We’re back for Day 3 of the Hereditary Disease Foundation (HDF) conference! First up is a session on RNA dynamics – what’s that?! Read on to find out!

Different HTT forms have different effects

Up first is Gill Bates, who will tell us about her work in understanding how somatic expansion causes disease and investigating ideas targeting different forms of HTT, to help develop therapies for HD.

The HTT gene is very long! And sometimes only parts of it get turned into protein, particularly the beginning part. This happens more frequently in HD. It turns out that first little bit – called HTT1a – is quite toxic to cells. Gill’s team research HTT1a in mouse models of HD and they have studied a series of mice with different CAG repeat lengths, spanning mice with a low CAG repeat number to HD mice with very large CAG numbers. Then they measure which forms of the HTT protein are made in these mice.

Interestingly, they find that the longer the CAG repeat is, the more of the HTT1a fragment is produced. So, perhaps, at least some of the disease-associated toxicity is driven by increased expression of HTT1a. They also find more sticky protein clumps of HTT in mice with longer CAG repeats and more HTT1a bits, suggesting HTT1a primarily makes up these protein clumps. Much less of the really big full-size HTT is made in mice with longer CAGs. Together this points to longer CAGs making more of the toxic protein forms (like HTT1a) and less of other forms.

Next, Gill’s team looked at what happened to HTT if they altered the protein with mutations, not in the CAG repeat, but in the protein building blocks directly preceding this region. This changed where and how many protein clumps they could see in mouse models of HD.

So what effect does HTT1a and other HTT fragments have on somatic expansion? This is something Gill and her team are working on in mice. Her team recently published this work. In that work, they used a mouse model with 185 CAG repeats. When they lowered a gene that is linked to somatic expansion, called MSH3, they were able to halt somatic expansion, but the signs and symptoms of HD still developed in the mice.

This might suggest that somatic expansion has to be halted before the CAG repeat reaches these very extreme lengths, like 185. However, those findings are from a specific mouse model of HD. We need more data to understand this better and know if the same thing happens in humans. A limitation of many HD mouse models is that they have extreme CAG numbers from birth so that scientists can see things that mimic symptoms of HD. It’s possible these models mimic juvenile HD, not the more common adult onset form which might be why they don’t see a change in symptoms.

Gill’s team are working with other labs to specifically lower either the full-length version of HTT or the HTT1a fragment, which Gill’s team think might be an ultra toxic form of the protein. Interestingly, they only see an effect if they dose mice when they are young. When they look at the effect of lowering both forms on HTT protein clumping, they find the biggest effect when they specifically target HTT1a. They’re also able to reduce protein clumps more if they treat the mice earlier.

A theme from recent research seems to suggest treating HD early might be our best bet, but that doesn’t mean treatments won’t work for people later on. A great thing about the HD field is that many people are working on a variety of approaches. Our eggs are in many baskets!

Changes to the recipe

Up next is Anukur Jain, who will be telling us about his work on how the RNA message molecule folds within cells and how that process can go wrong.

A brief Bio101 lesson may be helpful here. DNA is made into a message called RNA before it’s turned into protein. Proteins are the functional molecules of a cell, like the product of a recipe. But they can’t get made without the RNA message, it’s the protein recipe molecule.

The RNA messages from genes that have repeat expansions, like the CAG repeat in HD, are prone to folding strangely, causing problems in how the protein is produced from that message. Like if you spill something on your recipe copy and add 1 egg instead of 2. Oops! Ankur is telling the crowd how altered RNA message folding causes the cell to produce different protein forms and fragments. Just like how the product from your recipe would turn out a bit different if the copy you were reading from was altered.

Using molecules that are designed to glow under microscopes, Akur can follow these misfolded RNA messages in cells in real time. So over a course of just 10 minutes, he can watch them form structures that look like droplets in the cell. Very cool!

