Huntington’s Disease Clinical Research Congress 2025 – Day 3

Welcome back for the final day of the Huntington’s Disease (HD) Clinical Research Congress in Nashville, Tennessee!

Translational issues in HD

The first session will focussed on translational issues in HD – how we get research to people that need it most, HD families. Dr. Sarah Tabrizi from UCL opened with an introduction discussing translational issues in HD. Translational science bridges lab discoveries from the bench to clinic, with the aim that research findings impact patient lives sooner. She started by highlighting some of the challenges in translating research to the clinic. Things like finding good biomarkers, creating scales to rate disease stages, applying imaging technology, responsibly testing new treatments, and developing different models to test potential drugs. 

We’ve heard about the HD-ISS (integrated staging system) from several people so far at this meeting. Sarah shared that a large collaborative team is working on a 2nd iteration of this scaling system to better capture how HD progresses. A scaling system that accurately captures the progression of HD will help with participant selection for clinical trials, allowing researchers to better understand which groups of people may most benefit from potential treatments. 

Sarah pointed out several biomarkers that people are advancing to track HD progression: NfL, expanded HTT from the CSF, and lesser known biomarkers like proenkephalin. She also gave a high level view of another topic we’ll dive into in this session – moving potential treatments from “mice to men.” Making sure drugs work once they move out of animal models of HD is critical for developing treatments. 

Up next was Dr. Sam Frank, a clinician from Harvard. His talk will detail how the HD-ISS – developed solely for research – might someday guide patient care, from early detection to clinical decisions. The question of how the HD-ISS should be used comes up a lot for families and clinicians. 

Sam spoke about how patients often ask him what stage they are, with the hope that this information could help to determine how to view their own HD. Should they get an MRI? Can they participate in research? How long might they have until they stop working, driving, walking, or need 24 hour care? These are challenging questions and Sam believes the ISS could help with answers. 

Sam highlighted the differences between staging systems and rating scales, and says he doesn’t feel we have enough clinical data yet to use the HD-ISS in clinic, still considering it a research tool. He points out that the patients he sees with HD are quite savvy and they’re tuned in to what the HD-ISS is. He underscores that the HD-ISS is intended for research – we’re getting there for clinical use, but we’re not quite there yet. 

Sam emphasized that the HD-ISS plays a role in inclusion criteria which in turn has implications for who will have access to a drug and how insurance companies could handle reimbursement. It also means companies can begin to target people at earlier disease stages with this granular understanding of HD. 

So, how does Sam address the question when his patients ask him what stage they are? He prefers to look at their total functional capacity (TFC) instead of the HD-ISS to help them understand their progression and trajectory. He also tries to understand why they want to know. Do they want to participate in research? Or are they going to scour the internet and fall into a rabbit hole of scientific literature?  

He cautioned providers in the room to be careful about their language in the clinic, to avoid making folks feel excluded when discussing clinical trials. This is particularly important for the HD-ISS because it is currently a research tool, not a clinical classification for HD. He then went through some of the limitations of the HD-ISS, one of which is that most people with HD are cared for by doctors who aren’t familiar with HD. Sam wrapped up by stating that the HD-ISS is a critical tool for research right now, but cautioned physicians who aren’t HD specialists against using it in the clinic. 

The next speaker was Dr. Joel Braunstein from C2N Diagnostics. Joel started by sharing some info about C2N Diagnostics. They are a clinical diagnostic lab, meaning they analyse biological samples, from companies trying to understand how their drugs may be working, and from patient biofluids. Early research that launched C2N involved injecting a tracer molecule into people to deeply examine newly created proteins from the fluid that bathes the brain (CSF). This allowed them to better understand the formation and the “lifespan” of disease proteins. 

Joel shared that economics are playing an increasing role in determining if technologies and treatments will advance, underscoring the need to have a reasonable price point and working with “payers,” i.e. insurance companies. He shared that a few weeks ago they filed with the FDA for their blood test to measure proteins that detect Alzheimer’s disease. They overcame “a number of firsts” to get there, a process which took 7 years. Being the first to market a new technology is exciting, but it requires breaking through many glass ceilings. This typically paves the path and makes it easier for others to follow suit.  

