacho said, “We came up with Gratitude Day because we wanted to make sure that the immense contributions, particularly from the Venezuelan families, to research and clinical development are not forgotten.”
As Gratitude Day 2025 approaches, let’s take a moment to honor these families, amplify their voices, and reaffirm our commitment to a future where hope, not hardship, is the defining factor in their lives. So, this Sunday, March 23rd, take a few minutes to extend your hand to the most vulnerable members of the HD community and participate in the hope and humanity that are the primary factors in HD by joining Factor-H’s Gratitude Day live stream.
Stay tuned for our full interview with Dr. Ignacio Muñoz-Sanjuán, President and Founder of Factor-H, to be published on Gratitude Day, Sunday, March 23. There, we’ll do a deep dive into the unexpected genesis of an organization born out of the desire to make a positive change, the inspiring work that Factor-H is doing, and the unique issues faced by these incredibly vulnerable populations of HD families. It truly is a profoundly moving and eye-opening read on what we all have to be grateful for—a must read.
The Huntington’s Disease Youth Organization (HDYO) is an international non-profit dedicated to supporting, educating, and empowering young people up to the age of 35 who are impacted by Huntington’s Disease (HD). Founded in 2012, HDYO provides a safe space for young individuals and their families to access resources, connect with peers, and find professional support. During HDYO’s International Young Adult Congress held in Prague, Czech Republic on March 14-16, HDBuzz was honored to be in attendance, sharing accessible, research-driven insights to empower young people affected by Huntington’s disease.
A Mission Focused on Young People
HDYO’s work revolves around three key areas: support, education, and empowerment. Support is at the heart of the organization’s mission, ensuring that no young person faces HD alone. The organization provides peer-led support groups where young people can share their experiences in a safe environment. Professional support services also help connect individuals with resources in their communities, ensuring they receive the guidance they need.
Education is another crucial aspect of HDYO’s mission. The organization simplifies the complexities of HD through accessible, age-appropriate resources. These materials help young people of all ages and their families understand the disease, learn about its impact, and stay informed about the latest research. By making scientific information more digestible, HDYO bridges the gap between complex research and everyday understanding.
Beyond support and education, HDYO empowers young people to become advocates for themselves and their families. Through personal storytelling, mentorship, and leadership opportunities, the organization helps young individuals develop confidence and a sense of agency. Erasing stigma and fostering resilience within the HD community are fundamental goals of this empowerment work.
What Makes HDYO Unique?
HDYO stands out as the only organization dedicated exclusively to supporting young people affected by HD. Its youth-centric approach ensures that all programs and resources are tailored to the unique challenges faced by young individuals. This includes navigating the decision of whether or not to have a genetic test for HD, care-giving responsibilities for loved ones, especially parents, struggles with social and romantic relationships, as well as challenges to typical education and career paths.
The organization provides a vast array of online and in-person resources, making vital information accessible to young people around the world. These include educational videos, interactive tools for understanding HD, guides for parents and professionals, and virtual and in-person support events. Importantly, HDYO’s website and resources are available in multiple languages, ensuring global accessibility.
A key part of HDYO’s impact comes from its international presence. Through initiatives like the International Representatives program, the organization extends its reach by engaging young volunteers who spread awareness and provide localized support. This model ensures that HDYO’s mission resonates with and benefits communities worldwide.
The HDYO International Young Adult Congress
One of HDYO’s flagship initiatives is the International Young Adult Congress, a gathering designed by and for young people impacted by HD. The 2025 Congress took place last weekend, March 14-16, in Prague, Czech Republic, bringing together young people from across the world for education, connection, and advocacy.
The event’s agenda was structured to address the most pressing concerns facing young individuals in the HD community. Day 1 focused on mental health and community-building, creating a safe space for attendees to share their experiences. Discussions around self-care, grief, and loss helped participants develop coping strategies while interactive sessions encouraged networking.
Day 2 highlighted scientific understanding and personal narratives. Attendees learned about the latest HD research, clinical trials, and treatment developments through accessible presentations. Alongside this, community members shared personal stories about relationship dynamics, communication challenges, and cultural perspectives on HD.
Day 3 provided practical guidance and future planning on topics such as family planning, maintaining a healthy lifestyle, and navigating life after genetic testing. Sessions also explored complex emotional topics like survivor’s guilt and strategies for living at risk. These discussions offered attendees the tools and knowledge to make informed decisions about their futures.
Why Awareness of HDYO Matters
It is essential that young people affected by HD know about HDYO—they are a unique resource for those navigating the challenges of growing up in a family impacted by HD, offering guidance, reassurance, and community support. For many, discovering HDYO provides a sense of belonging and understanding that may be difficult to find elsewhere.
Equally important is ensuring that adults—whether family members, educators, or healthcare professionals—are aware of HDYO’s work. By understanding the resources available, adults can better support young individuals, guiding them to the information and communities that will help them navigate their HD journey.