Ankur is interested in understanding if the spelling code of the RNA message affects where these droplet-like structures form in the nucleus of the cell. Using cells making different RNA messages with CAG repeats, his team are trying to find answers to this question.

So far, Ankur has done this work only with messages of pure CAG repeats, not the HTT message itself. This allows him to track how CAG repeats affect droplet-like RNA messages, but it doesn’t answer questions about what’s happening with this process in HD.

Modifiers of expansion and symptom onset

Next up is Darren Monckton, who will be telling us about some cool details about HD genetics. Darren and his team look at the different flavors of the HD gene that people have, and how this affects the path of disease progression they experience.

Darren is able to look in blood samples from people with HD to look at somatic expansions, using very sensitive measurements. In blood, they often only see a single extra CAG, which is very different to the 10s to 100s of extra CAGs we see in some cells in the brain. Looking at thousands of samples from people in the Enroll-HD trial, they have tracked somatic expansion over time. The 2 biggest factors contributing to somatic expansion are age and longer starting CAG lengths.

Interestingly, this is also seen in folks with intermediate CAG numbers, corresponding to 27 to 39 repeats. These people are unlikely to present with clinical HD symptoms in their lifetimes, yet Darren’s team see that they also have somatic instability. Darren thinks that this means that somatic instability per se is not enough to trigger disease. Perhaps we need the more extreme somatic instability that we see in people with adult-onset HD, usually with 40-50 CAGs, to initiate signs and symptoms of disease.

Some people experience more or less somatic expansion than we might expect on average. Using data from 1000s of people with HD, Darren’s team can pull out the genetic modifiers which affect the rate of somatic expansion. In this dataset, we can see many of the same genes previously identified as modifiers of HD symptom onset – many of which are genes critical for repairing DNA, in particular the little loop out structures that scientists think are commonly formed in repeating CAG DNA strands.

This is relevant because it suggests the very genes that control somatic expansion might be the same ones that control age of symptom onset. Something that has piqued the interest of many in the field recently! BUT, not all genes associated with DNA repair come up as modifiers of both age of symptom onset and somatic expansion. Why is that? That’s something Darren is interested in understanding.

Darren postulates that this may be related to the amount of each of the DNA repair proteins that are present. The cell can only use so much of some molecules, so more doesn’t always mean a stronger effect. Like a glass can only hold so much water, pouring into an overflowing cup doesn’t mean you’re adding more water.

Many of the hits are helper proteins which assist in DNA repair and processing, so their role is perhaps more subtle in somatic instability. Clearly this is a complex process, so HD scientists are going to be busy figuring this all out.

Darren’s also told us that the HTT gene itself modifies somatic instability! This is not caused by the CAG repeat, but by other changes in the HTT gene letter code, and in the DNA regions which surround the HTT gene in the genetic code. Altogether, this suggests that there are likely different mechanisms all working at the same time to alter the rate of somatic expansion and the onset of clinical symptoms. HD is often called the most complicated single gene disease – we believe that is probably true!

Darren’s team also looked at another CAG repeat disease, called SCA3. They see somatic instability in samples from these people too at the affected gene, ATXN3, but the effect is not as strong as it is in people with HD, at the HTT gene. So, like we’ve heard from several other talks, defining these processes in one disease will have implications for other diseases.

Big data to solve big problems

Next up is X. William Yang. His lab creates mouse models of HD that he shares with researchers across the globe to study the disease. In his talk today he is going to be talking to us about why he thinks some cells seem to be sicker than others in HD.

William is showing a super cool movie that moves through a mouse’s brain with markers that glow to show where the sticky HTT protein clumps are. They’re primarily in the center of the brain, in the striatum, and at the outer wrinkly edges, in the cortex. They are looking to see how the clumps match up with where they see somatic expansion in different parts of the mouse brain, and how this impacts which genes get turned on and off. This way they can try to unpick why some cells might get more sick in HD.

