Huntington’s Disease Therapeutics Conference 2026 – Day 1

Team HDBuzz was recently in attendance at the 21st annual Huntington’s Disease Therapeutics Conference (HDTC) in Palm Springs, CA. From February 24th through 26th, we provided live, front-row coverage of the meeting, sharing cutting edge science in the field of Huntington’s disease (HD) research. Our posts have been compiled below in a summary of the entire conference. Let’s dig into what happened on day 1!

The team at HDBuzz was thrilled to be back in sunny Palm Springs for another year of exciting Huntington’s disease science – this year with stickers!

David Margolin – Update on uniQure’s AMT-130

Before the meeting kicked off with its basic research talks, we heard from David Margolin from uniQure, sharing some info from the ongoing trial testing AMT-130. His focus will be on how they’re using statistics to reduce bias in their trial. 

David begins with an overview of AMT-130, a huntingtin-lowering gene therapy that is delivered via surgery into the striatum, the part of the brain that’s most vulnerable to HD. He’s talking about the criteria that they used to determine who could join the study and how it would be analyzed. 

Some of the data from people who received AMT-130 wasn’t compared to a placebo group, but rather participants in ENROLL-HD, an observational study that follows people with HD over time. 

uniQure applied statistical methods to the data known as “propensity matched scoring.” This is a way of matching trial participants to similar people who are not part of the trial. So people in the trial were matched with people in ENROLL who were at a similar stage of disease. The idea is that this will help reduce variability within the dataset. 

The main question the study was trying to answer was whether AMT-130 could help slow the progression of HD symptoms as measured with a group of tests known as the cUHDRS, that measures movement and thinking symptoms of HD. 

This is data that uniQure has previously shared: their biggest finding was that in the 17 people who had the surgery ~3 years ago, AMT-130 slowed down (by 60%) the progression of a movement measure known as the Total Motor Score (TMS). 

Additionally, NfL, a biomarker that can measure damage to nerves, usually increases by 10-15%, but in this study it declined by 8-9%. A slower rise in NfL suggests brain cells are being protected. Exactly what we want to hear! 

People who began the study with higher striatal volumes seemed to benefit most from AMT-130, suggesting that early treatment may be important. Eligibility criteria were very narrow, as participants had to be in a particular stage of HD based on both symptoms and brain volumes, and only around 30% of those screened entered the study. 

One thing they weren’t able to compare when matching folks from ENROLL-HD was brain volume measured by MRI, because that data isn’t collected in ENROLL. To help reduce this bias, uniQure applied highly specialized matching statistics. 

The more closely the control and participant groups are matched, the more confident we can be that the slower progression is due to AMT-130, and not just because they would have progressed more slowly anyway. 

They also report having recruited and enrolled a new cohort of six more trial participants who will receive AMT-130. 

While the most exciting piece of this data was already widely reported a few months ago, today’s talk applied new statistical methods to reinforce it. This will hopefully further strengthen uniQure’s case with the FDA to move towards accelerated approval.  

Condensed Views: New Perspectives on HTT DNA, RNA, and Protein

Cliff Brangwynne – Introduction to “Phase Separation” 

The next talk jumps back into laboratory research, with Cliff Brangwynne from Princeton University. He’s not an “HD person”, so hearing his perspective from outside the field can help HD researchers think about their own work in a different way. It’s always great to have new people join the field! 

According to Cliff, his work studies “the physics of squishy materials” – gels, foams, emulsions – and notes that our bodies most resemble these “squishy” structures. 

He’s talking about cells as machines, with the caveat that the structure of things inside of cells is very dynamic, and most proteins have regions with lots of disorder – while we might think of them as well-oiled, according to Cliff things can get messy! 

Cells are made up of many smaller parts, called “organelles”. Organelles are tiny specialized pockets within cells that carry out specific functions, ranging from storing genetic material (the nucleus) to breaking down unneeded protein parts (the lysosome). 