A Community Built for the Future
HDYO is more than just a resource; it is a movement dedicated to uplifting young people affected by Huntington’s Disease. Through its unique focus on youth, accessible educational materials, and global outreach, the organization plays a critical role in the HD community. Events like the HDYO Congress reinforce the importance of connection and knowledge-sharing, ensuring that no young person has to face HD alone.
Increasing awareness of HDYO’s mission is vital for the next generation. Whether through online resources, peer support, or global events, HDYO continues to provide young people with the tools they need to face the future with confidence. If you know a young person impacted by HD, consider sharing HDYO’s resources with them—your support could make all the difference in helping them feel informed, connected, and empowered.
A new study bolsters our confidence that neurofilament light (NfL), a protein released by damaged brain cells, could serve as an early warning signal for Huntington’s disease (HD) progression—appearing in the blood many years before symptoms start. Tracking NfL levels may revolutionize HD research by helping predict when symptoms will appear, improving clinical trial design, and opening the door to earlier interventions.
Cracking the Silent Phase
One of the trickiest things about HD is its long silent phase—those years or even decades when someone carries the HD gene but hasn’t yet developed any symptoms. Most people with the gene for HD don’t start noticing changes until their 30s or 40s, but behind the scenes, the disease has been quietly reshaping the brain for years.
Scientists believe that starting treatments early—long before symptoms appear—will have the best shot at slowing or even stopping HD in its tracks. But how can we intervene early if we don’t know exactly when someone will develop symptoms?
What if there was a way to detect the earliest whispers of HD before the disease starts making itself known? That’s been one of the biggest goals in HD research for a long time, and a growing body of evidence suggests that the tiny protein NfL is giving us hope that it might be possible.
What is NfL?
NfL isn’t a new protein on the block, it’s been hanging out in our brains all along. Brain cells release little bits of NfL when they’re damaged or under stress. Think of NfL like a distress signal—a subtle siren going off in the brain, hinting that something isn’t quite right. The more damage happening, the louder that siren gets.
Scientists can measure NfL in the blood with a simple blood test, making it an easy and non-invasive way to peek inside the brain. In fact, clinical trials testing new HD medicines are already using NfL to help measure how well those treatments are working. But what if NfL could tell us even more, like who’s likely to develop symptoms soon, or how quickly HD is progressing? That’s exactly what a new study set out to investigate.
The Gift That Keeps on Giving
This study followed people with HD for an impressive 14 years—long enough to span everything from the rise of Instagram to the return of high-waisted jeans. Back in 2009, a group of volunteers with and without the HD gene signed up for the Cambridge Huntington’s Sleep Study. While the original goal was to track sleep patterns, participants also gave blood samples and completed tests to measure their thinking and movement abilities.
Fast forward to today, and those carefully stored blood samples have become a scientific goldmine. The researchers recently asked participants for permission to test their old blood samples for NfL levels, and 21 gene-positive and 14 gene-negative folks agreed. This kind of long-term follow-up study is incredibly valuable to research, and it shows how one study can keep giving back to the HD community, even years later.
Warning Signs in the Blood
At the start of the study, everyone with the HD gene was still symptom-free. But as the years went on, some people with the HD gene began showing those subtle early signs of HD—small changes in movement or thinking abilities that doctors can measure on a standardized rating scale.
When the researchers looked at the NfL levels in everyone’s blood, they found something remarkable. People who eventually developed symptoms had higher levels of NfL in their blood—even as early as 10 years before any symptoms appeared. This is consistent with a recent study that also found increases in NfL long before symptoms were predicted to appear.
Even more interesting, the speed at which NfL levels rose over time seemed to match how severe symptoms became. It wasn’t just about having more NfL, it was about how fast those levels were climbing.
Imagine standing outside and hearing a faint siren in the distance. The closer it gets, the louder and faster it sounds. That’s what NfL seems to be doing in HD—giving us an early warning of what’s coming and how quickly it’s approaching.
A Window into the Future
If scientists can confirm these findings in larger studies, it could be a game-changer for people with HD. Imagine having a simple blood test that could give you a sense of whether symptoms might start in the next decade, and how quickly the disease might progress. That kind of knowledge could be incredibly empowering.
For some, having that information might help with making decisions about family planning, careers, or finances. Others might prefer to live life as they always have, without that extra layer of information. Both choices are equally valid. What matters is giving people the option to know if they want to.
Supercharging Clinical Trials
NfL could also help solve one of the biggest challenges in HD clinical trials—how much people’s progression rates vary from person to person. Right now, everyone in a trial is compared to the average rate of disease progression, but not everyone follows the average timeline. If someone is naturally a fast progressor, a drug might look like it’s not working even if it’s actually slowing things down.
With NfL, researchers could tailor trials more precisely, identifying the people who are likely to show symptoms sooner and tracking whether the drug is slowing down their NfL rise. This could make trials faster, smaller, and more reliable, helping new treatments reach families sooner.