William’s team did a massive experiment where they switched off 100+ different genes in their mouse model. Wow! This is a ton of work that will generate lots of useful data for everyone in the field. They focused on switching off genes that they think could be controlling the global changes of genes that get turned on and off in HD.

Once they did this, they looked to see how each gene being switched off affected signs and symptoms of HD. When they switched off many of the DNA repair genes from modifier studies, this made things better – good news for folks working on these as drug targets!

And if that experiment wasn’t big enough, William and his team then looked at those mice using a single cell analysis, looking how each cell in the mouse brains was affected. In line with what others have shown, the striatum was the most affected area of the brain.

William is highlighting data from a specific experiment where they switched off expression of MSH3, a popular target since it influences somatic expansion in HD. When MSH3 was lowered, sticky HTT protein clumps were reduced in his mouse model.

Connecting all of this together to work out exactly what is going on in HD and which events happen in which order is still a tough task for HD scientists to tackle. There is not a clear consensus… yet! But there are lots of smart folks, like those in William’s team, all on the case.

Working together

Up next is Anna Pluciennik, who studies DNA and is looking into a gene called FAN1, which has been shown to modify when HD symptoms might begin. People who have higher amounts of FAN1 get symptoms of HD later than those with lower levels. But why is that and how does that happen? That’s what Anna is interested in finding out!

Anna’s lab doesn’t work with cells in a dish or with mouse models of HD, but only with the precise molecules they are interrogating. In this type of reduced system, they can get into the nitty gritty of exactly how all these molecular machines are working. It turns out that in order for FAN1 to do its job repairing DNA, it needs to work together with other protein molecules. Anna’s team have elegantly defined exactly which proteins are needed for FAN1 to work. We previously wrote about Anna’s work.

Anna’s team used powerful microscopes to look at FAN1 bound onto DNA and one of its partners, called PCNA. By collecting lots of images, they were able to generate a detailed 3D model of the complex of molecules, and so can work out exactly how they work together. She shows that the CAG repeat extrudes out from the DNA helix, and bends awkwardly when it binds proteins like FAN1 and PCNA. This allows FAN1 to precisely chop the DNA nearby the extrusion to begin the DNA repair process and fix the funny looking extrusion.

Anna is teasing out exactly which letter in the genetic code of FAN1 allows it to bind and chop these extrusions – a very high level of detail! She can map some of the variations identified in large genetic studies to her model and test these forms of FAN1 in a test tube. This is cool as her team are able to work out exactly why some genetic variations affect the FAN1 protein, providing great evidence for why these variations impact HD progression.

Learning from others

Our last talk of Day 3 is from Alice Davidson, who studies another repeat expansion disease which affects the eye, called Fuchs dystrophy. This is one of the leading underlying reasons for why some people might need a cornea transplant. Alice and her team have been researching the underlying genetics of this condition to figure out what is going on. In a gene called TCF4, there is a CTG repeat. If this is expanded beyond 50 repeats, then people are at much higher risk of developing Fuchs.

Alice believes that Fuchs could be a good system to test drugs that generally target repeat diseases, given its late onset and the ease of delivering drugs to the eye compared to the brain or muscle for example.

There are a lot of parallels between Fuchs and other repeat diseases, like HD, including toxicities observed with RNA message molecules, sticky protein clumping, and other features, like somatic expansion. Similar to the findings of Darren’s team that we covered earlier, Alice shows us that there is more instability in people who inherit a longer repeat. They next looked to see what might be causing repeat instability.

Alice and her team are interested in defining some of the underpinning mechanisms that lead to Fuchs. And perhaps the underlying theme of the conference so far has been that there are lots of similar mechanisms across diseases that could help inform treatments for many disorders.

That’s all for the research updates for Day 3 – we’ll be back tomorrow for updates from the last day of the conference!

The HDBuzz team was back in Boston this year to livetweet updates from the Milton Wexler Biennial Symposium hosted by the Hereditary Disease Foundation (HDF), the first of which was held in 1998! This is a 4-day event that brings together almost 300 world leaders in Huntington’s disease (HD) research to share their current data, generate new ideas, and get us closer to a treatment for HD.

