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.
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.
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 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.
People with Huntington’s disease (HD) may develop a number of symptoms which can be identified by other people. These symptoms include uncontrollable muscle movements, difficulty with swallowing, and struggling to move around. These symptoms are often the focus for many research projects because they are easier to recognise for other people, as problems that people with HD can face. However, what about social struggles people with HD may have, which are not as obvious to other people? Scientists are now beginning to investigate these less obvious effects of HD because there is an increasing awareness of how much these can impact an individual and their quality of life.
The missing link – a connection between quality of life and social skills?
Quality of life simply means how satisfied a person is with their life, overall. Quality of life may be considered from multiple approaches. Some of these approaches include, physical well-being (how healthy someone feels), emotional well-being (mood and mental health), and social well-being (strength of relationships and how supported they feel). Physical, emotional, and social well-being are believed to be the three building blocks to determine a person’s quality of life.
People with HD may struggle with social skills, causing greater difficulty with social situations. For example, understanding and explaining how other people might feel in particular social situations. In addition, people with HD may experience an increased difficulty in understanding emotions from facial expressions and body language in other people.
Previous scientific research has uncovered two interesting findings about people with HD. Firstly, they have shown that quality of life is reduced in people with HD (particularly at later stages of the condition), compared to the general population. Secondly, some people with HD have greater difficulty with social situations. However, scientists had not yet researched if there was a link between these two ideas until recently, in work led by Professor Hugh Rickards from the University of Birmingham in the United Kingdom.
So, how do we tap into our life satisfaction radar?
Hugh and his team are studying what could link these two ideas, on quality of life and difficulties with social situations in people with HD. To understand quality of life, a questionnaire was given to people with HD that measures physical, emotional, and social well-being.
Scientists also asked people with HD questions about feelings they were experiencing. Some questions explored how frustrated people with HD could become, or how overwhelmed they felt. These questions helped scientists to understand the many different emotions people with HD can experience.
Scientists were particularly interested if people with HD were having trouble expressing their usual feelings. For example, your friend has a real sweet-tooth and presenting them with their favourite bar of chocolate usually makes them feel very happy. However, one day you give your friend their favourite chocolate bar and strangely, they do not seem to express any feelings of happiness. This represents a situation where a person may not be expressing their usual feelings.
What’s your social IQ?: measuring interpersonal skills in people with HD
To understand difficulties with social situations, people with HD were invited to complete different tasks. One example is the ‘Animations Task’. In the Animations Task, people with HD watched cartoons of two triangles. These triangles moved in ways that looked like real-life social situations. For example, two triangles dancing together, or one triangle trying to ‘persuade’ the other triangle to come out of the box. After watching the cartoon, people with HD had to explain what they thought the triangles were doing.
How well people can think and plan activities may also affect how they respond to social situations. Imagine a chef preparing a complicated meal. The chef would have to plan what ingredients they need to gather, organise the pots and pans needed, and control their impulses to eat the entire lasagne in one go! This is the perfect example of the many important skills required when thinking and planning activities.
One question you might be wondering is, how were these thinking and planning skills measured in people with HD? These skills were measured using a ‘Trail Making Test’. In part one of this test, people with HD had to draw lines between circles which each contained a number in the centre (from numbers 1-25). These lines had to connect the circles from the lowest number to the highest number.
Part two of this test was more complicated. This time, there were circles containing letters (A-L) and circles containing numbers (1-12). People with HD had to switch between drawing lines from circles with numbers, to circles with letters. They joined the circles up from the lowest number to the highest number and in alphabetical order. For example, a line would be drawn from circle 1 to circle A and then from circle A to circle 2, and so on. This task helped to give the scientists a measure of how well people with HD can think and plan.
Does being the Sherlock Holmes of social skills mean a happier life?
This study found that a reduced quality of life (specifically, a decrease in social and emotional well-being) in people with HD could be predicted by several social skills and behaviours. One social skill that predicted a reduced quality of life in people with HD is the ability ‘to put yourself in someone else’s shoes’ to figure out their thoughts and feelings.
This was shown in the study when people with HD, who had a poorer overall social well-being, were less likely to be able to explain what the cartoon triangles looked like they were doing (in the Animations Task). For example, one triangle appears to be trying to persuade or encourage the other triangle to come out of a box. When people with HD (who had a lower social and emotional well-being) were asked to explain what the triangles were doing in this video, they simply described that the triangles appear to be ‘moving’ around each other.
Additionally, the results concluded that a reduced quality of life in people with HD could also be linked to having trouble expressing their usual feelings (think back to the chocolate bar example).
Take a deep breath and make a plan
Another interesting finding from this study suggested that a reduced quality of life (in terms of a person’s ability to carry out daily tasks at work and/or home), in people with HD, can be linked to how overwhelmed or frustrated they feel. This decreased ability to carry out daily activities could also be due to having trouble when trying to plan activities (remember all those important planning and organisational skills a chef needs to make the perfect lasagne!).
Together, these results may hint that by improving these particular social skills in people with HD, it could improve their quality of life.
In a nutshell: key insights and the road ahead
The key message from these findings is that when people with HD struggle to understand social situations, it can really affect their quality of life. In the future, scientists should consider exploring solutions to help people with HD improve their social skills.
Some specific social skills to address include, improving people’s ability to express their feelings, addressing their difficulties with planning and organisation, or tackling their feelings of frustration. This is because these are the social skills that have been highlighted as important in determining quality of life, in people with HD.
So no need to break out your cherrywood pipe or wool plaid hat to search for hidden jewels – working on these social skills could be the gem itself in improving quality of life and increased feelings of happiness for people with HD.