What’s Next?
Like any good detective story, there are still a few missing clues. Because this study used stored samples from a different research project, not all participants had blood samples at every time point—life happens! The researchers were upfront about these study limitations, and noted that the next step will be to confirm these findings in bigger studies with more consistent data collection.
Still, this study is an exciting first step toward making NfL a powerful tool for tracking HD progression, testing new treatments, and—maybe one day—giving people with the HD gene a clearer view of what the future might hold. The whispers of HD may be faint, but thanks to NfL, we’re starting to hear them a little more clearly.
After getting a poor night’s sleep, anyone would agree that good sleep makes a huge difference in day-to-day life. (Just ask any student who has stayed up all night to cram for a test…or anyone with a newborn baby.) It’s so critical that there’s an awareness week dedicated exclusively to sleep! So during this Sleep Awareness Week, March 9th through 15th, we’re sounding the alarm on sleep issues related to Huntington’s disease (HD) by sharing new research that suggests sleep-related changes may be happening even earlier than we previously thought.
Your brain needs sleep!
Sleep problems are common in people with HD after they begin to experience symptoms. We know that people with HD tend to have less deep sleep and insomnia is really common – in fact, 88% of people with the HD gene report having disturbed sleep. But much less is known about whether sleep issues also occur in people with the gene for HD before symptoms arise.
This is an important area of study, because poor sleep can cause problems with thinking, memory, and mood – already common features of early HD. Plus evidence from other diseases, like Alzheimer’s, has suggested that chronic poor sleep might even accelerate dementia on a biological level.
So if sleep problems were present in people with the gene for HD before other symptoms appear, it makes researchers wonder: If we could intervene and improve sleep, could it lessen thinking, movement, and mood symptoms associated with HD, and perhaps slow down disease progression?
Restless nights start up to 15 years before symptoms
A new study from Monash University in Australia, led by Emily Fitzgerald and colleagues, has recently helped to extend our understanding of how early sleep issues arise in people with the gene for HD.
They recruited a group of 48 adults without the gene for HD alongside a group of 36 people with the gene for HD who were not yet experiencing symptoms. Based on age and CAG repeat length, around a third of the people with the HD gene were predicted to be more than 15 years from developing symptoms, while two-thirds were predicted to be less than 15 years from symptom onset.
They asked study participants to wear a motion sensitive device on their wrist (a bit like a research-grade ‘FitBit’) continuously for two weeks to record their sleep and activity patterns.
They found that sleep in people with the HD gene who were more than 15 years from predicted symptom onset was no different to that of people without the HD gene. However, people with the HD gene who were less than 15 years from symptom onset had markedly disturbed sleep, characterised by broken sleep and more time spent awake during the night. This wasn’t just limited to the study participants who were close to symptom onset; it was even present in those 10-15 years from symptoms.
‘But I carry the HD gene and I sleep fine’
Additionally, they found no relationship between the presence of these sleep problems, and what people with the HD gene reported on subjective sleep questionnaires.
This means that many people with the HD gene who are not yet experiencing other symptoms may be unaware of or underestimate their sleep problems, or that sleep questionnaires fail to capture these sleep problems. So this area may well be a bigger problem than we currently know about.
Don’t turn out the light yet
Before we can say we’ve put sleep issues in HD to bed, it’s important to acknowledge some important caveats related to this research.
Even though the devices used in this study are much more accurate than ‘consumer-grade’ devices like FitBits, it’s important to remember that they only record movement, so their ability to reliably distinguish wakefulness from sleep isn’t 100% accurate. It’s possible, therefore, that some of the movement they picked up was while people were asleep – like turning over in bed.
It’s also important to acknowledge that around a third of the people with the HD gene who were less than 15 years from symptom onset were taking antidepressants, which can impair sleep continuity. When the study team re-analysed the data excluding these individuals, the findings were less extreme.
A high proportion of the people with the HD gene were also women of peri-menopausal age. Women are 40% more prone to insomnia than men (wow!), and on top of that, perimenopause often causes poor sleep, so this may have influenced findings.
Nevertheless, there have been other studies directly recording sleep brainwaves of people with the HD gene who don’t yet have symptoms, including in those not taking antidepressants, that have found similar patterns – suggesting the findings from this recent paper are robust.
Tips for counting sheep
Naturally, the next question is: How could we improve sleep for people with the HD gene who don’t yet have other symptoms?
The answer is NOT to be reaching for traditional ‘sleeping pills’ (things like Valium, Ambien, or drowsy antihistamines), as these induce poor quality sleep, alongside lots of negative daytime side effects like hangover drowsiness, memory problems, and in some cases, dependence.
