• TRIGGER WARNING: This article contains a frank discussion around the challenges and realities of living with Huntington’s disease, as well as caring for those affected by it. Topics include suicidal ideation, threats to family members, financial distress, paranoia, severe anxiety, feelings of hopelessness, and loss of identity. We understand that this may be a difficult article for some to read and caution people about reading this article who may not be in an appropriate headspace to think about such topics. While these types of conversations are difficult, they are necessary to inform those who are unfamiliar with the disease, to help them try to understand the stark realities of living with Huntington’s, and the devastation that it causes for those from affected families.

The regulatory agency in the US that approves all medications, the Food and Drug Administration (FDA), considers disease severity and availability of other treatments throughout the approval process. FDA representatives participate in meetings with those living with the diseases to hear their lived experiences. This can be critical for advancing therapeutics in a timely manner that meet the needs of a patient population. On November 13, 2024, such a meeting took place in College Park, Maryland, bringing people living with Huntington’s disease (HD) and their caregivers face-to-face with the FDA.

The opportunity

The Huntington’s Disease Society of America (HDSA) coordinated the Externally-led Patient Focused Drug Development (EL-PFDD) Meeting between HD families and the FDA. HDSA organized a similar meeting in 2015, but a lot has changed in the past 9 years – research has taken great strides, we’ve gone from having one disease-targeting clinical trial to having many, and there are dozens of pharmaceutical and biotechnology companies interested in advancing drugs for HD.

The 2024 meeting was described as “a one-time opportunity to provide the FDA and other key stakeholders, including medical product developers, health care providers, and federal partners, your perspectives on the symptoms that matter most to you, impact the disease has on your daily life, and your experiences with currently available treatments”. This was a once-in-a-lifetime chance for many to be heard by the agency that has the chance to approve medicines for people living with HD.

The goals

The goals for the meeting were to educate, inform, and advise the FDA and medical product developers on the challenges of living with HD and advocating for disease modifying drugs. The impact of living with HD at pre-symptomatic, early, and mid stages was shared.

The agency was informed about the treatment outcomes that the community prefers and the risks that they’re willing to take to get treatments for HD. Advice was given so that the FDA could understand the challenges people with HD face with current clinical trial participation and how it could be improved.

The structure

Following opening remarks and a clinical overview, the day was divided into two panel discussions, one on health effects and daily impacts and another on current approaches to treatments.

People living with pre-symptomatic, early, and mid-stage HD shared their stories and experiences along with caregivers. Together, these perspectives and the information collected in this meeting will be used to “inform FDA’s decisions and oversight both during drug development and during the review of a marketing application to treat HD”. Put simply, teaching the FDA what it’s really like to live with HD could have a big impact on advancing treatments for HD.

After the personal statements, there was a large group facilitated discussion using specific survey questions that were distributed to the HD community by the HDSA ahead of this meeting. This survey, on HD Symptom and Treatment Impact, will be open until December 31, 2024 and the HDSA expects to have results from that survey available in February of 2025. At the event, various HD family members were asked to share their lived experience with the FDA as it related to the question in the survey.

Opening remarks:

Dr. Arik Johnson, Interim CEO and Chief Mission Officer, HDSA

The morning opened with a welcome message from Dr. Arik Johnson, thanking everyone for participating in this important meeting – both those from HD families for sharing their stories and the FDA for listening. There were over 60 people living with HD in the room and over 140 people who registered to attend virtually from across the globe, from 43 US states and 8 countries. The HD community was ready to be heard!

Arik said, “The time is now, for this meeting and for this opportunity”. There is more research happening now at earlier disease stages. As trials shift to testing drugs at earlier disease stages, there are different outcomes and risks, of which regulatory agencies and product developers need to be aware.

Dr. Teresa Buracchio, Director, Office of Neuroscience, Center for Drug Evaluation and Research, FDA

Dr. Teresa Buracchio’s job at the FDA is to oversee drugs in development for a variety of neurological conditions, including HD. She assured the crowd that many people across the FDA are listening, and that the FDA takes these meetings very seriously. She noted that the people living with HD and their caregivers are the experts, and the FDA is eager to listen to their stories. Teresa said, “the voice of the patient is very important to us”, and the FDA references these reports when working to advance drugs for diseases.

It is the job of the FDA to ensure that the benefits of therapeutics outweigh the risks. So understanding how patients view the risks and benefits of treatments will help them advance treatments that will have a positive impact on people with HD. Teresa noted the exciting advancements that have been made for Alzheimer’s disease and genetic forms of ALS and she said they’re excited to incorporate similar advances to the field of HD.

Dr. Victor Sung, Professor of Neurology, Division of Movement Disorders and Director of the HDSA HD Center of Excellence, University of Alabama

Dr. Victor Sung gave a clinical overview of HD, sharing details about the natural history and progression of HD. He noted that HD is considered a rare disease and is less well known than other diseases. Even still, the prevalence of HD is actually similar to ALS, which gets a lot more “press time” and is more recognizable by name.

Even as a less well-known rare disease, HD has had massive importance in the landscape of genetics – the discovery of the gene that causes HD, led by Dr. Nancy Wexler with the help of families from Venezuela, directly led to the Human Genome Project.

Victor detailed the genetics of the disease; that it is caused by the repetition of a C-A-G letter code in the huntingtin gene that’s on the 4th chromosome. But he also highlighted the socioeconomic burdens of HD and how it differs from other diseases. HD impacts wage earnings from people affected by the diseases as well as caregivers, generation after generation. It also differs from other brain diseases that are sporadic, like ALS, in that it can impact many people within a family, sometimes entire generations. The details that Victor shared demonstrated to the FDA that the tragedy of HD is truly unparalleled.

He then showed data that suggests there are changes occurring before people start to show symptoms of HD, like behavioral and cognitive changes associated with thinking, learning, and memory. This suggests developing early treatments for HD is potentially feasible.

He ended by saying that we have no disease modifying treatments for HD right now, but we are pushing into that realm. “The future is bright. There are lots of things happening in the disease-modifying space for HD. But we can only do this together, and we will do this together.”

Panel 1: Health effects and daily impacts

The first panel began with representatives at the pre-symptomatic, early, and mid stages, as well as a family member. They shared their stories about living with HD at each of these stages, highlighting how the disease, or knowledge that they’ll develop the disease without some sort of intervention, has affected their lives.

Speakers underscored the impact that HD has had, influencing the decision to have biological children, creating early conversations around life insurance and retirement planning, and becoming a caregiver to parents who represent a constant reminder of what the future holds unless we figure out a way to slow or stop HD.

Speakers detailed the changes they’ve experienced because of HD, such as a reduced ability to think through problems, multitask, and organize their lives, which has led to a loss of jobs, the ability to drive, and independence, causing an overall feeling of a loss of identity. Physical exercise and outdoor walks that used to be the highlight of a day now brought feelings of dread because of balance issues that have caused falls, leading to cuts so severe they require stitches. The emotional changes that HD brings were also discussed, with the onset of depression, anxiety, and panic disorder.