Many organelles, such as mitochondria (the cell’s powerhouse), are separated from the rest of the cell by a membrane. But what’s becoming more and more clear is that cells can use “the physics of squishy materials” to compartmentalize organelles and keep them organised. 

Early in his career, Cliff was studying tiny laboratory worms, called C. elegans, which contain these uncontained (no membrane) structures called “p-granules.” Over time they end up on just one end of the worm. He showed that they’re liquid-like and behave kind of like the stuff inside a lava lamp. Very physics-meets-dorm room chic. 

This “liquid-liquid phase separation” and how it occurs in living cells is the main focus of Cliff’s lab. They’ve done a lot of work on this in both tubes and in living cells. It’s relevant to HD because these liquid-like materials have been implicated in diseases that have protein aggregates. 

If we could gain some control over the liquid-y states that huntingtin takes, by stabilizing or modifying it, that could change the toxicity of the protein and might represent a novel therapeutic path, which is already the case for some other diseases, like cancer. 

There is some evidence to suggest that huntingtin transitions between liquid-like and solid-like states, and lots of debate as to which forms of huntingtin are most toxic. Cliff uses special microscopes and lasers to visualize the formation of protein structures and ask how they condense and move. Using this technology, he can even draw hearts and smiley faces in cells! 

This work also applies to HD because phase transitions play a role in DNA damage repair, which has emerged as a potential driver of disease. The state of these repair proteins might affect the expansion of CAG repeats (somatic instability), which is currently a huge focus of drug development.  

Rachel Harding – PolyQ Effect On Phase Separation 

HDBuzz’s own Rachel Harding wowed the crowd at the 2026 Huntington’s Disease Therapeutics Conference in Palm Springs, CA!

Up next is HDBuzz’s own Rachel Harding! When she’s not Buzzing away, Rachel studies how the HD-related expansion of the huntingtin protein affects its 3D structure and its function. 

Her lab makes high-quality, full-length huntingtin protein with different lengths of polyQ (the protein equivalent of CAGs) that can be studied in test tubes – no mean feat for such a huge protein, one of the largest in our bodies. 

Huntingtin is almost always found “partnered” with a protein called HAP40. Both proteins are very stable when they are studied in tubes (outside of a cell or an organism). There, huntingtin doesn’t “aggregate” in the way we see in actual brain tissue when it’s bound to its BFF HAP40.  

Regardless of how long the polyQ section is, the stability and the structure of huntingtin remains pretty similar. This is a big conundrum, because we know that HD symptoms in people and animals arise from the expansion of huntingtin. 

Some of her lab’s experiments have shown that huntingtin has those “lava lamp” properties where it gets floaty and clumpy, and that it might be binding to DNA and RNA.  

They next asked what this might mean in cells, and found that huntingtin binds a special RNA molecule called NEAT1 in a type of “condensate organelle” that Cliff talked about in the last talk. 

But is huntingtin actually separating into different “phases” of liquids? Rachel compares this to what happens when you make an oil and vinegar salad dressing – you can mix it up, but eventually it separates into its components. They can measure this by how cloudy the solution gets. 

Huntingtin does seem to separate into dynamic droplets that can pass in and out of the cell’s “oil” and “vinegar” stages – and the properties of these droplets change depending on how long the polyQ repeat is. 

They can even hold droplets in place using what Rachel called “Star Trek tractor beams” to look more closely. The longer the polyQ gets, the wonkier the droplets look, and the harder it is for them to merge together. The implication is that the longer the polyQ is, the more solid and inflexible huntingtin protein droplets become. 

Rachel’s emerging theory is that huntingtin droplets become less dynamic and more solid over time, creating a threshold where long CAG repeats become more toxic as they become less dynamic. It’s tough to speculate exactly how, but she has a long list of questions for her lab to explore! 