A new kind of ‘sleeping pills’, known as orexin antagonists, have recently been licensed and appear to induce healthy sleep with a much better side effect profile. However, they are still being studied and have not yet been directly tested in people with HD. Regardless, before any ‘drug-based’ treatment is considered, several other steps are recommended. Our take-homes would be:
Take the time to consider your lifestyle factors and how they might be affecting your sleep quality. Things like caffeine, alcohol, nicotine, or lack of daytime activity/light exposure all adversely affect sleep quality, and can be easy to overlook. The same goes for poor ‘sleep hygiene’ – things like sleeping at irregular times, evening screen exposure, or working in the same space that you sleep. Organizations like Sleepstation and The Sleep Charity in the UK and the National Sleep Foundation in the US have great tips on this.
Think about having a discussion with your HD clinician or family doctor as to whether you have any symptoms of common sleep disorders – things like ‘restless leg syndrome’ or sleep apnoea (where there are long breathing pauses in sleep). As far as we know, these aren’t more common in HD, but if you did happen to have one of these coincidentally, there are many good treatments available that could improve your sleep quality. So it would be a good idea to get these addressed if they’re present. Likewise, night-time urinary problems, menopausal symptoms, pain, or untreated depression can all really impair sleep – so try to get them addressed with a healthcare professional where present.
If insomnia and broken sleep remain an issue after the above steps, consider asking your HD clinician or family doctor if they think a referral for ‘cognitive behavioural therapy for insomnia’ (CBT-I) would be appropriate. This is a highly evidence-based treatment that can really make a difference, and quite a few places now offer it through a digital app, so no need for face-to-face appointments. For instance Sleepio offers CBT-I, which may be covered by your employer’s health care plan in the US and is free through the NHS in the UK.
We still have some way to go before we fully understand the nature and repercussions of sleep problems for people with the HD gene who don’t yet have other symptoms. But if we could hit the snooze button on sleep issues, it’s tempting to dream that this could help keep people with HD healthier for longer. So while work remains, it’s an interesting research area to shine a (night) light on.
We’re back for the 3rd and final day of CHDI’s Huntington’s Disease Therapeutics Conference!
New Technologies and Breakthrough Science
This morning’s talks are kicking off with new technologies that have the potential of leading to breakthroughs in science for neurodegenerative diseases, like HD, and transform the field.
Ross Wilson: Molecular Scissors To Chop Out CAGs
Our first speaker is Ross Wilson, who is working on using CRISPR to selectively remove the disease-causing CAG repeats within the huntingtin gene. Whoa!
CRISPR is a molecular technique that began taking the scientific world by storm when it was broadly introduced in 2012. Just last year the first CRISPR-based drug was approved for blood diseases, like sickle cell anaemia.
You can think of CRISPR like molecular scissors. Researchers can use these molecular scissors to very precisely edit the genetic code to make all types of different changes. It’s a super powerful technique with many applications for diseases, including HD.
Ross recaps work by others who showed that CRISPR editing of the HTT gene increases lifespan and improves behavioural characteristics of HD mouse modes. However, this approach targeted both copies of HTT – totally shutting off both copies of HTT wouldn’t be a good therapeutic.
An updated approach he presented uses some genetic tricks to use CRISPR to only target the disease-causing copy of HTT. This was a great proof-of-concept paper, but there were concerns with “off target” effects – unintended editing of other genes that could come from this approach.
Ross’ lab has combined CRISPR strategies for improved efficiency and precision – selectively hitting just the expanded HTT. His big improvement is to break down CRISPR machinery after it does its job. If it sticks around in the cell, it can increase the chance of off target effects.
Ross went into some technical details about exactly how they’re getting the CRISPR machinery to shut off after it edits expanded HTT. The trick seems to be to deliver CRISPR pre-assembled. This is something that has only been possible because of recent achievements.
Ross highlighted some advantages of his system: it’s easy to manufacture, he can scale production quickly, it’s smaller than other approaches (which matters when you want to get things into the brain!), AND it turns off after it does its editing job. Quite a long list of advantages!
While it may be possible to deliver this into the brain using a harmless virus, Ross is describing an alternate method that uses special types of small particles that can carry the CRISPR ingredients into the brain in a ready-to-go format.
His team is also working on improving ways these types of drugs can be delivered to the brain, which currently require brain surgery. They’re testing various approaches in mice, but the hope is that they’ll be able to adapt their findings to people one day soon.
When they tested the effects that their potential drugs have in mice that model HD, they showed they can specifically edit just the expanded copy of HTT using CRISPR. Ross highlights that this competes with the currently best-in-class CRISPR approaches being used. Great news!
They also tested their CRISPR tools in pigs to get an idea of how well it works in larger animal models with a brain closer in size to that of people. No one likes to experiment on animals, but this is the best way we currently have to get drugs tested for safety before clinical trials in people.
In the pigs, they found some limitations with their approach around how well the material was distributed throughout the brain. These experiments are helping them improve their approach. They already have some ideas of how to improve the system, such as a “shell” for the CRISPR machinery, decorated with keys that fit into the locks of certain cells (neurons!). This is a HUGE advantage since we know that HD preferentially impacts certain cells in the brain.