Joel discussed some parallels between AD and HD – it can take months to years for someone to get an accurate diagnosis. 85% of dementia diagnoses are made in primary care environments, rather than with a neurologist, and it can be hard to tease out the symptoms from the underlying biological changes. 

Clinical benefit is highest when diseases like AD are treated early and by specialists. That window closes when time to proper diagnosis is delayed, which can happen when people are initially seen and screened by primary care physicians rather than a neurologist. Having accurate and fast diagnostic testing can speed this process up drastically. The AD blood test developed by C2N Diagnostics is 90% sensitive and 90% accurate, meaning there is a low rate of false negatives and the test results are very likely to be correct. 

In the US there are about 7 million with dementia and another 13 million with mild cognitive impairment. If they can identify people with early pathological features of disease, early intervention steps can be taken to give the highest level of care. 

Next, Joel is dove into some of the specifics of the blood test, including that it assesses two biomarker proteins that suggest that someone is likely to have brain pathology features related to AD. C2N asked clinicians how this has impacted their diagnosis of AD, and it has come up from about 62-71% to 90% accuracy. Getting a diagnosis as fast as possible for people with early HD symptoms is important for getting them the best level of care. The AD field is now working on staging systems, similar to the oncology field, in the same way that the HD field is moving forward with the HD-ISS. 

Looking at what’s happening in other brain diseases can help us advance how we think about HD. While we have a blood test for the causative gene, one could envision a blood panel test to help us better understand staging, progression, and drug development for HD – a reason that accurate and reliable biomarkers are so critical. 

Our last speaker for this session was Dr. Dirk Keene from the University of Washington, presenting on neuropathology needs in HD. Research on human research is essential for understanding what drives neuronal loss in HD and how we might stop it. Dirk is a neuropathologist, so he is a super brain geek who examines how diseases affect the structure of human brains. He opens by showing the tremendous size difference between a human brain and mouse brain. While mice are critical for us to understand biological pathways and the mechanisms of drugs, to really understand any human disease, we need to look at human brains. 

About 10 years ago, an emergent technology allowed researchers like Dirk to study the genetic profiles within brains at the single cell level. This massive library of information allows researchers to build intricate maps of the human brain to understand how it’s built and how it works. To apply this technology to human brains, Dirk and his team had to rethink how they are collected and stored. If you’ve ever taken an anatomy class, you may remember the noxious smell of formaldehyde-preserved tissue, which isn’t compatible with these single cell techniques. 

So for the past 8 years, they’ve been “modernizing neuropathology” so that it’s compatible with new techniques like single cell analyses. This greatly expands what we can learn about the human brain. With this data, they’re building a “human brain cell atlas” that gives researchers a framework for studying the human brain during health and disease at the level of genes, proteins, and cells. 

Currently, Dirk’s team is applying this approach to Alzheimer’s disease. They are working to analyze brain pathology across the entire spectrum of the disease, from the very earliest changes to late stage. While Dirk and his team are specifically focused on AD right now, this type of deep analysis is something people are working toward applying to HD as well. 

Brain donations are truly the most generous gift an HD family can give to science. While it’s a deeply personal decision, if it’s something you’re interested in, you can learn more in our previous article on this topic. The Allen Institute for Brain Science, which has created the brain atlas for AD, will soon launch the Human Brain Accelerator Initiative which will help apply new technologies to the study of human brain tissue. This initiative for HD will be called HD-BRIDGE – Brain Resource Initiative for Discovery and Global Engagement. This will give every HD family the opportunity to donate their brain for this initiative at any brain bank. 