Loss and grief were common themes. Along with the emotional ups and downs of HD, hope itself has become an emotional rollercoaster for those affected by HD, with the highs many experienced during the start of the GENERATION-HD1 trial, and the lows from the halting of that same trial in March of 2021.

Panel 1: Group discussion around health effects and daily impacts

Questions that were discussed with the group from the HD Symptom and Treatment Impact survey around the health effects and daily impacts of living with HD were:

• Of all the symptoms that you have experienced because of your condition, which 1-3 have had the most significant impact on your life?
• Are there specific activities that are important to you, but that you cannot do at all or as fully as you would like because of your condition?
• As it relates to your condition, what does a good day / bad day look like?
• How has your condition changed over time?
• What worries you most about your condition?

Pre-symptomatic

People living with pre-symptomatic HD said that cognitive and psychiatric symptoms are the primary issues, citing anxiety, depression, emotional outbursts, mind fog, and difficulty concentrating.

People shared that even at this stage they began to feel a loss of identity. Some people with high-level jobs, such as those working in finance on Wall Street, were fired because of changes experienced due to HD even 5 to 10 years before anyone on the outside would say they had symptoms.

The group noted that even though they are typically considered pre-symptomatic until HD-associated movement symptoms begin, there are real problems that begin to present in this stage. People overall felt like they were being forced to live their lives in a holding pattern, unable to receive treatment because they didn’t yet have symptoms, but also unable to receive treatment for the symptoms they were experiencing because they were being told they aren’t severe enough.

Early-stage

People living with early-stage HD cited some of the same issues as the pre-symptomatic group, highlighting problems with anxiety, depression, difficulty concentrating, and memory lapses. While the overarching issues were the same, the tone captured the more advanced state of these issues.

Overall, people cited that at the early-stage HD has caused them significant worry about the future. They fear becoming a burden to their loved ones and the impact that HD will have on their children. The thinking problems that increase during this stage cause people to make poor financial decisions and prevent them from being able to pay their own bills.

Participants stated that the early-stage brings changes related to independence – those who were once fully independent transition to being fully reliant on others for many basic functions, which is devastating, particularly for those who don’t have a support system. And for those seeking intimate relationships, HD has made dating “impossible”. An audience member with early-stage HD shared that they’re afraid to hold their grandchildren because of balance issues. Others shared that they avoid family functions because they don’t want to go in public or be seen for fear that people will think they’re drunk or on drugs.

This group also said emotional outbursts were a serious concern, becoming dangerous at times with the fear of law enforcement involvement. Others detailed the increase in paranoia at this stage, causing one person to hold a shotgun up against their own child because they didn’t know who they were or why they were there. Situations with law enforcement and nursing staff can easily become reactive because of such paranoia.

Mid-stage

People living with mid-stage HD shared that they’re unable to do work that they’ve done in the past or have been trained for, that they’ve lost independence, that they’re no longer able to drive, and that they’re financially unstable. The massive financial burden that HD causes was noted, both from the loss of income for the person living with HD as well as the loss of income from the caregiver rerouting their time to take care of the person with HD.

At the mid-stage, components of a good day related to things many of us often take for granted – a good night’s sleep, forgiving yourself for missteps and realizing it’s okay to not be perfect, and not having urinary incontinence. Those in this group cited bad days as those fraught with obsession over death and suicidal ideations.

For people in the mid-stage of HD, participants cited that symptoms around clumsiness, movements, anxiety, and difficulty concentrating have had the biggest impact on their lives. They shared that their ability to walk and speak has degraded to the point of constantly stumbling and having slurred speech, which causes them to feel uncomfortable in social situations and lose social connections and peer support. Gastrointestinal issues, which are a known problem for many people living with HD, were brought up for the first time in this group.

For people in mid-stage HD, many were most worried about the capacities they’re losing, or will lose next. They shared grief over loved ones constantly losing pieces of themselves. Caregivers expressed worry over what will happen when loved ones need more consistent full-time care and the financial impact that will have on their families.

Panel 2: Current approaches to treatment

The second panel centered around current approaches to treatment, bringing in a different group of panelists, one each with pre-symptomatic, early, and mid-stage HD, along with a family member of a person living with pre-symptomatic HD.

Panelists shared that the psychological and physical toll of HD is grueling. People with pre-symptomatic HD want to participate in trials to prevent the onset of the most severe symptoms but are told their disease hasn’t progressed enough to be considered for trials. The frustration around wanting to try but not being able to is defeating. One panelist stated, “We know what happens when we do nothing. We just want a chance to fight.”

Those with multi-generational experience with HD shared stories of watching their parents use treatments for their movements, only to have their engagement with the world slowed. Panelists shared their experiences participating in clinical trials that were ultimately halted, saying that even though they felt they were benefiting they no longer had access to that medication. They also detailed the heart wrenching conversation with their children, having to explain the lack of access to a drug they thought helped.

A heartfelt plea was made to the FDA for a special designation for unproven and unapproved treatments that make people feel better regardless of trial outcome, to help develop better determinants for trial endpoints, to move trials into pre-symptomatic groups, to focus on cognitive, psychiatric, and behavioral symptoms, and to help increase funding for HD research.

Panel 2: Group discussion around current approaches to treatment

Questions that were discussed with the group from the HD Symptom and Treatment Impact survey around the current approaches to treatment for HD were:

• What are you currently doing to help treat your HD symptoms?
• How has your treatment regimen changed over time and why?
• How well does your current treatment regimen treat the most significant symptoms of HD that you experience? How well do your treatments improve your ability to do specific activities?
• How well have these treatments worked for you as your condition has changed over time?
• What are the most significant downsides to your current treatments and how do they affect your daily life?
• Short of a complete cure, what specific things are most important to you around delaying the progression of HD?
• If you could have a reduction in symptoms, what would make the most positive change in your life?
• Do you have any concerns around participating in a clinical trial?

Pre-symptomatic

At the pre-symptomatic stage, many people indicated that they’re taking medication for anxiety and depression. Tellingly, caregivers also stated they’re on similar medications along with blood pressure medication, suggestive of the ripple effect that HD has through families. Participants also cited non-medical treatments that have been suggested to slow disease onset, such as exercise, good sleep, a healthy diet, and a positive mindset.

By and large the most significant downside noted from the pre-symptomatic group was their inability to qualify for clinical trials. While they see massive changes in themselves that they believe are from HD, they’re constantly told they don’t have symptoms and thus don’t qualify for trials.

For people with pre-symptomatic HD, they expressed a strong desire to try anything in trials that could slow disease progression or delay onset. They noted that a treatment wouldn’t have to even hold the promise of a cure, and that delaying onset would be enough. People were most interested in medications that could potentially treat thinking changes brought about by HD, which could help them keep their jobs for longer to offset the financial burden associated with HD.