”I’m glad you’re sitting down for this”

Our first talk is by Fyodor Urnov, who will give us an update on editing the brain with CRISPR for therapeutics. Interesting! Dr. Urnov starts by reminding us how far things have come in brain research in the last few years, stating that he can give us a “healthy dose of optimism”.

He started by showing us a timeline of data that has led to medicines for editing DNA. It’s been an explosion over the past few decades! All culminating in the development of a regulatory approved drug, for blood-based diseases. HDBuzz wrote about that drug, called Casgevy, recently.

Fyodor will tell us about drivers of CRISPR progress, the revolutionary gene editing technology, and how they build on each other. Let’s go!

Fyodor works with Jennifer Doudna, one of the inventors of CRISPR. Who better to have on team HD to help us develop medicines!? He very excitingly is showing data about a company he works with, Intellia Therapeutics, and how they’re moving forward with CRISPR-based treatments for other brain diseases with over 700 participants. Unthinkable just a few years ago!

And all of this has spurred from a scientific discovery that was made only 12 years ago for which Jennifer was awarded a Nobel prize. Quite amazing! Fyodor keeps stating, “I’m glad you’re sitting down for this” as he tells us about more stellar science that is knocking our socks off.

CRISPR is being used for other diseases, but what is learned from these diseases can be streamlined to be used for HD. This will take efforts from many companies, which they plan to “daisy-chain” into a platform of CRISPR cures, bringing everyone’s expertise together.

Fyodor is sharing a platform that could be a game changer for genetic diseases. He talks about a world where children that have a gene that can be edited could potentially have a cure in 4 years for $25-70 million dollars. Currently a dream which may soon become reality.

Now he moves on to the good stuff – therapeutics for Huntington’s disease! He’s sharing his research working to correct the expanded version of huntingtin (HTT), the molecule that causes HD. As the CRISPR technology quickly improves, so do the options for HD. There are lots of different flavors of CRISPR, so we have all sorts of tools in the toolbox to work out the best path forward to potentially make a HD gene therapy.

Foydor makes a bold prediction that there will be a CRISPR-based drug for cholesterol within 3 years. This will provide a regulatory track record for CRISPR-based drugs, making the path clearer for diseases like HD. Fyodor is telling us about the successes of CRISPR approaches in other diseases, since information from these clinical trials will help inform therapeutic strategies for HD.

For HD, Fyodor and his team is planning to use CRISPR to change the way the HTT gene is put together – something called splicing. They’ll specifically do this to target only the expanded, disease-causing copy of HTT.

Like an approach from a super villain movie, they’ll use something called a “poison exon”. Sinister sounding… All this means is that they’ll splice in a piece of genetic code that causes the expanded HTT copy to get sent to the cellular trash bin.

So far they’ve only done this in cells in a dish, but this approach seems quite promising. Using this technique, they can reduce the amount of the expanded HTT copy by ~70%. Impressive in the world of molecular biology!

Another challenge for HD gene therapies is getting the CRISPR drug into the brain, no mean feat. Instead of a harmless virus usually used to deliver these types of drugs to the brain, tiny carrier molecules called lipid nanoparticles seem to do the trick, at least in mice and cells grown in a dish.

Fyodor left the group with a swell of hope that the currently approved CRISPR drug, Casgevy, along with the massive amount of data moving forward for other diseases will be the rising tide to lift the ship for CRISPR therapeutics for HD.

A light at the end of the tunnel?

Our second and last talk for tonight is from the one and only Ed Wild, co-founder of HDBuzz. He’ll be sharing an exciting update on clinical trials in the HD space.

Ed starts by reminding us about the state of play the last time we gathered for this meeting in 2022 – we had just had a slew of sad and disappointing news about many HD clinical trials which HDBuzz readers will remember well.