Their updated approach looked to improve things in pigs, so with that improved strategy they’re going back to mice that model HD to see how their new and improved CRISPR machinery may influence signs and symptoms of HD.
Despite the advantages of the CRISPR delivery particle, it may be easier to move to the clinic using the harmless virus approach, so Ross’s group is exploring that too so they can get to the clinic as fast as possible. Exactly what all HD families and researchers want!
Zaneta Matuszek: Editing Single Letters In The Genetic Code
Our next speaker is Zaneta Matuszek, who recently graduated from the lab of David Liu at MIT. She’ll be sharing a similar story about precisely editing the CAG repeats, but with the goal of reducing somatic instability.
While we know that the length of the repeat within the HTT gene strongly contributes to the age of symptom onset, we also know there are other factors at play. The exact code of the repeating DNA seems to really matter. Small interruptions in the CAGs seem to have a big influence.
Zaneta is trying to capitalise on these small changes that can have a big impact. She uses a super cool variation of CRISPR called “base editing”. This is an ultra specific version of CRISPR that lets her edit single letters within the genetic code.
Within a genome of 2 meters of DNA per cell that codes for over 20,000 proteins, CRISPR base editing is like being able to target a specific letter in a single word from a library of hundreds of books and know that is the single letter that you want to change. The specificity is AMAZING!
Zaneta is using base editing to alter the CAG repeats with interruptions of CAA – something we know can delay the presence of HD symptoms in people by up to 13 years. She has data to show that she’s effectively able to do this in cells grown in a dish.
She’s also looked at how this may influence somatic instability. Excitingly, her data shows that the CAG repeat tract doesn’t get bigger when she uses base editing to alter some of the CAGs to CAAs in the cell model they are using for this in the lab. Zaneta thinks that this suggests that this approach could be a good way to go about controlling somatic instability, but also that CAA interruptions themselves might be influencing somatic instability in some way.
They also looked at other genes with long runs of CAGs to see if there are off target effects in those genes. While they mostly saw changes in the HTT gene, there were also changes in these other CAG-containing genes. So there is some work to do to make sure this approach is safe and on target.
Next they moved into mice that model HD. In these mice, they were able to target the expanded copy of HTT and also have data to suggest somatic instability is more stable. They also seem to see repeat contractions! Zaneta highlighted that the team are busy in the lab looking into this more.
William McEwan: Hijacking The Cell’s Garbage Disposal
Up next is William McEwan, who is working to target a protein called TRIM21 that he hopes will have a positive impact on both protein clumping and somatic instability in HD. William begins by talking about neurodegenerative diseases more broadly, starting the discussion with Alzheimer’s and a protein called Tau that causes protein clumping in that disease. In Alzheimer’s, Tau clumps can spread from cell to cell in the brain, something called “seeding”.
William highlighted that we have the ability to remove these Tau clumps from external compartments within the cell, but not the major internal compartment, called the nucleus. It’s protein clumps here that seem to be responsible for causing disease features of Alzheimer’s.
His work focuses on a protein called TRIM21. TRIM21 is a receptor – a protein stuck out on the cell surface like an antenna to catch cell signals. The signals TRIM21 catches are antibodies, specialized immune proteins that keep us healthy and help with fighting disease. William’s work suggests that TRIM21 could allow for the breakdown of Tau within the cell. Learning more about this interaction could help advance therapeutics for Alzherimer’s and help us learn about similar mechanisms that exist across neurodegenerative diseases.
William is exploring TRIM21 in HD by looking at how it may interact with HTT protein clumps in cells grown in a dish. One of his goals is to add special molecular decorations to help degrade these clumps. It’s always great to see what we can learn from other disease fields and new tools to apply to HD.
Ajamete Kaykas: AI-Guided Insights Into HD Drug Discovery
Our next speaker is Ajamete Kaykas from Insitro, a company that’s trying to use computers and machine learning to help us understand disease better and drive clinical decisions for therapeutic development with AI-guided insights. His focus today will be on their biological discovery platform that they’ve focused on human genetics for drug discovery to identify targets that they can advance. We’re living in the age of artificial intelligence (AI)! And it’s exciting to see these new tools being applied to HD research.
After they use their computer wizardry to identify new possible drug targets, they then move into cells grown in a dish to validate their findings – computer predictions alone mean very little without real world validation. They’ve scaled other technology platforms developed by others that allows them to quickly visually scan cells using fancy robotics in a completely automated way. This is technological advancements at their best to save hard working scientists lots of time and effort!
There are lots of advantages to using this platform, the first of which is that it’s great for looking at neurons! Neurons are a sensitive cell type that don’t like to be lifted off of cell dishes once they’re there. But that’s actually what a lot of traditional experiment approaches require. Insitro’s method allows the neurons to remain in the dish while they’re analyzed. This preserves information that is lost with other techniques. Neurons are shaped like a tree, with a trunk, body, and branches. Preserving these structures for analysis can be very informative for diseases like HD.