Dirk ended by thanking the brain donors and their families, saying that each donation is a true gift which he tries to honor by learning as much as possible about that brain so all scientists can advance disease knowledge. That’s a sentiment that we want to echo to all HD families who donate brains, tissue, and cells, and who participate in observational and clinical trials. The massive advancements that we’ve made, particularly this year, are because of you. Thank you! 

Science for Clinicians: Hot Topics That Are Important to Communicate in the Clinic

Dr. Davina Hensman-Moss from UCL was the first speaker in this session. She started by going over some basics of somatic instability that frequent HDBuzz readers will be familiar with – CAG repeats over 40 will cause disease, those between 27 and 35 are a gray area, and those below 27 aren’t associated with disease. HD is just one of many diseases caused by a repeated expansion of the genetic letter code. Together this family of diseases are mostly neurological and together affect about 1 in 3,000 people worldwide. 

While every cell in our bodies has the same genetic information overall, there are small differences, like the number of the CAG repeat size. In someone with HD their blood cell may have 42 repeats, but some cells in the brain may have many more. These numbers can change even more as people age. The biological phenomenon of increasing CAG repeat size in the HTT gene in people with HD is known as somatic instability. 

Davina shared a recent model in the field that HD pathology might be a 2 part process: somatic expansion in brain cells drives how quickly the disease begins, then HTT protein produced from the gene with the CAG expansion drives toxicity of the disease in those cells. CAG repeat expansion doesn’t happen in all affected cells at the same time, but in each cell on its own timeline. This means that impacted cells aren’t lost all at once, but rather there is a slow loss of each cell as it reaches the toxic threshold. 

There are also genetic variants that affect HD onset and progression that were discovered in a large genetic study called GeM-HD, where genetic information from over 16,000 people with HD was collected and analyzed. Interestingly, many of the genes that modify when HD signs and symptoms will appear are involved in DNA repair. This is the same process that controls somatic instability. That means the same genetic variants that can control onset of HD symptoms also control expansion of the CAG repeat, which seems to be a driver of toxicity and cell death. This suggests that if we can harness these modifiers, we may be able to control the onset of HD symptoms. 

When CAG repeat expansions occur, the DNA has to take on a loop structure. Understanding this structure and that of the proteins involved in the process of DNA repair and expansion may also lead to a therapeutic opportunity to control these expansions. With a list from the GeM-HD study of potential modifiers, researchers are tasked with deciding which would be best to target. 

DNA repair genes play many roles in health and disease, and in particular, fiddling with them could lead to cancer, so we have to be careful. Several of the genes identified as modifiers of HD can also contribute to a type of cancer called Lynch Syndrome, which causes many cancerous tumors to grow in people who have variations in some of the DNA repair genes. Nevertheless, scientists working on safely targeting HD genetic modifiers have shown encouraging results in mice when they lower the DNA repair genes MSH3 and PMS1. What we’ve learned from HD mice is that targeting these genes might help us control somatic instability, but there is a “sweet spot”, where we have to treat before the toxicity threshold is crossed. 

After we figure out what genes to target, Davina suggests the next big question is when we should treat. Dr. Sarah Tabrizi’s HD-YAS (Young Adult Study) has generated data about the early appearance of symptoms, giving researchers a timeline for when to treat prior to disease onset. Davina ended by thanking all the people who have participated in studies that have contributed to knowledge about genetic modifiers somatic instability. Without HD community partnership between researchers and families, we wouldn’t know about the findings Davina shared today.  

Next up was Dr. David Howland from CHDI. David starts with a “nomenclature check” to make sure everyone is on the same page as far as the different forms of the HTT protein. While we often talk about unexpanded and expanded HTT, there are different forms and fragments of expanded HTT that contribute to disease. One form is a fragment of expanded HTT called HTT1a. This is a toxic piece of the HTT protein created from the first little bit of the expanded HTT genetic code, which includes the expanded CAG region of the gene. 

This toxic HTT1a fragment is created through a biological process called “splicing” – you can think of this as similar to how movie reels can be cut and spliced together to alter scenes, ultimately piecing together the final product. When the cell does this, it splices the rest of the HTT product. Many different types of HTT fragments can be made from the same gene, and it’s not known which bits of the protein are actually driving toxicity within cells. 