Early-stage

Along with anxiety and depression medication mentioned by the previous group, people living with early-stage HD stated that they’re prioritizing exercise, getting outside more, and participating in music therapy. People also said that they’re challenging themselves intellectually, by going back to school and playing brain games.

In the early-stage HD group, some felt that medications used to control movement symptoms have been critical. However, some of these medications don’t work for everyone, so trying several regulatory approved medications allowed them to find one that helped control their movements while also decreasing negative mental side effects that caused suicidal ideations. Others found that ADHD medication has helped with thinking and memory problems. One participant stated that medication that she takes for anger outbursts has allowed her to keep her job and has helped keep her family together. Several in this group cited medical marijuana as being a “game changer”, although laws vary state-by-state in the US, which some noted as being an issue for access and regulation.

Many people in the early-stage group noted challenges around trial participation related to traveling far distances and logistical difficulties for caregivers who often coordinate care and trial participation. Others detailed challenges with navigating the US healthcare system. Some HDSA Centers of Excellence don’t accept some insurance plans and some medications prescribed by physicians for HD symptoms aren’t covered by insurance.

As in the previous group, people living with early-stage HD stated that they want medications that could help with cognitive effects and thinking problems. This could help with time management issues, help people keep their jobs for longer, and defray financial concerns by extended wage-earning years. Improving cognition could also help people communicate better and maintain independence for as long as possible.

One person from the early-stage HD group cited that they just wanted to retain their dignity. Being able to go to the bathroom and take a shower on their own would have the most positive change in their life.

Mid-stage

From the mid-stage group, some cited that they’re taking sleep medication. One said that sleep apnea machines have helped with getting better rest. Others said they’re working to improve the small things that affect health, like dental, vision, and hearing problems, that can add up over time.

Others mentioned small lifestyle changes that have made a difference, such as always using a straw and moving to a single level house so that falls down stairs are less likely. Those in the mid-stage group stated they’re working to make accommodations for what they or their loved ones are experiencing, which can be as simple as putting a tablecloth down instead of trying to get someone to eat more neatly. Astutely, one participant noted that you have to think outside the box for HD to find things that will work at each stage.

One participant said that her life changed when her husband went on antipsychotics, which helped control abusive and paranoid behavior.

As for the previous groups, trial location was a concern. One participant from the mid-stage group said, “I will do anything if it means helping my husband and helping my kids”. HD is a family disease, evidenced by the caregivers that stood up, literally and figuratively, at the recent FDA meeting for their loved ones with HD. Another woman said she would give her life in a trial if she thought that meant it would secure the future for her daughter and granddaughter. A sentiment she said that she hopes doesn’t fall on deaf ears.

The conversation will continue

A representative from the FDA shared that they’re having a virtual patient listening event on December 4th to hear from the community on what they think about enrolling in a trial at pre and early symptomatic stages. She encouraged everyone to register, listen, then add their thoughts into the meeting notes. After the meeting they’re going to develop a summary to help inform the FDA and stakeholders in drug development. Registration for this event will close December 3, 2024.

Arik delivered closing remarks, thanking everyone who participated, both in person and online. He noted that we have a lot of work left to do and this is just the first step in the process. There is still a lot that wasn’t said, but the work will continue to ensure that everyone is heard. Every lived experience with HD, in every stage of HD, is impactful and matters, and will be used in future decision making.

Arik noted that there are things that can be done right now, such as participating in observational studies like ENROLL-HD, POWER-HD, and MyHDStory. He noted that it’s important for everyone to take care of themselves and reach out to people if you need help.

The takeaways

The discussions with the pre-symptomatic group highlights that the term “symptomatic” needs to be reconsidered, as the time when many are considered to be without symptoms is filled with behavioral and psychological changes. For them, the pre-symptomatic stage doesn’t mean they don’t have symptoms. People reported feeling frustrated that they see that they’re changing, with anxiety, depression, or executive functioning, but people don’t see that on the outside and doctors will tell them to come back in 5 or 10 years when they start to show symptoms.

At points, an FDA representative took the microphone to directly ask the audience what types of medications would be most useful for them. Almost everyone agreed that having something that works to improve cognition would be their number one choice. This could improve their thinking so that they could keep their jobs longer, defray the financial burden of HD, and help them communicate better with loved ones.

The direct exchange between the FDA and HD families underscored what this meeting was all about – a two-way conversation to help the FDA understand the needs of HD families to get this community treatment options as soon as possible to improve their lives. The HD families were heard.

Thank you!

Any meeting to educate the uninformed about HD will be emotional. There’s no way to describe HD without stirring feelings of loss, grief, and despair. Even through that though, a strong, bright thread remained – that of resilience, that of hope, that of determination.

Many experiences were punctuated with statements around wanting to not just survive but to live, wanting to participate in trials, wanting to be a part of the science that will get us a treatment for HD. Along with the heartache that HD brings, there’s no doubt that the FDA also heard the underlying message of strength within this community.

To everyone from the community who participated, attended, and shared your stories – thank you. Thank you for your willingness to be vulnerable. Thank you for your honesty. Thank you for standing up to change how the FDA views HD. You represented every HD family member who couldn’t be in that room, and you did it gracefully. Because of you, the needle was moved today. Because of you, we’re one step closer. Because of you, the HD community stood face-to-face with the change makers and was heard. Thank you.

The Huntington’s disease (HD) community received the news on November 20, 2024 that Sage Therapeutics would be halting the development of their drug dalzanemdor (previously SAGE-718) for HD. Sage had hoped that dalzenemdor would work to improve thinking problems experienced by people with HD and had recent setbacks with the same drug for other diseases. There’s no other way to say it: this is disappointing news and many people will feel disheartened today. Let’s break down what we learned from Sage in their recent press release and what this means for the HD community.

Thinking and memory in Huntington’s

HD is classically thought of as a movement disorder and onset is still often clinically defined as when these motor symptoms begin. However, HD causes many other effects, such as changes in cognition (thinking, learning, and memory).

Newer types of tests can measure cognitive changes in people with HD. The Huntington’s disease cognitive assessment battery (HD-CAB) was developed about a decade ago specifically to look at changes in thinking, learning, and memory in people with HD. This is a set of tests that measures things like problem solving, matching, language, and other aspects of thought and executive function.

These new tests show that the cognitive changes that happen over time as HD progresses can be measured. With that, it has allowed drug developers to target thinking, learning, and memory, with the hopes of developing drugs to improve these cognitive symptoms. Medications targeted at cognitive changes could have a massive benefit for people with HD, such as helping them to maintain work performance and keep their jobs longer, which could expand working years for some people to defray the financial burden of HD.

Turning up the volume on thinking

Sage Therapeutics has focused on developing drugs to help treat cognition. Not just for HD, but for other diseases, like Parkinson’s and Alzheimer’s, where cognitive changes also occur.