Ralf Langen – Phase Separation of HTT1a Fragments

Next was Ralf Langen from the University of Southern California. He rounded out this session with another talk on these liquid-y solid blobs we see huntingtin form. 

Ralf studies tiny fragments of the huntingtin protein and their role in HD. His lab’s goals are to understand how these protein fragments form clumps (aggregates) and to design drugs that can bind to it and change how it behaves, to treat HD. 

Huntingtin can take many forms, from monomers (one protein), to oligomers (a few proteins that start to form a larger structure), to fibrils and bundles (many huntingtin proteins that stack in an ordered structure). Researchers think these different forms might differ in how toxic they are to brain cells. 

While Rachel talked about the full length huntingtin protein going in and out of the oil-and-vinegar states, Ralf reports that his lab can also see this happen with just the small fragment of huntingtin that contains the polyQ (the protein equivalent of CAGs) expansion. 

Ralf’s experiments show that when huntingtin fragments form “condensates” – beginning to form those droplets that Rachel described – this can act as a seed for rapid transitions into more stable structures that some researchers think may be more toxic. 

He bravely shared what scientists call “negative data” – meaning that some of the experiments they designed didn’t work, but they informed future ones so they still provide very valuable information.   

Experiments where they look at these condensates under a microscope allowed them to visualize the super-fast transition of huntingtin from floating diffusely around the cell to forming big stable clumps. And it happens quickly! Within about 10 minutes. 

To delve further into the phase separation (that oil and vinegar phenomenon) and understand where different huntingtin forms end up, Ralf’s team did clever experiments using a different disease protein (TDP-43) that plays a role in ALS. It seems that TDP-43 also forms condensates. 

Other groups have also looked into the role of TDP-43 in HD. TDP-43 has been found in the same places as huntingtin in human brains, so TDP-43 might control huntingtin condensation. 

Ralf’s group found that rather than TDP-43 affecting huntingtin phase separation, the small fragment of huntingtin affected TDP-43 phase separation, so there seems to be an interplay between these 2 molecules. 

Ralf’s lab is examining the interaction between huntingtin and other disease proteins and the interaction of different pieces of huntingtin to better understand how they influence each other’s structure, stability, and appearance. 

These interactions could potentially cause huntingtin to go places and attach to structures that it’s not supposed to, and understanding these interactions could help us to uncover new therapeutic pathways. 

Elena Cattaneo – Beyond CAGs

Elena Cattaneo uses stem cells to model Huntington’s disease. With those cells, she’s able to use microscopes to take images and examine how the CAG expansion impacts how they behave and look up close. 

Up next is Elena Cattaneo, a legend in the HD research space who has been working on HD for decades. She’ll be telling us about one of her projects, focused on a specific segment of the HTT protein. 

There are various “domains” in the HTT protein, like little lego blocks that combine to make the entire structure. Elena is looking at the lego piece called the “proline domain” – a stretch of repeating DNA letters after the polyQ (the protein equivalent of CAGs) that codes for proline, a protein building block. 

She thinks that this proline domain, not just the polyQ domain, contributes to the disease. Elena studies mice that differ subtly in these different domains. She suggests these small variations contribute to differences in toxicity: humans are the only species that naturally gets HD.  

Elena wonders whether the proline domain may contribute to the increased toxicity of HTT in humans. To answer this question, she’s using stem cells – cells that can be coaxed to turn into many different cell types, including brain cells. 

In these stem cells, her lab builds different variations of the DNA sequence – like combining the legos in various orders – and they can add more or fewer prolines by inserting more or fewer repeats. This allows them to study how different sequences might influence the toxicity of the HTT protein. 

She’s also swapped some of the lego bricks between the mouse and human codes to see how toxicity differs between species. 

Swapping the human proline domain for the mouse one reduces the harmful effects of huntingtin in the stem cells. This suggests there’s something specific about the human proline domain that’s driving toxicity in these cells. 