The HTT1a fragment is highly prone to forming sticky protein clumps. Mice designed to produce only this fragment show signs and symptoms reminiscent of HD, suggesting that this fragment specifically can cause disease. David believes that the HTT1a fragment itself acts as a driver of HD pathology. Current data seems to suggest that HTT1a is a key to toxicity. But there are still questions around how much of it is needed to cause disease, and limitations to how we can measure HTT1a. 

Because it’s part of a larger protein, specific tools are needed to measure levels of HTT1a. David and the team at CHDI have developed a protein visualization tool, called an antibody, that targets a region within HTT1a. This antibody is already helping researchers examine levels of HTT1a in tissue samples of people who have HD. So far they’ve found that it shows up in protein clumps, and seems to be more rare in people with HD compared to mice that model the disease. 

This type of data will help answer questions around the contribution that HTT1a has to HD pathology. While researchers still can’t measure levels of the HTT1a fragment in people while they’re alive, this is something they’re working toward. Researchers are asking (so far just in mice) whether lowering levels of the HTT1a fragment can provide a therapeutic benefit. In mice with long CAG repeats who can’t produce HTT1a, there are fewer protein clumps, lower NfL, and more regulated cell signaling. 

Some of the caveats around this work involve the fact that the mice we use to model HD have very high CAG repeat lengths, starting at 190 CAGs. This helps researchers to get answers faster, but may not accurately represent what we see in human disease. This is why it’s critical to work with tools that closely represent the human condition: cells from people, postmortem human tissue, and ultimately people living with HD. 

David ended by sharing his perspective that lowering HTT1a and full length expanded HTT are desirable paths toward treatment, but we still don’t have conclusive evidence. He hopes that the future of therapy could involve some combination of addressing mHTT and somatic instability. 

HD Insights of the Year: Emerging evidence for disproportionate benefit of HTT1a lowering

Kicking off the afternoon programming was Dr. Jeff Carroll, HDBuzz Editor Emeritus and HD researcher. Jeff has a personal and professional interest in HD; he comes from an HD family. His first publication came out in 2011, and today his lab does translational HD research. His original question was whether targeting just the expanded copy of HTT (“allele selective lowering”) was a better strategy than lowering all forms of huntingtin, both toxic and healthy. 

Jeff works with a type of HD mouse where he can study different CAG repeat lengths by inserting a part of the human genetic code. He reminds us that mice with long repeats are a great tool to understand relationships between biology and symptoms, which is much harder to do in people. His lab worked with Wave Life Sciences to develop a genetic tool, called an ASO (antisense oilgonucleotide), that targets all forms of HTT (known as a panASO) or expanded HTT alone (mHTT). Treating HD mice with the latter eliminates clumps of HTT that are normally seen in these models. 

Jeff detailed work from Gill Bates’s team that we heard about in the last session, showing that splicing creates a toxic Htt1a fragment, and also reminds us of work from Steve McCarroll’s lab showing that there’s a proposed threshold of CAG repeats (150) that becomes toxic. Treating with the ASO that specifically targets expanded HTT eliminated the toxic Htt1a fragment and reversed a lot of genetic changes that occur in these mice, whereas the panASO didn’t have these beneficial effects. Jeff summarizes his work on ASOs by reminding us that the way that HTT-lowering is approached can make a big difference in terms of effectiveness (at least in mice). 

Jeff believes that it will be important to consider how and whether different HTT lowering strategies target HTT in different ways. For example, whether they target the beginning of the gene where the CAG repeats occur and/or the supportive genetic code around it. This could have implications for current ongoing clinical trials, which Jeff separates into two groups based on how they target the HD gene. 

Young People and Huntington’s Disease

Dr. Erin Furr Stimming from UTHealth Houston Neurosciences introduced the next session focused on young people and HD. This was a vital discussion on youth, development, and inclusion. 