Their drug dalzanemdor works by amplifying molecular messages in the brain. These molecular messages help brain cells communicate and work to try and improve cognitive function. In diseases like HD, these molecular messages are lower. The hope is that by turning up the volume on these molecular messages, thinking, learning, and memory will improve

Dalzanemdor trials

Sage began running several trials to test the ability of dalzanemdor to improve cognitive impairment for various diseases, including Parkison’s, Alzheimer’s, and HD.

Unfortunately, they announced in April of 2024 that, while dalzanemdor was generally safe and well tolerated, the trial did not meet the clinical endpoints for Parkinson’s disease. The trial showed that people taking dalzanemdor did not have meaningful differences in thinking tests compared to those on a sugar pill. Then in October of 2024 there was a similar announcement for their trial testing dalzanemdor for Alzheimer’s disease.

The Phase 2 DIMENSION study in HD was the last major trial to see if dalzanemdor could improve problems with thinking, learning, and memory for people who had a disease that causes cognitive problems. Unfortunately, we learned today, that the outcome for dalzanemdor for HD was similar to the previous trials

DIMENSION

The DIMENSION study was a 12-week clinical trial testing the effects of dalzanemdor on cognitive function in people with HD. There were 189 people that were randomly assigned to either take the drug or a sugar pill. Overall, dalzanemdor was generally safe and well tolerated.

In the study, cognitive function was measured with various tests, like the Symbol Digit Modality Test (SDMT). In this test, people are essentially asked to break a code – numbers are assigned to abstract symbols and people are asked to read out the numerical code associated with a string of symbols. This test measures various components of cognition, such as attention, visual processing, working memory, and thinking speed.

Unfortunately, those taking dalzanemdor didn’t show any cognitive improvements when compared to the group taking the sugar pill. Overall, DIMENSION failed to meet the clinical endpoints of the trial. Because of this, Sage has decided to halt the trial and future development of dalzanemdor. This includes halting the PURVIEW Study, which was an open label extension of their previous SURVEYOR Study, a small 28-day trial testing dalzanemdor in HD.

No trial is a failure

Trials may fail to meet their clinical endpoints, but no trial is a failure. There’s always something to be learned. From dalzanemdor, there are three main takeaways:

Firstly, the HD community is eager to have drugs that could improve cognitive changes. A recent meeting with the US Food and Drug Administration (FDA) hosted by the Huntington’s Disease Society of America (HDSA) made that clear. This all-day event gave HD families a platform to share the effects and daily impacts of HD with the US regulatory agency responsible for approving HD drugs. What was clear from this meeting is that HD families want drugs to help with cognitive symptoms caused by HD.

Secondly, trials like DIMENSION collect a huge amount of data from a large number of people. These rich datasets and the findings of the trial can help researchers better understand different aspects of HD. Specifically, this kind of data can help to better pinpoint how HD changes cognition over time, and give insights into how drugs might be better designed in the future.

Thirdly, we now know that running clinical trials that test the ability of drugs to change cognitive symptoms is possible. The advent of tests like the HD-CAB and SDMT, along with their use in clinical trials like DIMENSION, show that we can objectively measure these changes in people with HD. Now it’s up to the drug developers to use this information and continue to advance drugs for cognitive changes in HD.

Dusting ourselves off

Sometimes bad news is just that, bad. There’s no doubt that this news will come as a massive disappointment to many people in the trial that felt they were gaining something from dalzanemdor. It’s ok to be upset about this, but try to not let yourself get stuck there.

There’s a lot of good that’s going on right now in HD research. There are over 60 companies working in the HD space right now. There are 13 clinical studies currently recruiting for HD and many more are being planned. We heard very positive clinical trial updates from four companies just this year for potential disease-modifying drugs.

We are living in the age of clinical trials for HD! It would be fantastic if every single one of these companies knocked it out of the park every time. Unfortunately, that wouldn’t be realistic. It’s of course disappointing when a trial is halted, but the fact that there are dozens of other companies looking to start new trials should be encouraging.

It’s not about how many times you get knocked down, it’s about how many times you stand back up. So while today may have knocked us down, tomorrow we’ll dust ourselves off, and stand back up.

A recent study published in Nature Medicine, looked at how common certain genetic diseases are within the population. The diseases they looked at are referred to as repeat expansion diseases and include Huntington’s disease (HD). The researchers found that the genetic traits which underlie these diseases are more common than previously calculated. In this article, we will get into what the scientists found, and what this will mean for the HD community and beyond.

What are REDs?

HD is caused by an expansion of a repeating stretch of -C-A-G- DNA letters in the huntingtin gene. Everyone has these repeating CAGs but if you have too many, then you will develop HD if you live long enough.

HD is not the only kind of disease caused by this type of genetic change. In fact, there is a whole family of genetic disorders referred to as Repeat Expansion Disorders, or REDs. These include diseases like spinocerebellar ataxias, some forms of ALS/Lou Gerhig’s disease, Fragile X disease, Friedreich’s ataxia, Myotonic Dystrophy, spinal bulbar muscular atrophy, and others.

Calculating how many people are affected by REDs

A long-standing issue in human genetics and the study of diseases like HD, is that most of our human data is limited to DNA samples from White populations in the west. This can lead to an inaccurate idea of how many people are affected by HD and can have real-world implications for how non-White people with HD can access healthcare and other resources.

We also only tend to genetically test folks who are symptomatic already or who we know to be at risk. This means if someone doesn’t have a textbook series of symptoms, they might not have a genetic test and it’s possible that their doctor might misdiagnose them.

These incidence numbers are also important when HD advocates and patient organisations appeal to governments worldwide to provide support for research and care for HD. Collectively, REDs tend to be referred to as rare, but with the limited data we have had to date, do we know this to be true?

Big data to answer big questions

A large group of researchers, anchored in University College London (UCL) in the UK, with Dr. Arianna Tucci, looked at a massive dataset of the entire genetic makeup of people to see how common REDs really are. This study used DNA from over 82,000 people randomly sampled from diverse populations worldwide. In these samples, a person’s entire DNA was sequenced, not just one or two genes.

Armed with this huge set of genetic data, they asked a series of simple questions: looking across many regions and ethnicities without any bias for any disease, do we continue to see these REDs are mostly in White populations? Are these diseases that mostly affect Europeans and people of European ancestry?

The answers from this study were profound in two aspects. First, REDs were seen in similar incidence across Europeans, Africans, Americans, East and South Asians. This challenges the status quo that REDs are primarily found in European populations, an assertion based on more limited historical datasets. In fact, they are represented in all broad populations.

The second surprise from this data was that the incidence of REDs was much higher than predicted in the past! The data show new incidence numbers of 1 in 283 for all REDs combined. From a different perspective, this means over 1.2 million people’s DNA contain the genetic traits corresponding to REDs just in the USA. For HD alone, the incidence was seen at 1 in 4100, but with a variance from 1 in 2700 to 1 in 6300. Older statistics had this number around 1 in 10,000.