She did a deep dive into levels of all the different proteins the cell makes, and the mouse-for-human proline swap also normalizes many of the HD-related changes. This suggests that the proline domain also contributes to molecular effects that influence disease. 

Elena describes the human proline domain as an “amplifier” of HD disease features.  

The next question Elena’s lab asked was whether the proline domain contributes to the production of a short, toxic fragment of the HTT protein, called HTT1a. Interestingly, the human proline domain seems to lead to increased levels of the toxic HTT1a fragment. 

These results suggest that the proline domain does seem to play a role in how toxic the HTT protein is. Very cool! Following this line of thinking could give us another target on the HTT molecule to try and lower toxicity. 

Elena has done a lot of cool work in the past looking at HTT in different species, including plants! 

She’s now elaborating on her lab’s efforts to understand why the mouse proline domain doesn’t appear to contribute to toxic behavior of HTT, but the human proline domain does. Small differences between the mouse and human sequence of the huntingtin gene proline domain may lead to differences in its RNA structure, and in turn, interactions with proteins that link up with RNA, potentially contributing to HD. Other work in the field also supports this theory.  

Elena’s interpretation of her results and others is that the human proline domain remodels the structure of HTT RNA, allowing parts of the molecule to come in contact with RNA-binding proteins. 

The RNA-binding proteins may control how much of the toxic HTT1a fragment gets produced, so understanding these sequences and structures and developing ways to manipulate their interactions could represent another therapeutic pathway. 

Veronica Brito – Chemical Decorations May Contribute to Toxicity

Next up is Veronica Brito from the University of Barcelona. Her talk is focussed on the HTT message molecule, called RNA, and how it is made, processed, used to make the HTT protein, and turned over to the cell’s trash can. 

RNA molecules can be dotted with small chemical decorations that change how they behave, where they’re located in the cell, and what other molecules they interact with. Understanding how these decorations change with disease could help uncover new therapeutic pathways. 

Veronica’s team is interested in a decoration called “m6A.” It can impact various functions of RNA and how it may get cut into sections, allowing it to carry out different jobs within the cell.  

In mice that model HD, she found that different RNA message molecules are decorated with m6A. Interestingly, this decorative change didn’t alter the amount of RNA genetic message that was produced. This suggests that these subtle HD-related changes are missed by more common techniques. 

Veronica then zoomed in to see how HTT itself may be decorated differently with m6A based on the length of CAG repeats. Compared to healthy “wild type” mice, those with CAG repeat expansions that model HD have m6A decorations on specific parts of the HTT RNA message. 

These HD-specific m6A decorations on HTT seem to track with levels of the harmful HTT1a protein fragment, perhaps suggesting that this decoration influences toxicity. 

To test this, Veronica used chemical tools to block the process in cells that adds the m6A decoration. This caused a change in levels of HTT1a, suggesting that the m6A decoration might play a role in its regulation. Blocking the addition of m6A also seemed to boost levels of the full-length HTT protein. 

However, that chemical tool altered m6A across all molecules, not just HTT, so the results could be due to changes in another part of the genome. To figure this out, Veronica’s team are now engineering a way to specifically alter m6A decorations on HTT in mice that model HD. Understanding more about the impact of m6A on HTT could help us better understand how the toxic HTT1a fragment gets produced. 

Sarah Tabrizi – Mapping HTT1a and Therapeutic Interventions 

The final speaker of this morning’s session is Sarah Tabrizi from University College London. Sarah is a rockstar clinician scientist and her talk today is focussed on how our understanding of the HTT1a fragment protein might impact decisions for developing new drugs to treat HD. 

Work from others in the field has shown that the amount of HTT1a increases as the CAG repeat gets longer in mice. Sarah is now asking what happens in humans, how we can intervene with medicines, and what makes them effective or not.  

Sarah’s lab has succeeded in making a series of “isogenic” stem cell lines. This means that cells grown in separate dishes are genetically identical throughout the entire genome EXCEPT for the HTT gene CAG number. This achievement took more than 8 years – a tough experiment! 