Dr. Bruce Compas, a psychologist from Vanderbilt University, was up first. He began by noting that we are shifting from talking about genetics and biology to symptoms and behaviour. His work focuses on several questions about how expanded HTT affects the developing brain, and he’s highlighting cognitive symptoms as one example. 

There are different schools of thought around how thinking symptoms emerged in HD research. One theory says that cognitive issues emerge alongside movement symptoms. Another holds that CAG repeats actually confer an initial benefit for cognitive function in early life before a decline in HD. Yet a third theory says that impairments in thinking emerge early, with some apparent during adolescence. Bruce is showing evidence from different areas of HD research for each of these ideas. They all have different types of tests and approaches. 

When theories conflict so strongly, it’s important to gain an understanding of the underlying causes. Bruce is interested in the effects of expanded HTT on the developing brain, guided by what we know about brain development in the presence and absence of the HD gene expansion. He reviewed what we know about the developmental ages at which different brain regions, features, and networks mature to drive different functions, some of which don’t come online until after the age of 25.  

“Executive function” describes how people attend to information, problem solve, and stay on task. Bruce’s team studies different aspects of executive function and how it becomes impaired in HD. One project studies how CAG repeat length influences the progression of cognitive function. Another looks at how stress and inflammation influences cognitive abilities. A third will look at how social connectedness influences cognitive function. All of these projects involve assessing people with HD using different tests of thinking and problem solving, from working memory to symbol matching, among others. He and others have found a strong relationship between thinking abilities and coping abilities. 

One practical takeaway is that brain development happens on unique trajectories, but social support and treatment of individual symptoms can have a profound effect on a person’s ability to reason and consequently to cope with HD-related changes, especially for youth from HD families.

Next, we heard from Cristina Sampaio from CHDI who gave an overview of the inclusion and exclusion criteria in HD clinical trials, and how best to strive for balance and fairness. Inclusive trials ensure therapies reflect the diversity of the HD community and move faster to approval. 

Because HD is typically an adult onset disease, inclusion criteria focus on adults. Once a drug is successful, inclusion criteria are usually expanded after that to include more sensitive or resource intensive populations, including younger people and pediatric patients. Cristina explained the difference between cases that are considered juvenile, adult, or late onset HD. People who experience symptoms younger than 20 are considered to have juvenile HD, while those who develop symptoms over the age of 60 are considered to have late onset HD. 

Until recently, most HD clinical trials set inclusion criteria at age 18. This is because they were less complex, typically aimed at improving specific symptoms, like chorea. Because of that, the rate of progression was less relevant, so the lower limit was set to the legal age of consent. More recently, trials are aiming at disease modification and have updated the lower age limit to 25. This is because the rate of disease progression is highly relevant in this context. Because people with adult onset versus juvenile HD progress differently, these limits help to strengthen trial endpoints. 

Cristina made the point that there are many other inclusion criteria for clinical trials aside from age, such as disease stage. She also underscores that if there is a specific biological mechanism at play only in youth with juvenile onset, inclusion criteria would reflect the question the trial is trying to test. She reiterated that the minimum age is typically set to 25 years to exclude juvenile onset HD cases, because these early trials of disease-modifying genetic therapies are designed to test questions around the adult onset version of HD as safely and efficiently as possible. 

She’s also highlighted regulatory differences between the US, where the FDA approves drugs, and Europe, where the EMA approves drugs. The EMA requires a pediatric protocol for any trials that will include younger people, where the US FDA does not. So there are various practical, ethical, regulatory, and biological factors that guide how inclusion and exclusion criteria for clinical trials are selected. 

Ultimately the intent of clinical trials is to effectively and efficiently test if a drug will work in a population of people. Starting with a more uniform group of participants will speed answers around whether that drug will work. Any drug found to be effective in one group of people with HD can then be tested more broadly to see if it works in larger groups of affected individuals, including younger people, those with juvenile HD, and people who have progressed to later stages of the disease. 