This finding tallies with some of the research talks we covered from the CHDI therapeutics meeting earlier this year. Sahar Gelfman from the Regeneron Genetics Center presented data from a study where they had looked at the HD gene from nearly a million peoples DNA. Although their samples did not include many people from outside Europe and North America, they did see that the genetic trait for HD was found in ~1 in 2000 people.

Comparing genetic data to what is happening in the clinic

But does this mean that 1 in 283 people have these genetic diseases? Maybe not. The frequency of these genetic expansions does not match up with the number of people diagnosed by doctors to have REDs.

There could be two reasons for this. Firstly, many people may not yet have been properly diagnosed with a RED, or may be misdiagnosed with a different disease. Given how rare some of these diseases are thought to be, some non-specialist clinicians may have a hard time pin-pointing a diagnosis, especially if the presentation of symptoms is a little bit unusual or does not follow the textbook definition.

A second and more hopeful reason is that despite having a repeat expansion mutation in a known disease gene, some people will have very mild, limited, or no symptoms of these diseases. This is referred to in human genetics as reduced penetrance. This could be because of lifestyle factors or other genetic differences between people which can cause the disease onset to be delayed or progression of symptoms to be slowed down.

This has been an intense area of focus in HD research with Genome Wide Association Studies (GWAS). The hope is that we could design drugs to mimic the genetic traits which might cause someone to have disease later in life or a slower progression of symptoms. Now that we know even more people might have the HD gene but might not get sick as quickly, or at all, scientists could expand GWAS to include these folks, and maybe find new ideas for developing medicines.

Take home messages

From this study, the message to doctors worldwide is that REDs are a lot more common than they were taught in their training in the past. This will hopefully empower them to test for these disorders with specific genetic tests when symptoms overlap with more common diseases.

Often, diagnosing someone with a neurological disorder can be like solving a mystery, as symptoms can look and change differently in different people, symptoms between common and less common diseases can overlap, and family history is often not known. This may lead a doctor to test for certain common diseases, but not recognize a less common disease because they don’t experience it often in their careers.

The study also gives us an idea of what the HD mutations look like in different ethnicities – this is important information to potentially tune therapeutics designed to specifically lower the expanded copy of huntingtin so that they’re more effective in a broader range of people worldwide.

For example, the huntingtin lowering drug WVE003 from Wave Life Sciences currently in clinical trials, targets a genetic signature in the HD gene so that only the expanded toxic form of the HD protein is lowered. Current data suggests that the genetic signature they are targeting is found more commonly in people of European ancestry. Greater knowledge of the type of signatures found in different populations would help companies like Wave design drugs which might treat a more diverse pool of patients.

Importantly, this work will also be a message to governments and health agencies to rethink the term “rare” when it comes to these genetic diseases. Greater awareness of these diseases by policy makers and other stakeholders could help give communities, like ours, more resources and support to help affected families, provide appropriate healthcare, and develop new medicines.

We’re back for the 3rd and final day of the Huntington Study Group (HSG) Conference. You can also read updates from day1 and day 2. They saved the best for last – family day! Follow along for our last day of HSG!

Demystifying research

Family Day is opening with a talk from Dr. Martha Nance, a neurologist from the University of Minnesota. This “Demystifying Research” session will walk through the basics of research studies, participation, and how science leads to treatments. She reminds us of the benefits and challenges of working on HD research. For example, it’s caused by a single gene and has a wonderful, engaged participant community, but it’s rare, complex, and affects the brain.

Now Martha is revisiting the basics of genetics, how our genes are composed of a letter code that we represent with the letters A, C, T, and G. HD is caused by a change to a single gene called huntingtin, abbreviated HTT.

Within the huntingtin gene, everyone has repeats of the letters CAG – most people have between 10 and 26. Those with 40 or more will go on to develop HD. 36-39 repeats may or may not lead to HD symptoms in someone’s lifetime. CAGs of 27-35 can sometimes lead to longer repeats in the next generation – so the parent might not have HD, but their children could inherit more repeats and develop symptoms. It’s important to note that none of these ranges are absolutes; other genes and environmental factors can affect HD and its onset.

Martha reminds us that genes (DNA) can be made into genetic copies (RNA) which are used to make the cell’s building blocks (proteins). She also lists the different types of research approaches that can be productive for learning more about a disease and developing treatments.

Observational studies and surveys help researchers understand how genetics, biology, and symptoms connect, or how symptoms affect people’s lives. Examples are MyHDStory, JOIN-HD, CHANGE-HD, and ENROLL-HD.

Other studies focus on the biology of HD to study the “downstream effects” – what happens to brain cells because of a genetic change, like inflammation, damage, and dysfunction, and how to help clean up any cellular “trash”, like unused protein fragments or toxic proteins.

Martha talks about some of the approaches to treating HD, like targeting the underlying CAG repeats, addressing dysfunction in cells, lowering huntingtin, and focusing on symptoms to improve quality of life.

She discusses some of the nuances of huntingtin lowering and the many approaches being explored. Designing drugs to “stick” to the RNA message, focusing on one or both copies of huntingtin, how to deliver these potential treatments – there are many ways to address these challenges with novel science.

She also lists the different drugs already available for helping with HD symptoms, and mentions new ideas that have gone from basic research to drug development, like trying to slow down the gradual expansion of CAG repeats that can happen in brain cells over time (somatic instability).

Martha is now talking about how we measure the progression of HD and determine eligibility for trials. One example is a CAP score, a formula that takes into account CAG repeat size and age to determine an “expected” age of onset. This of course varies by individual.

She also touches on historical and current ways to separate HD into “stages.” For research purposes, today’s scientific and clinical community uses the HD-ISS.

Bridging research to treatment

The next session is a panel discussion and Q&A on clinical research participation, involving patients, researchers, doctors, and other community members who are here to speak about their experiences and answer questions about the path from research to treatment.

Topics that came up included perseverance despite setbacks, learning from clinical trials that didn’t end as expected, frustration with eligibility criteria, and contributing to research through participation in observational studies.

All of the panelists encouraged the audience to get involved with research and with their local communities in any way that they can, whether that’s a study of a medication, an observational trial, or simply connecting with others in the community to spread awareness and receive support.

HD biology and basics

The afternoon session begins with Dr. Victor Sung, a neurologist (and community advocate) at the University of Alabama who focuses on HD. He’s speaking about HSG’s work in the HD space from research basics to the clinic.

He’s got a great analogy for thinking about DNA repair and lengthening of CAG repeats – the two strands of DNA act like a stuck zipper that gets off track, mismatching with the opposite side. The attempt to fix the lopsided zipper adds even more CAGs by accident.

We’ve heard a lot about the biomarker NfL, which is released from damaged brain cells and goes up over the course of HD. Victor likens the release of NfL to a tornado, where things get flung around – the more damage, the bigger the tornado.