He shared that they’re using this to look at TDP43 – a gene we mentioned yesterday for its involvement in ALS. Using their system to analyze cells affected by TDP43, they pull out biological mechanisms already published, helping them to validate the approach they’re using. With enough data like this they can train their machine learning system to learn about the cells in great detail. Excitingly, they’re hoping to use this technology to start predicting biology that’s influenced by disease, without even doing experiments. Every PhD student’s dream!
So far, they’ve found that their machine learning models outperform other, more old-fashioned analyses. They can even use their models to predict where TDP43 would be located in cells to help predict disease. Incredibly cool! Briefly, he shared what he thinks they could do for HD. They could set up computer experiments to help identify new connections in human genetics and biological pathways to help us advance drug discovery. These technological advancements are an exciting way to speed our way to an HD treatment.
Kathleen McGinness: Getting To Undruggable Targets Through RNA
Next up is Kathleen McGinness from Arrakis Therapeutics. Her team is working to develop small molecule drugs which target RNA message molecules. RNAs are the message molecules which contain the instructions for making different protein molecules in the cell.
Traditional drug discovery has targeted proteins but now many companies are going after the RNA molecules insteads. That’s because many proteins aren’t druggable or are very hard to target with small molecules so instead, targeting the RNAs that encode them gives us another way to hit these targets with drugs.
Arrakis have a whole suite of tools to pursue small molecules for a given RNA target. They are trying to find small molecules which hit many different RNA message molecules. These small molecules come in lots of flavours and might have different effects on the RNA molecule. This includes blocking interaction between how RNA and proteins stick together, changing how RNA molecules are edited into their mature functional forms, as well as stopping production of the protein they encode.
One of the lead programs at Arrakis is focussed on Myotonic Dystrophy (DM1), another repeat expansion disease. For DM1, the RNA message molecule itself is thought to be what causes disease signs and symptoms. This message molecule contains a long string of toxic CUG repeats.
Arrakis have developed small molecules that bind the CUG repeat which they have tested in the test tube, cells in a dish, and animal models. These molecules block a protein called MBNL1 from binding onto the RNA message and the team has precisely determined how they bind to the RNA.
They also found that these drug candidates seem to help recover some of the signs of DM1 in cells and mice back to baseline at a molecular level. This included how gene messages are processed, protein clumps in the cell, and muscle symptoms in mouse models of DM1.
Arrakis are at this conference because they’re thinking about applying their technology to HD, and going after drug targets which have proved challenging with more traditional approaches so far. Woohoo! More people focused on HD!
Andreas Mund: Mapping Protein Levels On Top Of Brain Samples
Next up is Andreas Mund, who is using a super cool method to look at where different proteins are within a tissue sample. This is a massive advancement from standard techniques that smush up samples and look at bulk protein in a tube but give no information on where things are in tissues or cells.
These new techniques takes slices of tissue, like brain slices, puts them on microscope slides, then analyzes them with different probes against various proteins to reveal where proteins are within the tissue sample. They then put all the data together to build a big map of protein levels on top of the tissue. They can zoom in on the tissue samples and look at single cells that make up the tissue, where they can figure out where 1000s of proteins are located and who they are hanging out with. This super detailed analysis can give all sorts of insights about biology in health and disease.
Andreas is showing us some data where they used this technology to study an autoimmune-related skin disease. Using techniques that analyzed bulk protein in a tube, they could see that certain proteins involved in the immune response were elevated. Using their cool spatial protein technology, they looked to see exactly which type of immune cells had these kinds of changes and where they were in the layers of the skin. It turns out there is a drug that hits the elevated protein, so they treated a model of this disease which prevented onset of symptoms. Amazing!
Next, they showed this treatment also worked in people suffering from this skin condition after all drugs previously failed. A great success story! They are seeking to expand this platform to work in other disease areas, HD included, and use machine learning to provide new insights to their data that people might miss.
Looking at samples from the brain, they see that location matters: the same cell type in different areas of the brain have different proteins arranged in different ways. They are just getting started on HD, so we look forward to seeing their findings soon.
Clinical Biomarkers In HD Research
We’re back for the last session of the conference! And they saved a good one for the end. In this session we’ll be hearing about clinical biomarkers in HD research. These types of biomarkers will help clinicians eventually determine things like when HD symptoms begin and how rapidly disease will progress.
Jim Rosinski: Applying Machine Learning To Biomarker Identification
Our first speaker of this session is Jim Rosinksi from CHDI. Jim is a self-proclaimed data geek and is applying protein analysis and machine learning to the HD-Clarity dataset to identify biomarkers to help predict disease stage and progression.
HD-Clarity is a study that collects spinal fluid and blood from people with HD, led by HDBuzz superstar emeritus, Ed Wild. These samples help us find new biomarkers of HD so we can track disease progression, and figure out how well possible treatments might be working.