The next speaker was Dr. Martha Nance from the Hennepin HealthCare HD Clinic in Minnesota. Her talk will reflect on treating people with juvenile HD, what care looks like today, and where science can help tomorrow. She reminded us that HD is a family disease, and turns to the story of researcher and family member Dr. Nancy Wexler who initiated work in Venezuela that led to the discovery of the HD gene, and how so many researchers in this room were trained by those who led that project. 

Martha has spent her career in Minnesota, where she studied the inheritance of HD through generations of families, building family trees known as “pedigrees.” She has learned a huge amount about the meaning and structure of families, and how human complexity gets shrunk into a circle or square on a diagram. She stresses that all of the researchers and clinicians in this room are part of the HD family, because we are all in some way affected by HD, and reminds us that it’s our responsibility to be prolific in passing knowledge down to our “professional progeny!” 

In the absence of a treatment, Martha emphasized that any HD professional or member of an HD clinical team has an opportunity to give their trainees firm ground to stand on and to make a difference in the lives of families. 

Next, Martha moved some of the work she’s done in kids with HD. She notes that there was evidence of somatic instability in very young patients with juvenile onset HD (JoHD), long before it became a therapeutic target. She believes that the field has not paid enough attention to JoHD in humans. 

Martha also reminded us that there is power in partnership among clinical researchers, who can pool their human data and their experience to better understand diverse aspects of HD and what is most common and meaningful to families. She highlighted that clinicians should talk to the parents about symptoms their kids are experiencing, not just assume they know what symptoms they may have because of what they’ve read in a book. 

Martha shared with the clinicians some of the practical things she has learned over the years: Do not say no to seeing kids with HD just because you may be an “adult neurologist”. Access schools and community resources. Expand your practice beyond medications. She emphasized how important it is to support and learn from parents, who have vast experience with JoHD and their child. And to celebrate day to day and help patients to have fun despite the tremendous challenges their families are facing. 

Martha highlighted Dr. Ignacio Muñoz-Sanjuán who heads up Factor-H and journalist/advocate Charles Sabine OBE, who organized a meeting of Venezuelan HD community members with the pope in 2017 – check out the 2020 documentary about it, “Dancing At the Vatican”. She’s also using her platform to highlight that kids with JoHD can have a profound impact, from advocacy to research. In an emotional ending, she encouraged us all to learn from the youth and professional progeny we claim to serve!

Abstract Poster Sessions

In the final session of the conference we heard short talks that were selected from the poster submissions. 

Dr. Blair Leavitt from Incisive Genetics presented on the company’s HTT lowering gene therapy, which is allele-selective meaning it only targets the expanded HTT gene. Their technology uses CRISPR to make cuts that lead to lower levels of HTT. Blair reminds us that CRISPR is a tool involving a CAS9 enzyme, think of this like the molecular scissors that can cut DNA, alongside a guide RNA that targets the gene of interest (in this case, HTT). 

Gene editing was first accomplished in sickle cell anemia, and Incisive is working with similar tools. Incisive’s IG-HD01 leverages CRISPR technology as well as lipid nanoparticles (LNPs) which uses the body’s cholesterol system for delivery. You can think of LNPs as micro Trojan horses – they contain the therapeutic drugs against HD and the LNP gets them to where we want them to be. 

Incisive has done a variety of experiments to show that their methods lead to efficient delivery of gene editing technology, in cells as well as in different tissues in animal models. Blair is showing this with beautiful fluorescent images. They have also examined different aspects of safety and toxicity. 

Blair introduced Incisive’s therapeutic “pipeline” laying out methods, biological targets, and plans for trying to move their drugs into the clinic. He is focusing today on IG-HD01, their “lead candidate” (furthest developed drug) for HD. He believes that targeting the DNA, the source of the expanded HD-causing protein, should be the most efficient way to intervene in the toxic pathways leading to HD symptoms. 