Ed reminds us that everyone’s journey with HD starts with bad news, but we must get back up and come together to generate good news. Recently we’ve had a deluge of very much needed good news from many HD drug hunting companies that he will review for us now.

The first company and drug Ed talks about is tominersen from Roche. They’ve worked hard to comb through the data from the GENERATION-HD1 trial to determine if there is a way forward for this drug.

They’re currently moving forward with GENERATION-HD2, a Phase 2 trial to test tominersen in younger people with less pronounced symptoms of HD and a lower dose of the drug. Testing drugs in early HD was previously challenging, as it’s challenging to determine if the drug is working in someone who doesn’t have clear symptoms. This is now possible because expert HD scientists and doctors got together to work out a new staging system for HD to figure out what they could measure in younger people.

The fact that companies are shifting to testing drugs at earlier stages does not mean that it’s too late for people who have developed symptoms. Something that works to prevent or slow HD will likely also work in people at later stages.

You can learn more about the Roche GENERATION-HD2 trial from a recent HDBuzz article.

Ed then moved into talking about the recent good news from PTC Therapeutics, which was recently covered by HDBuzz. PTC Therapeutics are testing their HTT lowering drug PTC-518, which is a small molecule that is taken as a pill. PTC-518 lowers HTT levels in a dose-dependent manner i.e. the more drug you take, the more lowering that happens.

A new piece of data we learned from their recent update was that HTT lowering does not inevitably lead to high NfL levels, indicating damage to neurons. While this sounds obvious, we actually didn’t know this until recently.

Previous trials testing HTT lowering had all shown a spike in NfL levels – a molecule that rises when brain cells are damaged. So scientists thought this was causing things like brain swelling because of the drug or brain surgery, but no one actually knew. Until now! People who were given PTC-518 had flat levels of NfL, suggesting that HTT lowering itself wasn’t the cause of a transient rise in NfL levels in previous clinical trials. Good news!

We also learned that this type of drug, called a splice modulator, appears to be safe in treating HD. This is the same type of therapeutic as the Novartis drug branaplam that was halted, so this is also very welcome good news.

PTC also showed that people taking PTC-518 had HD symptoms that seemed to advance more slowly, perhaps suggesting that the drug is doing what we hope. However, this is a small trial, so we have to take this information with a pinch of salt. Excitingly, PTC are making moves toward a Phase 3 trial for PTC-518.

Next Ed shared an update from Wave Life Sciences, which we also recently covered. Wave are testing a HTT lowering strategy that specifically targets the expanded copy of HTT. This leaves the unexpanded copy alone, left to work in the body and brain, to perform its normal functions. Again, it seems that WVE-003 seems to be doing just this!

Ed suggests we should keep tabs on the NfL data from this study, as the data does show somewhat of a spike for a few folks. Ed thinks that HD researchers need to put their heads together to figure this out before we test this drug in more people.

When things are all going in the right direction, they’re easy to interpret. But already confusing things can confound our interpretation. So proceeding cautiously is best.

Ed is now providing an update from the uniQure trial, which you can read more about here. This trial is testing yet another HTT lowering strategy; this one involving a single dose of a drug delivered by a harmless virus via brain surgery. With this kind of approach, things must move very slowly to ensure safety at every step of the way.

uniQure’s drug, AMT-130, caused an initial spike in NfL. This was expected since any brain surgery will at least temporarily harm some brain cells. However, it looks like NfL goes down back to baseline, and possibly drops below baseline – we’ll see if this trend holds!

While uniQure also shared data suggesting AMT-130 slowed disease progression, again, it’s important to note that this is a small number of people. So results here also have to be interpreted with caution. However, any movement of the needle is welcome news in our books!

Up next is an update on Skyhawk Therapeutics, who recently released data from their Phase 1 trial testing a HTT lowering drug, called SKY0515, that can be taken as a pill.