He also revisits the HD-ISS staging system and how it is helping to design trials to slow down the progression of HD. Having a way to better define the pre-symptomatic and very early stages of HD will be an asset when deciding when to treat.

He notes that the field has evolved from vitamins (and even blueberries!) as experimental treatments, to a wide variety of genetic and biology-based approaches in just a decade. The field welcomes researchers to “throw their hats in the ring” and attack the challenge of HD from all angles.

Victor also reminds us that 2024 is the first time we’ve had four positive press releases so close together about milestones in huntingtin-lowering drug development (from Wave, uniQure, PTC Therapeutics, and Skyhawk).

Launching hope from the lab to the clinic

Our next speaker is HDBuzz’s own Dr. Sarah Hernandez! Her talk is about hope in research, from the clinic, to experiments, to ideas. She’s first sharing her own family’s HD story and how far we’ve come from before the discovery of the HD gene to today.

Sarah’s family background and discovering the story of Nancy Wexler’s Gene Hunters led her to pursue a PhD and to study HD. She now heads up “all things science-y” at the Hereditary Disease Foundation, an HD research-focused nonprofit started by Nancy Wexler.

She revisits the rapid-fire good news from the summer of 2024, which HDBuzz covered following press releases from Wave, uniQure, PTC Therapeutics, and Skyhawk. Sarah encourages a bird’s-eye view of this positive news, which together is starting to show that HTT-lowering could become a successful treatment approach. She reminds us that there are even more HTT lowering strategies in the works, from companies like Latus Bio, Incisive Genetics, Atalanta Therapeutics, and Alnylum Pharmaceuticals.

She also mentions approaches to stopping the expansion of CAG repeats, from companies like Rgenta and LoQus23, or stem cell replacement therapies, in development by Neuexcell, Sana Biotechnology, and universities like UC Irvine and UC San Diego. Sarah also finds hope in basic research, like new tools to zoom in on single brain cells, and efforts to improve delivery of drugs to the brain through the nose, or using ultrasound!

Sarah shouts out the many HD organizations dedicated to care, support, research, and education in the US, like HDF, HDSA, HDBuzz, HDYO, HSG, HD-Reach, Help4HD, and more. She also reminds us that there is ongoing research into improving quality of life for people with HD, through studies on sleep, lifestyle choices, and equity in research and care. A hopeful talk indeed!

Igniting hope for HD

The next session is a panel discussion on hope, from HD community members on their personal stories about what inspires them to keep pushing for treatments and cures for HD.

Erin Patterson, author of Huntington’s Disease Heroes, shared her personal history with the disease, being gene positive as a caregiver for her father. She finds hope in the grace with which her father faces HD. She says even if there isn’t a treatment in time for her, she knows that she’ll be ok because of the way her dad approaches life.

Charles Sabine, OBE, founder of the HiddenNoMore Foundation, relays the hope that he helped foster when he orchestrated a meeting between Pope Francis and HD families. He made a movie about this encounter, called Dancing at the Vatican. Charles recently shared his story in a TED talk.

Dr. Karen Anderson shared that she gets hope from the HD families that come to community events like HSG. This wasn’t the case when she first got into the HD field! She’s worked with HSG on MyHDStory, which is an online research platform to connect people affected by HD, to better understand the needs of those living with HD, and break down barriers for clinical trial participation.

That’s all from us for HSG 2024! HDBuzz had a great time sending live updates to the community and we hope you enjoyed the coverage!

The Huntington Study Group (HSG) is a clinical research network focused on accelerating treatments for Huntington’s disease (HD). This year, the annual conference is being held in Cincinnati, where clinicians, clinical coordinators, social workers, researchers, and pharmaceutical companies are all gathered to share research updates and exchange ideas. HDBuzz is attending the meeting, live tweeting scientific updates as they happen. For those who couldn’t catch our live updates, we’ve compiled our tweets into a summary. Read on to learn what happened on Day 1 of #HSG2024!

Welcome to HSG 2024!

HSG leadership is kicking things off with a series of intros and brief updates about the meeting agenda and the future of the organization. Stay tuned today as well as Friday and Saturday as we share updates on clinical trials and content from sessions on genetic therapy and innovative drug development.

MyHDStory

The next session involved a few brief updates on clinical trials which are being run by HSG. First, Dr. Karen Andersen from Georgetown and Dr. Alex Dalrymple from the University of Virginia spoke about two research projects under the MyHDStory platform.

MyHDStory is an at-home online study that anyone from an HD family in the USA can participate in. The speakers explained that the study allows people to share their experiences with HD and to participate in upcoming online studies to help improve HD research and care.

KINECT-HD

Next, Drs. Erin Furr-Stimming of the University of Texas at Houston and Dr. Olga Klepitskaya of Neurocrine Biosciences talked about the KINECT-HD study of valbenazine, which was approved earlier in 2024 by the FDA in the USA to treat HD chorea.

KINECT-HD successfully showed that valbenazine can help control unwanted movements. Newer data analysis shows that the biggest side effects, like episodes of sleepiness, happen in the first few weeks of taking the drug, then taper off.

A pro and con debate on huntingtin lowering

For huntingtin lowering

The next session is a keynote involving a bit of debate about the pros and cons of huntingtin-lowering therapies. First, Dr. Blair Leavitt, a clinical HD researcher at the University of British Columbia, will talk about the pros of this approach.

As a refresher, the extra CAGs in the huntingtin gene lead to an extra-long protein. Dr. Leavitt is first presenting evidence from studies of the human gene and protein to show that this expanded form of huntingtin can be harmful. He points to evidence that people with HD who naturally produce less expanded huntingtin protein have delayed onset of HD symptoms.

He also shares data from studies in different animal and cell models showing that it’s safe to lower huntingtin, and often beneficial. The amount of lowering to aim for remains a major question that many laboratory and clinical researchers continue to explore.

Blair also emphasizes that the huntingtin lowering clinical trials of tominersen (Roche), branaplam (Novartis), and Wave drugs were not failures, as researchers continue to learn from them, redesigning drug chemistry, reimagining how therapies are trialed, and incorporating community feedback.

Against huntingtin lowering

Next Dr. Alberto Espay of the University of Cincinnati is speaking to the challenges of huntingtin lowering and the evidence against this approach. He reminds us that huntingtin is found in many, many species, and has multiple functions in different cells and organs, so we need to be careful about removing too much of it.

He states that we are certain that the huntingtin protein can function when it is a typical length, but we are not completely sure it can’t function when it’s extra-long. He is urging everyone to consider a gray area where an “abnormal” protein can do both good and harmful things.

Clumps of huntingtin appear in brain cells over the course of HD, but this is not always directly connected to the loss of brain cells. Plus, huntingtin has hundreds of “dance partners” and not all scientists are convinced that it’s a good idea to cut in and break up the dance!

Overall, his argument is that defining extra-long huntingtin as “toxic” might be jumping to conclusions, and we should be careful when deciding when and how much huntingtin-lowering to attempt.