IG-HD01 is an allele-selective gene editor, meaning that in each cell it reaches, it chops out a portion of the copy of huntingtin containing the CAG repeat expansion, while leaving the healthy copy intact. Of note, this means that Incisive’s technology targets DNA, not the mRNA copy message. Blair touched on some of the elements of research that are more often presented to investors – considerations around intellectual property and plans for manufacturing. These factors are important as young companies seek investments in early stage clinical studies! He also highlighted that they’re moving forward with development plans and hope to start a clinical trial in 2027. 

Next was Dr. Christopher Mezias from the Critical Path Institute, who discussed frameworks for regulatory science and biomarker validation. Standardizing biomarker assays and benchmarks is key to accelerating approval of HD therapies. The HD-RSC (Regulatory Science Consortium) is a partnership between the Critical Path Institute, an organization that brings people together in various disease spaces, and other organizations, like HD nonprofits, companies, and the FDA. 

Chris recapped the definition of a biomarker, something we can measure to track disease and determine how treatments are working, and reminds us that many approaches to tracking HD are necessary at different stages of the disease. There are different ways to get a new biomarker to be accepted by a regulatory agency like the FDA as an endpoint in a clinical trial. These are formal processes that have to be approached in collaboration with researchers, companies, and affected communities. 

Chris touched on the many categories of biomarkers and the complexity of how they are used to focus on disease progression, treatments, and response. CHDI and C-Path recently held a workshop to discuss how best to use imaging as a biomarker for HD progression. C-Path uses a framework to make decisions about what aspects of collaboration, data, and drug development to prioritize. It incorporates perspectives from many “stakeholders” including family members, patient facing orgs, regulators, scientists, clinicians, and companies. 

Chris highlighted the complexity of approaching regulators like the FDA with a new biomarker to use in clinical trials, which requires providing evidence on its usefulness, in what context it will be used, and what it adds to the field. One of C-Path’s goals is to make sure that measurements made across many locations using diverse technology (like different MRI machines) will be consistent enough across the board to use in a clinical trial. When there’s a lot of variation, that requires a closer look.  

The final talk of the conference was from Dr. Jang-Ho Cha of Latus Bio, who presented data on targeting MSH3 to prevent CAG repeat expansion, thought to be one of HD’s root causes. Latus was founded by Dr. Bev Davidson, a world leader in gene therapy and HD research. They work on one-and-done gene therapy treatments for serious brain diseases, and lots of their leadership have a background in the HD field. 

As a neurologist, Jang-Ho reminds the crowd that medicine in neurology is driven by 3 rules – “location, location, location”. In other words, for a gene therapy to work, it has to hit the right part of the brain and it has to be distributed in an efficient way. Latus targets the brain areas most affected by the diseases they study, which for HD is the deep brain structures known as the striatum. 

Latus has engineered specialized, harmless viruses (AAVs) to deliver genetic drugs to brain cells – they are specifically focused on ways to do this in the right location and at low doses. Historically it has been very difficult to get these viruses to areas deep inside the brain. Jang-Ho is showing fluorescent images demonstrating that their virus can enter and spread from the deep brain areas that drive changes in movement and motivation in HD, and outward to the areas involved in cognition and executive function. 

So they’ve got this very effective “envelope” that can be delivered to the right place, and inside it they put a piece of man-made genetic code that can target a DNA repair gene called MSH3. In people, tiny changes in MSH3 can dictate how early or late HD symptoms appear. In different models, knocking out MSH3 has slowed the expansion of CAG repeats and led to improvements in cell health and behavior. 

Latus has data to show that their MSH3-targeting virus can reduce the expansion of CAG repeats in HD mouse models – the higher the dose, the more it reduces somatic instability. 

Next steps for their company involve preparing to submit an IND (investigational new drug) application with the FDA, the first step that tells regulators about plans to move towards clinical trials in humans. 

Thanks for following along!

That’s all for us from the HD Clinical Research Congress! We hope you enjoyed the coverage and we’ll see you next year!