They made the cells with CAG numbers of 30, 47, 70, 93, and 125 (the CAG number of the original donor). They also made much longer CAG numbers including 130, 140, 175, 185, 190, and 210!! These longer numbers are important to investigate the consequences of super-long CAGs in cells.  

All of this awesome science is enabled by the generous and selfless donation of a blood sample from a person with HD. Sarah’s team is able to take the stem cells produced from this sample and grow them into any cell type they like, including neurons. 

These cell lines are awesome tools to measure all kinds of hallmarks and features of HD, including which genes are switched on and off, somatic expansion of the CAG number over time, and the health and function of HD neurons.  

They looked at how fast the CAG repeats expanded over time in cells with different starting CAG numbers. With a beginning length of around 70-90 CAGs, there is a pretty big increase in the speed of somatic expansion. 

The longer the starting CAG length, the sooner it is expected to begin expanding further (somatic instability). With 50 repeats she estimated it would take about 12 years for a cell to gain 1 CAG repeat, but starting at over 150 repeats, a cell could gain additional CAGs in a matter of months. 

In these cells, Sarah also sees clumps of the HTT protein, which are historically difficult to observe in human cells grown in a dish (though we almost always see them in human and mouse brain tissue). This gives researchers a new, powerful tool to study HTT protein clumps in living human cells. 

Sarah collaborates with a company called Takeda, applying drugs to alter the levels and stability of expanded HTT. These drugs, called zinc finger proteins (ZFPs), can lower expanded HTT by about 60%. 

Additional ZFPs can lower by ~80% levels of a molecule called MSH3, which scientists have shown contributes to the perpetual expansion of the CAG repeat in people with HD in some cells over time. 

In HD mice, they’re testing both of these drugs alone, as well as together. She mentions it’s likely that future therapeutic approaches will target both expanded HTT and MSH3.  

Both the expanded HTT and MSH3 targeting ZFPs slowed expansion of the CAG repeat in mice – the MSH3 targeting drug by 94%! Lowering expanded HTT slowed expansion by 76%. Interestingly, when both HTT and MSH3 were lowered, the slowing effects plateaued at a level similar to MSH3 lowering alone. 

Sarah points out that some of her results match what others have found in studies of human brain tissue. In both systems, CAG repeats expand slowly at lower repeat lengths and increase in speed as the CAG size grows.

This work highlights the importance of brain donations from HD families for the advancement of HD research. It’s a tremendous gift that may not be right for everyone. But it’s one that has been instrumental for advancing what we know about HD.

The power of having a cells-in-a-dish model that mimics this data generated in human brains is that additional experiments can be done on cells that can’t on human brains, like genetic manipulations and drug testing. 

Somatic Instability 

We’re back from lunch for a scientific session exploring the phenomenon of somatic instability, with a focus on the DNA repair machinery that goes awry and leads to the expansion of CAG repeats in brain cells over time.  

We know that genes involved in DNA repair influence CAG repeat expansion from large-scale human genetic studies, and this connection has held up in many animal and cellular models of HD. 

Karen Usdin – Repeat Contractions in HD

Up first in this session is Karen Usdin who runs a lab at the NIH. Her lab studies somatic instability – the phenomenon by which DNA is unstable. This can happen in a whole host of diseases, not just in HD. Karen’s lab focuses on instability in diseases caused by repeat expansions. 

Instability means that DNA can not only expand but also contract. This has been observed for a long time in HD research, where mouse models can suddenly have a collapse in their repeat number. Karen shows us how this sudden contraction can happen in other repeat diseases, like fragile X.  

In fragile X, these contractions are not because of machinery used to copy the genome or repair the DNA; they happen when the gene containing this repeating sequence is switched on, in a process known as transcription. Karen posits that perhaps the same is true for HD? 