Jim is explaining how amazing the data are because of how many people from the HD community have generously participated. He calls it “ridiculously high quality”. They have so much data now, that he can’t tell us about it all in one talk! So he will focus on the proteins found in the spinal fluid.
Once the samples are collected from sites around the world, they are analysed by specialised scientists who figure out what markers are present and how they might track with HD. Encouragingly, all the expected biomarkers come up as strong hits. This is important because it validates what we already know and lends credibility to the scientific approach being used. This includes some biomarkers HDBuzz readers will probably know, like huntingtin and NfL, as well as newer ones, like NPPB.
One of the new ones Jim and his team have been looking at recently is NPPB, or natriuretic peptide B, which goes down as HD progresses. This is an established biomarker for heart disease where high levels are bad. So NPPB going down means the marker is trending in a positive direction for people with HD.
Jim comments that CSF biomarkers seem to be much simpler to figure out and identify than those in blood. We probably need more samples and more complicated analyses to figure out blood biomarkers completely.
The next step for biomarkers is to use them to predict disease stage. Jim and other biomarker data nerds have been collating tons and tons of data from people with HD as their disease progresses to feed machine learning programs to see what patterns they can spot and use to make predictions.
There are all types of questions they can ask with these models. If they have CSF data from 2 people, can the program correctly identify who has HD? Where are they in disease progression? Turns out that the models are pretty good at this! They can figure out pretty well who doesn’t have the gene for HD and at what stage of disease they are. It will take a little more work to be able to distinguish between early stages, where outward symptoms are not apparent. For example, distinguishing HD-ISS stage 0 and 1 is very challenging for these models so more work is needed there.
Rather than relying on looking at the levels of just one protein, like those we already know about (ie. NfL), they look at the levels of a panel of proteins. This seems to be critical for making accurate predictions with this model. The good news is that once other types of molecules are added to the protein analysis, the model should get better.
Next, they are looking to expand these models to other types of biofluids, looking at other types of molecules in these samples, like fats, and building new models for these types of predictions. These models will be especially helpful for understanding the impact of different therapeutics in clinical trials.
Leslie Thompson: Cell Free DNA As A Biomarker
Up next is Leslie Thompson from the University of California, Irvine. She will be telling us about her research on cell free DNA and special chemical decorations on DNA which could be used as a biomarker for HD. This type of approach was originally proposed as a biomarker for cancer research. The hope is to transfer those successful techniques over to HD.
Leslie is using Enroll-HD and Clarity-HD samples. So another big thanks to all who have participated in those observational studies!
But what exactly is cell free DNA? The idea is that people take a blood sample, which contains free-floating, fragmented pieces of DNA. Thus, the DNA is free from a cell – cell free DNA. In this cell free DNA, Leslie and her team are looking at small chemical marks that decorate the DNA, one of which is called methylation, and how that might differ in people with and without the gene for HD.
There’s already a kit for liver cancer on the market in China that can distinguish between different stages of liver cancer using this technology. Cell free DNA is also being investigated for tracking other diseases, like diabetes and prenatal diagnosis.
For brain diseases, it’s being used for multiple sclerosis and Alzheimer’s. This type of testing is very sensitive, and would be a fantastic biomarker to have for HD if it does in fact track with disease progression – and that’s exactly what Leslie is trying to figure out. So far Leslie and her team have collected pilot data from a small group of people without HD or with varying stages of HD showing that they have this experimental setup working in their lab. Always the first step!
While this data is preliminary and from a very small number of people, it seems to show that there are some differences between people with and without the gene for HD with additional separation of samples based on HD disease stage. Overall, she identified lots of different targets with methylation changes and showed data from a few key genes. These types of experiments give researchers large datasets to dig into!
Leslie explained that the changes identified are primarily from blood cells, not brain cells, which only made up about 3% of the cell free DNA. Interestingly, there are some changes they identified that correlate with disease progression, supporting the potential of cell free DNA as an HD biomarker.
Excitingly, Leslie thinks this type of analysis could be used for predictions. Meaning, once they work out all the kinks for this experiment, if they were to get a sample, they may be able to predict exactly where in disease trajectory someone is to monitor disease progression.
Their next steps are to expand this study to blood samples from many more people and look at cell free DNA changes in CSF samples, which will clue Leslie’s team into what’s happening in the brain.
Manuela Moretto: Brain Scans To Find Biomarkers Of Brain Health
Next we’re hearing from Manuela Moretto from the University of Padova and King’s College London. Manuela will be talking about her research on using brain scans to track HD in the iMarkHD study.
iMarkHD is a 5 year study taking lots of measurements, including different types of brain scans and biofluid samples from people at different stages of HD, some from people who are many years before predicted symptom onset. Studies like this can help us better understand the brain changes which happen during HD in much more detail, as the same people are measured again and again over the 5 year timeframe.