While they didn’t release much data with this update, they did show that they’re able to lower HTT in a dose dependent manner. So the drug does what they want! They’re now moving on to a third arm of the study that will test SKY0515 in people with HD.

Ed shared a quick update about Prilenia. Ed noted that pridopidine failed to meet its primary or secondary endpoints of their recent trial testing this drug. Despite this setback, you may have seen some news stories about how Prilenia plan to move things forward.

Ultimately, Prilenia sliced and diced the data after the trial was over to try and gain some insight. These aren’t conclusive since the study wasn’t designed to test this. Under this extremely distorted lens, Prilenia think that neuroleptics might affect how the drug works.

Neuroleptics are antipsychotic medications often prescribed to people with HD to manage psychiatric symptoms, like depression, that are sometimes associated with HD. This is a key part of treatment for many people with HD.

Ed is somewhat worried about the confusion generated around neuroleptics. Before we make decisions about which drugs people with HD should be taking, he believes we should be informed by clinical trial data.

Anyone who has been prescribed neuroleptics by their neurologist should not go off their medication without first speaking with their medical team. A blinded clinical trial would need to first be run to make any conclusions about how neuroleptics affect the severity of HD.

Ed then went into a long-winded explanation about the stars in London – apparently he’s gotten into astrophotography…. In a way that only Ed can, a moderately self-congratulatory departure was used to wrap and liken HD drugs to the stars in our sights.

That’s all for Day 1. The HDBuzz team will be back for Day 2 with some hot off the presses HD science updates!

Welcome to Day 2 of the Hereditary Disease Foundation (HDF) conference! The morning was spent listening to an interview between a neurologist and their patient living with HD. All HDF meetings begin this way, to better connect scientists with the people who matter most, those living with HD.

Different flavors of HTT

Up first is Tony Reiner, who studies the structure of the brain and how it changes in HD. Interestingly, HD doesn’t affect the whole brain equally. There are certain parts that are more vulnerable – specifically, a region called the striatum, which is found almost exactly in the center of the brain.

Cells found within the striatum tend to get sick and die in HD, causing this part of the brain to get smaller as the disease progresses. The outer wrinkly bit of the brain, called the cortex, also shrinks in HD.

The gene that causes HD produces a protein (huntingtin, HTT) that is quite sticky, and clumps up in the brain. Tony’s work examines brains generously donated from HD families to track where these sticky clumps are found throughout the brain.

Tony’s lab has studied donated brains to measure the loss of different brain regions at different stages of disease, to ask whether the most vulnerable regions are those with the most HTT protein. Surprisingly, this is not always the case.

In fact, certain cells within the brain that aren’t very vulnerable to HD produce lots more HTT protein than very vulnerable cells in the striatum. Quite surprising!

If not the mere presence of the HTT protein, then what causes cells in the striatum to be so vulnerable? To answer this question, Tony is meticulously tracking different forms of the sticky HTT protein throughout the brain.

Like chocolate can come in different forms (hot chocolate, bar, chips), proteins can come in different forms too. These different protein forms can perform different functions, good or bad, perhaps making some forms of the sticky HTT protein toxic.

Knowing which form of the protein is found in which areas of the brain will help researchers understand if certain types of HTT are more toxic than others, which could help with understanding the details of how HD affects the brain.

It’s not all about neurons

Up next is Osama Al Dalahmah, who is another brain pathologist – someone who studies the structure and function of the brain. He’ll be talking to us about his research on a star-shaped cell in the brain called astrocytes.

Neurons get a lot of attention in HD – and rightfully so! Neurons are the cell type that send electrical signals to help us think, move, and feel. And they’re the cell type most affected by HD. But neurons aren’t the only cells that make up the brain.

Astrocytes connect to neurons to help maintain the environment of the brain to keep neurons happy and healthy. We’ve previously written about astrocytes and the role they play in HD.

Osama’s group is asking how astrocytes in people with HD may be different and if astrocytes may even be protective against the disease! Using donated brain samples and cutting-edge technology, they can study minute differences in each astrocyte cell within a brain sample.