Karen’s team and others have also shown that repeat contraction seems to happen in some tissues more than others. The pituitary, at the base of the brain, seems to have the most repeat contractions compared to brain tissue, skin, or other organs. 

These contractions occur throughout the lifetime of the mice they study, with more drastic pituitary contractions occurring in mice that begin with longer repeats. There also seems to be an initial increase in repeats, followed by contractions later on. 

Altogether, this points to a more complex view of somatic instability, with different types of changes occurring in different types of disease model mice, in different tissues, and at different time points. 

Her team have been exploring ways to encourage contractions, which would be beneficial for many repeat diseases. Eliminating a gene called PMS2 (which is known to influence when HD symptoms begin) seems to promote more contractions.  

However, Karen and her lab are still trying to pin down the precise molecular details of the contraction process. It seems that somatic instability involves different (and sometimes competing) processes in different cells over varying timeframes – an exciting but complex area of HD research!! 

Petr Cejka – The Molecules of Expansion and Contraction

Next up is Petr Cejka from the Institute for Research in Biomedicine (Switzerland). In Petr’s talk, we will learn more about the detailed molecular underpinnings of somatic instability. This work is important to pin down how human HD symptoms arise, and what to target with novel drugs. 

Petr’s team apply biochemistry techniques to study cellular machines in a test tube to figure out exactly how somatic instability might be happening in the cell. They are interested in understanding how 2 of these machines, called MutSβ (beta) and MutLƔ (gamma) work to “fix” CAG repeats. 

When there are lots of CAGs in a row within a DNA strand, loop-outs can occur where the DNA strands don’t form the familiar helix structure – kind of like when a zipper goes off track. Turns out MutSβ and MutLƔ cut the strand across from the one which forms the loop out structures, just above the loop.  

Certain DNA sequences (combinations of letters) seem to influence the location of the DNA cut that begins the repair process. The cut always seems to come after the DNA letter A, where there are lots of the DNA letters G or C either side. 

These machines work best on smaller loop outs and minor mismatches in the DNA helix formation. Bigger loops are not “cleaned up” as well by MutSβ and MutLƔ.

It’s important to remember that this is what Petr’s team observes in a test tube. He reminds us that we should be cautious in how we apply these findings to our understanding of HD in humans.

Petr’s team also looked at another molecular machine called FAN1. This gene is known as a “genetic modifier” of HD, because small DNA letter changes in the FAN1 gene can influence the timing of HD symptom onset.  

FAN1 can cleave DNA in many places, but when the regulating proteins RFC and PCNA are added into the mix, FAN1 cuts become focused to a precise region. Early data suggests that after FAN1 chops up the DNA, another molecular machine called POLD1 (“pole-D-1”) can tidy up the loop-out. Less is known about this particular player, but the more we learn about the molecules that direct this process, the more potential drug targets we have.  

Richard Fishel – Watching the Molecules at Work

Next up before we break for coffee is Richard Fishel from Ohio State University. His lab has developed methods for imaging these DNA repair machines in real time.  

Richard’s lab uses fancy microscopes with specialised lasers to see molecules one-by-one – an amazing level of detail to understand complicated cellular processes. Molecular machines are carefully labelled with glowing tags so Richard’s team can track how these proteins move around when repairing DNA. 

The Fishel lab is using their specialized tools to look at some of the same DNA repair machines we learned about earlier – MutS⍺, MutLƔ, and PCNA. They can work out how long these repair proteins sit on the DNA, how they move along the DNA, and how they work together.  

Mutations in these molecular machines can drive some cancers and cause instability within the genetic code. However, another molecular machine, called MutSβ, does NOT seem to play a role in cancer and DNA damage, which is why HD researchers consider it a good drug target to go after to influence somatic expansion. 

Loop-outs are common in DNA with lots of repeats, like the CAG stretch in the HD gene. Different molecular repair machines slide along the DNA, find one of these loop-outs, and can’t cross. MutSβ gets stuck with the smallest loop-outs, whereas MutL machines only get stuck at much bigger loop-outs. 