He also suggests that we could consider approaches to increase the amount of “normal” or “wild-type” huntingtin as an alternative to lowering the extra-long or “mutant” kind. The only problem with this suggestion is that this has been tried in mice that model HD and the effects weren’t notable, so it wasn’t worth advancing toward trials.

Data will advance therapies

This lively session is staged in “debate” format! Dr. Leavitt concedes that huntingtin is very important, but counters Dr. Espay’s point that we could try increasing wild-type huntingtin with the point that lots of evidence points to the expanded copy being toxic. Just adding more wild-type protein won’t get rid of the toxicity of the expanded copy. However, there is probably a therapeutic window for each huntingtin-lowering drug where the right timing and level of lowering will be essential to figure out.

Dr. Espay urges all the companies and researchers in the room to think about the huntingtin protein and its important role in cells as they continue to innovate in the huntingtin-lowering therapy space.

HD advocate and journalist Charles Sabine, OBE has taken the podium to remind everyone that there remains hope in huntingtin lowering, but that a diversity of research approaches will lead us to a better future for people with HD. A strong conclusion of this interesting debate from Dr. Blair Leavitt: “We will advance therapies based on data!”

Drug delivery

The next session will feature speakers talking about drug discovery. Dr. Mali Jiang from Johns Hopkins is designing novel delivery systems for huntingtin-lowering and other approaches to genetic therapy. Her work in Dr. Lishan Lin’s laboratory focuses on a way to re-program liver cells to produce little “bubbles” known as exosomes that can help deliver genetic drugs throughout the bloodstream.

The lab is working on a drug called ER2001 which has already been tested in a very small human trial in China. Dr. Jiang showed data on levels of the drug in the body after it was given through IV injections over the course of a few months.

The ultimate goal is to use this new approach to lower huntingtin. The Lin lab and the company behind this work (ExoRNA Bioscience) are hoping to move forward with larger studies (~30 participants) in China and the US if they are able to find financial support.

PTC-518 has a new name! Votoplam!

Next, Brian Beers from PTC therapeutics is speaking about the PIVOT-HD study of PTC-518, now named votoplam. We wrote earlier this year about the early positive results of this study.

Brian is re-capping the results from people who were on votoplam for up to 12 months. These folks had lower levels of huntingtin in their blood and spinal fluid compared to those who got a placebo (pill with no drug).

This study has enrolled participants across a broad spectrum of early-stage HD symptoms. The side effects reported, like headaches, have been mild, and one update at this conference is that there were no immune system reactions. As we shared in June, PTC is also seeing some early trends in improved function.

Controlling CAG repeats

Up next is a research session on gene editing (altering DNA) and combatting somatic instability (stopping CAG repeat expansion). First Dr. Vanessa Wheeler from Mass General Hospital and Harvard Medical School detailed recent work looking at CAG expansions at the single cell level. This technique has really taken off in the past 10 years and gives researchers TONS of data. Compare looking at the stars with your eyes, or using a powerful telescope. A huge difference!

Vanessa also discussed GWAS data – genetic data that analyzes every single gene in a person. Using these large datasets from lots of people with the gene for HD, scientists can start to determine what genetic information affects age of symptom onset.

This identifies genetic markers (called modifiers) that track with earlier or later age at symptom onset. Getting a better understanding of these genes that modify the course of HD helps identify potential targets for drugs to delay HD symptom onset.

Vanessa and her team are currently looking at modifiers of somatic instability – the perpetual expansion of the CAG repeat in vulnerable brain cells. They’re hoping to identify genes that control somatic instability that they can target therapeutically.

Right now they’re testing these target genes in mice that model HD. When they use CRISPR to alter levels of these targets they find that they’re able to control the amount of somatic instability. So far they’ve tested 60 different targets. That’s a lot of work!

Every modifier gene that controls somatic instability in cells or mice has the potential to become a therapeutic target. They’re also testing combinations of targets, which, as you can imagine, gets quite complicated with 60 targets!

Vanessa and her team are also considering how single or combined targets could have different effects in different types of cells. So one modifier that slows or stops somatic instability in support cells in the brain (glia) may have a different effect in neurons.

She also shared details about a specific modifier that they’re examining, called LIG1, that seems to reduce somatic expansion in the brains of mice that model HD. We’ll be eagerly waiting for more data on this modifier!

Ultimately, Vanessa’s goal is to identify genetic modifiers of somatic expansion that will control instability, keep brain cells healthy for longer, slow symptom onset, and give people affected by HD more healthy and happy years.

CRISPR for gene editing

Up next is Dr. Ricardo Mouro Pinto, also from Mass General Hospital and Harvard Medical School. He’ll be talking to us about gene editing – the approach of changing the DNA blueprint to investigate and ultimately to treat HD. Exciting!

Ricardo started with a primer on CRISPR – a powerful genetic editing tool that you can think of like molecular scissors. Researchers can identify DNA targets that they want to edit, deploy CRISPR against that DNA letter code, and swap it out with a new sequence.
We wrote about the advancements made in medicine for Sickle Cell Disease using CRISPR.

Ricardo’s getting into the nitty gritty of how different DNA letters can be swapped out using different techniques. There is so much innovation in this area since the advent of CRISPR technology just 10 short years ago.

Ricardo touches on two major challenges for CRISPR in clinical HD research: delivery and safety. How do we get the drug to the brain, and how do we make sure that the drug is only making the DNA changes we want it to?

He notes that the NIH (science/medicine funding agency in the USA) has created a new funding initiative to support the advancement of gene editing therapies. Two of the 5 currently funded projects are focused on HD!

One of these projects focuses on trying to chop out extra CAG repeats from within the huntingtin gene, and the other tries to prevent CAG repeats from growing longer, combating somatic instability.

Some people with HD have “interruptions” in their CAG repeats, with a CAA thrown in instead. These folks tend to have later onset of symptoms. One group of NIH-funded collaborators (including Ricardo) is working on techniques to change CAGs to CAAs.

Ricardo refers back to some of those “modifiers” of somatic instability that Vanessa brought up. He is focusing on one called MLH3, exploring complex CRISPR editing techniques to tamp down its levels. In cells, this can slow or stop the growth of CAG repeats. The next step is to test these techniques in mice and in human cells that more closely mimic HD.

We’re likely quite far from human trials of these approaches, but it’s exciting nonetheless to see that this work is gaining traction and funding. The great potential advantage of a gene editing therapy is that it could be administered once with permanent effects.

Current strategies for HD therapeutics

In the next session, companies developing innovative therapies for HD will each give short talks on their most recent updates. HDBuzz’s own Dr. Sarah Hernandez is beginning with a brief overview covering the basics of different approaches and companies in the space.