They are relying on several different high tech ways of imaging the brain to paint a more thorough picture, which should help figure out some of the very subtle changes which happen in HD throughout the disease course. One of these approaches uses special tracer molecules that light up the brain when they stick on to certain markers. Many of these markers are known indicators of brain health. Seeing how much the brain lights up in different people at different stages of HD could help us understand changes to brain health in HD.
This study has done a ton of work! The findings so far are very interesting. Some of these measures showed clear differences between the groups assessed whereas others were less obvious. This helps HD researchers know the brain features to which they need to pay attention.
Manuela finishes by thanking the participants in this study, who went through so many brain scans! It is a huge commitment of time and energy, and a truly impactful contribution.
Peter McColgan: Roche Moving Toward Selective HTT Lowering
For the penultimate talk of the day, we are hearing from Peter McColgan from Roche. If you are having deja vu, don’t panic, Peter did already give a talk on Day 1 and is back on the roster for Day 3. He will tell us about Roche’s selective approach for lowering the expanded copy of huntingtin, which they are developing. This differs from the total HTT lowering approach they’re currently exploring with their tominersen trial.
The new strategy Roche is using is to target a short region of the huntingtin gene that is only found in the expanded copy of the gene. The unique genetic area they have chosen is found in about 40% of people with HD. While this obviously means that, if successful, this specific drug wouldn’t work for 60% of people with HD, if this is successful Roche would certainly work to develop other iterations that do work for everyone with HD. This is very similar to what Wave Life Sciences are doing.
They have already tested this new drug candidate in mouse models of HD and shown that their drug preserves regular huntingtin whilst lowering the expanded huntingtin. Great news!
With the knowledge that this approach seems to work in mice, they turned back to their data from people from the GENERATION-HD1 trial. This lets them see exactly how many people have the unique genetic area on their expanded HTT gene that they want to target.
One of their goals now is to identify the number of people across the globe that have this unique genetic signature and so might benefit from this new drug candidate. They’re also collecting geographic data to see exactly where in the world these people are.
During the Q&A portion, someone asked Peter when they think they’ll be ready for clinical trials for this approach that specifically targets the expanded copy. Peter said they’re planning to start trials for this approach by the end of this year. Stay tuned!
The final talk of the conference is from Hilary Wilkinson from CHDI. She will be telling us about different types of CSF and blood-based biomarkers that are used in HD clinical research. Biomarkers can be used for LOTS of different things in HD research. These uses could be diagnosis, prognosis, safety or efficacy of drugs, as well as disease progression.
Hillary and the team are working to answer various questions about how we can most logically apply biomarkers across all of the uses they have. Just some of those questions are, how should we collect samples to optimize detection? How do we decide on the context of use for a biomarker? What sorts of statistical tests should we use for various approaches?
They’re not just asking these questions about new biomarkers, but also old biomarkers. Some of our oldest and currently most reliable biomarkers in HD research are expanded HTT and NfL.
Hillary is sharing an experimental plan for looking at levels of biomarkers using samples from the HD-Clarity dataset. When they look at expanded HTT in CSF, the fluid that bathes the brain, they see good reproducibility across site visits. This is critical for a good biomarker!
She thinks that blood levels of expanded HTT will make a good biomarker for intervention trials because distribution levels correlate with disease severity. This helps researchers stratify people with HD by disease stage just by looking at levels of expanded HTT that they have in their blood. However, a very important caveat is that expanded HTT levels don’t correlate with HD signs and symptoms. So there are clearly limitations with using this specific biomarker for measuring certain clinical changes associated with HD.
Now Hillary is moving on to the data she has looking at NfL as a biomarker. Levels of NfL in CSF seem to tally with the amount of neuronal damage caused by HD. Also, like expanded HTT, NfL levels in CSF are reproducible across visits for people in the HD-Clarity trial. Like others have shown, Hillary also sees an increase in NfL in CSF through HD disease stages with elevated levels seen very early, before symptoms are obvious.
In looking at NfL data from both HD-Clarity and Enroll-HD, Hillary feels it could be used for selection of clinical trial participants and may be useful for clinical trial design. Having such a powerful biomarker with multiple uses would be a big advantage.
Now she’s switching gears to newer biomarkers in the HD space, PENK and PDYN, which may have potential as disease activity biomarkers. Right now they’re working on figuring out how they can robustly measure these two new biomarkers.
Hillary also brought up some of the advantages of using somatic instability as a biomarker, but there are limitations here too. We can’t measure expansions in the brain while people are alive and what we can measure in blood is very subtle. There is work to do before we can use this in clinical trials.
She ended by stressing that sample collection and storage is critical for successful evaluation of biomarkers. This remains a high priority for CHDI as well as all researchers working on biomarker development.
That’s all for this year folks! We hope you enjoyed following along and learning about all of the super cool new HD research going on all over the world.