Next Richard’s team tried to figure out how the distance between loop-outs affects the recruitment of these different molecular machines that help fix the DNA. Richard thinks this molecular-level analysis could help us figure out why diseases like HD have specific repeat thresholds. 

Companies Targeting Somatic Expansion

The next set of talks is from companies that are developing HD therapeutics that target somatic instability. Each of them is in the pre-clinical stage of research – they’ve identified molecules that are predicted to make a difference in HD, but they aren’t ready to test in people just yet. 

Andy Billinton – Increasing Levels of FAN1 to Control Expansion

Our first talk in the pre-clinical session is from Andy Billinton, representing Harness Therapeutics. They have a unique strategy to target somatic instability: increasing levels of a protein called FAN1. 

We hear a lot about targeting molecules to lower their levels, but increasing levels is actually trickier. This requires clever drug discovery tricks, the secret sauce behind Harness’s approach. 

Harness is interested in FAN1 because it was a strong hit in large studies that looked at the entire genetic makeup of folks with HD. People with HD who had a small genetic change causing higher FAN1 protein levels showed signs and symptoms of HD later than expected. 

FAN1 is a gene that helps to regulate the expansion of the CAG repeat in some cells over time. Because of that, researchers think that if we can increase levels of FAN1, we could slow down the expansion of the CAG repeat, and delay the onset of HD symptoms. 

The method Harness is using takes advantage of tiny pieces of genetic material, called antisense oligonucleotides (ASOs). Their ASO drugs bind to messages used in the cell to decrease FAN1 levels (called micro RNAs). 

When they block those micro RNAs, the FAN1 message sticks around longer, which allows the cell’s machinery to make more of the protein from that message. Quite clever! 

The increase in FAN1 helps to balance DNA repair, stabilizing the CAG repeat length. Harness hopes that this will be helpful in treating HD. 

Harness is working with stem cells that have been coaxed into becoming brain cells. Applying their ASO drug, they’re able to double levels of FAN1. In turn, this reduced CAG somatic expansion. 

Harness technology is called MISBA, microRNA site blocking ASO – what a mouthful! It targets micro RNA that regulates FAN1, keeping this message around for longer, and helping to boost levels of the FAN1 protein. 

ASO1025 seems to be the best drug-like molecule to come out of the Harness platform so far. It can boost the levels and activity of FAN1 in lots of different types of cells. This in turn helps to slow down somatic instability – good news! 

They have also tested ASO1025 in “mini brains,” complex layers of human cells grown in dishes which display some of the features of the human brain. These mini brain models show somatic expansion, just like the brains of people with HD. 

ASO1025 can spread efficiently through these mini brains, and Harness is now working to figure out if it is hitting the message molecule, and whether it is able to boost FAN1 protein levels and activity – more updates to come! 

In the future, they will look to target not just FAN1 but also MSH3 – this two-for-one approach could really dial in somatic expansion for HD. 

This is an exciting update from a new-ish company in the HD drug discovery space but there is still a long road ahead for ASO1025 before it can be tested in people. We look forward to more updates as Harness proceeds with testing in models on their way to the clinic. 

Jang-Ho Cha – Lowering MSH3 and Using Computers to Predict Results

Next up is Jang-Ho Cha from Latus Bio. Latus are also working to develop new kinds of therapeutics to target somatic expansion and hopefully treat HD. 

Latus’ main focus is designing harmless viruses to get drugs into specific places in the body, including the deep brain structures affected in HD. The other cool thing about Latus is that although they are a young company, most of their scientists have been in the HD field for a long time. 

Their approach is to try and lower levels of MSH3. This is a key component of the MutSꞵ DNA repair complex we heard about earlier in this session. It was identified in genetics studies as a “genetic modifier” of when HD symptoms begin.  