Sarah is getting into the alphabet soup of huntingtin lowering techniques and delivery methods, like ASOs, RNAi, AAVs, and splice modulators. Several companies will have a chance to talk about their drug development efforts in more detail. She also mentions other therapeutic approaches to HD, like targeting somatic expansion, replacing lost brain cells, and enhancing cell-to-cell communication.

Sarah concludes with an exciting slide showing the many dozens of companies working in the HD space. We’re truly living in the age of clinical trials for HD research!

Alnylam Pharmaceuticals

First up in the innovator’s forum is Dr. Kevin Sloan from Alnylam Pharmaceuticals. They’re using a strategy called RNAi – RNA interference – that adds a bit of genetic code targeting the huntingtin message to lower the protein.

Kevin first covered the details of how RNAi works. One of the major challenges for RNAi-based drugs is delivery. They want to make sure the drug gets to where it needs to go – for HD, that’s all over the brain. Alnylam is also working on other diseases, and Kevin is sharing data from an RNAi drug they have for Alzheimer’s disease that’s moving into a Phase 2 trial.

Now they want to do the same thing for HD. They have an RNAi drug designed for huntingtin called ALN-HTT02. It targets all forms of huntingtin, including short bits prone to clumping. These are called huntingtin exon 1 fragments and they are thought to be toxic to brain cells.

We’ve written about these huntingtin exon 1 fragments, also called HTT1a. This tiny little fragment of the huntingtin message seems to code for a protein only made in people with the expanded huntingtin gene.

Alnylam is now testing ALN-HTT02 in monkeys, the step before moving drugs to human clinical trials. Just this week Alnylam announced that they’re starting a Phase 1 trial for this drug! This early trial will be initiated in the UK and Canada with recruitment in additional countries planned to follow.

The primary goal will be safety and tolerability, but they’ll also look at how well it targets huntingtin and how levels change in the CSF, the fluid that bathes the brain. They’ll use clinical tests to measure symptoms, but would need a larger trial to understand if ALN-HTT02 works to change clinical features of HD. It’s always exciting to have new trials announced and we’ll be eagerly waiting for new updates from Alnylam!

Rgenta

Up next is Dr. Travis Wager from Rgenta Therapeutics. They are developing small molecules that could be taken as a pill to target somatic instability, the perpetual expansion of the CAG repeat in vulnerable brain cells.

Rgenta are trying to target a gene called PMS1 – not the PMS related to mood swings… Levels of PMS1 are higher in people who show symptoms of HD earlier. Rgenta are trying to decrease its levels in the hopes of delaying the onset of signs and symptoms of HD.

Travis tells us how it’s super important to choose the right place on PSM1 to target. So they’ve spent a lot of time developing small molecules that target PMS1 in the right spot. The best candidates also check other boxes, like getting into the brain when taken as a pill.

Rgenta has been testing their drug in lots of different animal models. They’ve shown that it’s very robust. Lowering PMS1 by 50% stalls instability by 70% – the rate of CAG expansion slows down a whole lot. Exciting!

Travis gave a big shout out to all the researchers in the HD community for being so collaborative and sharing their resources. He said Rgenta wouldn’t be where they are today without HD scientists being so collaborative and willing to share.

LifeEdit

Our next speaker is Dr. Logan Brown from LifeEdit Therapeutics, who are advancing gene therapies for HD using CRISPR technology. LifeEdit is working on a CRISPR-based therapy called LETI-101 that selectively lowers expanded huntingtin. They can do this by targeting a genetic signature that differs between a person’s two copies of huntingtin.

Not everyone shows this small genetic difference between their two copies of huntingtin. For this reason, LifeEdit estimates that if LETI-101 were to become a drug, it would work for 30% of people with the gene for HD.

The good news about this approach is that because it uses CRISPR for gene editing, it would be a one-and-done approach, so people would only need this treatment once, in theory, to lower huntingtin for the rest of their lives.

So far, they’ve tested LETI-101 in cells grown in a dish and mice that model HD, and now they’re testing it in monkeys. But they’re also working to develop a strategy for moving into people, which will require brain surgery.

Sana Biotechnology

Next up is Dr. Joana Osorio from Sana Biotechnology, who are working on cell replacement therapies using stem cells. Sana’s technology grew out of experiments showing that support cells in the brain, called glia, contribute to HD disease features in neurons.

With this knowledge, Sana then asked if transplanting non-HD glia cells could improve disease features in mice that model HD. When they did this, they saw improvement in movements and other features of the disease, including increased the lifespan of the mice.

Scientists at Sana found that when they transplanted non-HD glia into the brains of mice, they “out-competed” the HD glia – they essentially replaced the sick HD glia in the brain! HDBuzz previously covered this work when it was published.

Sana is now working to move these findings into clinical trials, and while they’re not quite there yet, they have a plan for getting there. So stay tuned!

Spark Therapeutics

Dr. Juha Savola from Spark Therapeutics is our next speaker in this session, sharing work Spark is doing to advance gene therapies. Spark is best known for their development of a gene therapy for a hereditary form of vision loss (back in 2017). Now they’re focusing on HD.

Spark is developing a gene therapy called SPK-10001, which is designed to slow down or halt progression of HD by lowering huntingtin. Right now they’re testing SPK-10001 in monkeys and they’re seeing that for up to 12 months, HTT levels remain lower.

In the monkeys, they’re testing different doses of SPK-10001 and tracking HTT lowering in different brain areas. This will help them to choose doses to test in people when they move into clinical trials. Juha is sharing details for inclusion and exclusion criteria for the upcoming Phase I/II trial that Spark is planning in people with HD, which will test 2 doses, a low dose and a high dose.

The primary objective of this trial will be safety, but they’ll also look at a few clinical metrics to try and get some hints about whether SPK-10001 will work to treat HD symptoms. We’ll be eagerly awaiting the recruitment announcement for this trial!

Atalanta Therapeutics

Our last speaker of this session is Dr. Serena Hung from Atalanta Therapeutics, who are working on RNAi-based therapeutics for HD. As Sarah explained earlier in her overview, this is one among several approaches to lower huntingtin.

The advantage of Atalanta’s approach is potency. They use a novel technology that helps the drug spread easily to deep regions of the brain. With delivery using a spinal injection, they see that their drug, called ATL-101, is still active out to 6 months in animal models.

Atalanta has shown that in monkeys, they can lower HTT by 75-90% and levels of NfL remain stable. NfL is a marker of brain health that increases as brain cells are damaged and increases as HD progresses. So lots of people keep their eyes on NfL in trials because keeping it level (or even lower!) would be a good thing.

Atalanta is planning to initiate clinical trials for ATL-101 in 2025. We’ll keep you posted when we learn any updates about the advancements of this exciting research!

Tune back in tomorrow!

We are off to explore more than 80 research posters presented by HD scientists and clinicians from all over the world. Brief talks will shine a spotlight on brain imaging biomarkers and aspects of the Enroll-HD platform. See you tomorrow for sessions on clinical challenges in HD, biomarkers, trial design, and more.