As a clinical neurologist, Jang-Ho shares with the audience that the 3 rules for brain therapies are: location, location, location. Getting therapeutics to the right area of the brain is critical. Thankfully, we know the parts of the brain most affected in HD, which is where Latus plans to deliver their drug. 

Jang-Ho is sharing data from non-human primates treated with their harmless virus drug package, a key step for many gene therapies before human testing. The Latus drug reaches the exact areas of the brain most vulnerable in HD. 

Another question Latus is addressing is how much MSH3 lowering is needed to make a difference in HD progression? They have developed a very cool computer simulation based on what we know about CAG expansion and disease onset. This computer modeling lets them predict, given a certain CAG length and specific amount of MSH3 lowering, how much clinical benefit they think they should expect.  

For example, if they target 50% of the cells with 50% lowering, at a CAG length of 40, they think they could see over 50 years of benefit. Whoa! Even though this is just computer modeling predictions, it’s very encouraging to see! 

While people treated with higher CAG repeats at a later age are predicted to have a less impressive benefit, the computer model prediction Jang-Ho showed suggested that everyone could benefit from MSH3 lowering. 

Mice dosed with their drug that lowers MSH3, LTS-201, were shown to have significantly reduced rates of somatic expansion, suggesting that this drug is working as the Latus team expected. But mouse brains are small and much less complex than human brains, so what about larger animals?  

In non-human primates, delivery of LTS-201 reduced MSH3 in the deep structures of the brain. Based on their computer simulation predictions, they think that the amount of MSH3 lowering they observe would make a meaningful difference in disease progression 

It’s helpful for researchers to use predictive computer modeling to try and gauge certain metrics ahead of clinical trials, like most effective dose, CAG repeat length and disease stage to target, and expected effects. This is becoming more common prior to human testing.  

Nandini Patel – Lowering PMS1 With a Pill

The final talk of Day 1 was from Nandini Patel from Rgenta Therapeutics. Rgenta are working on a few splice modulators, but are focusing today on their drug designed to lower levels of PMS1, a modifier of HD symptom onset. 

Splice modulators alter the way that genetic message molecules (called RNA) are processed. This can in turn alter the levels of the proteins they encode. They can usually be taken as a pill by mouth, which is an attractive approach because it’s much easier than brain surgery or repeated spinal taps. 

Over the course of many stages of chemical design, Rgenta have worked to make their drug safe, brain penetrant, and potent, so that it can be used at low doses. They also focused on selectivity, attempting to target only PMS1 without greatly influencing the levels of other proteins. 

Rgenta have put a lot of work into optimizing their lead candidate. While other splice modulators, like branaplam, aren’t very specific for HTT and change levels of many other targets, they’ve done a lot of work to improve selectivity of their drug. 

The splice modulator Rgenta has developed is called RGT-0474060 (catchy!). It is designed to reduce levels of PMS1, which is expected to slow down somatic expansion, hopefully in turn slowing down the onset of HD symptoms. 

Splice modulators tend to hit multiple targets. While PMS1 is the primary target, it seems their drug hits 4 other genetic targets. Still, a big improvement from the first generation splice modulators (like branaplam) in the HD field that hit ~50 other targets! 

In different types of cells grown in a dish, it seems like RGT-0474060 was able to lower PMS1 levels. In even better news, RGT-0474060 slowed down somatic expansion in HD cells, whilst a control compound did not – hoorah! 

They also checked the behavior of the drug to see if it could potentially work as a daily pill. All of these checks looked encouraging – the drug was able to hit its target in animal models, and get into the brain, as well as passing with flying colours through other benchmark assessments. 

Rgenta are gearing up for studies that will generate the data needed to get them to the clinic and thinking about what they will measure in people dosed with their drug to see if it is safe and working as expected. This is a bigger task than it seems, as measuring changes in somatic instability in people is not trivial! 

That’s all for Day 1. Stay tuned for exciting updates about the science shared on Day 2.