In particular, they are looking to see which genes get turned on/off in the astrocytes found in the brains of people with HD. There seem to be some patterns that make up a “molecular signature” for astrocytes in HD. Interestingly, it seems that cells with some of these molecular signatures are actually adapted to work to help protect the brain during HD.

Osama likens neurons to crowd surfers being carried by the crowd, in this case, supporting astrocytes. Some astrocytes in people with HD support crowd surfing neurons, but others, without the right signature, allow for stage dive fails. No fun for crowd surfing neurons!

The cellular trash bin

Up next is Joan Steffan who is going to be talking to us about her research looking at what the HD protein does normally. We know the HD protein, HTT, doesn’t work well in disease. But the HTT protein has lots of important jobs to do in healthy cells and Joan, and the other speakers of this session, are interested in investigating these functions.

Joan is studying the role of the HTT protein in cleaning up components of the cell that are no longer needed. This process, called autophagy, is very important to keeping cells healthy. Joan found that HTT works with lots of protein friends in the cell to take out the cell’s trash.

Many proteins involved in autophagy bind to the cell trash via a molecular tag. So Joan’s team asked if the HTT protein could also bind this tag. Turns out it can in a test tube!

The HTT protein is huge, one of the largest that our bodies make. Joan and her team have mapped the exact part of HTT which binds onto this tag. The tag-binding region is right on the edge of the donut structure of this massive molecule.

Looking closer, Joan asked what cellular trash might be bound by the HTT protein. She found that lots of these were proteins whose job is normally to bind genetic message molecules, called RNA. Joan has lots of ideas about what this might mean for HD biology.

She also found that the expanded form of HTT, which causes HD, interacted more tightly with the trash tag. This gives us more clues about the normal role of HTT and what might be going wrong in HD.

Huntingtin’s BFF – HAP40

Next up is HDBuzz’s very own Rachel Harding! She’ll be telling us about cool new tools she’s using to better understand the structure of our favorite protein.

Rachel reminds us of how very big the HTT protein is. She’s very interested in its shape: one half looks like a donut, which is connected to the other half through a bridge. These two halves are held together by another protein called HAP40.

Rachel’s lab is very good at producing the HTT protein in a test tube. This is used by labs all over the world to understand what the HTT protein does.

An important part of understanding what a protein does is knowing what other proteins it interacts with. One of the tools used to discover these interactions is antibodies. So it’s very important that the HTT antibodies are of good quality. The good news is, we have some great antibodies. The bad news is, some of the antibodies regularly used by HD research labs are not so great.

To make sure we’re using the best tools possible, Rachel is developing an alternative to antibodies called macrocycles. These are small molecules that bind to HTT very tightly and can be attached to other things like fluorescent tags that will make the HTT protein glow. Very cool!

Using several fancy technologies, Rachel’s group is figuring out exactly where each macrocycle is binding on the HTT-HAP40 structure.

Macrocycles can be used for much more than just studying HTT in a test tube. They can also track HTT in cells, which will be pivotal in helping researchers understand the function of HTT and what might be going wrong in HD.

They may also be used to find “pockets” in the HTT protein that would make good drug targets.

Picking up speed

Next up is Bob Handsaker who will talk to us about somatic expansion in HD – the idea that in some cells, the CAG repeat can get longer over time. HD scientists are trying to figure out how this might contribute to the path of disease progression, a very exciting area of research.

Bob and the team he works with at Harvard have built a model of how they think somatic expansion happens in cells, first in a slow and then in a rapid phase. They have collected evidence from brain tissues analyzed from people who have passed from HD that they believe supports this model.

Next, Bob tells us about changes to genes being switched on and off and how this correlates with somatic expansion of the CAG tract. Interestingly, they don’t see much difference until the expansion becomes very large, around 150 CAGs.

After the cells reach this very long CAG repeat length (which takes decades), they start to see accelerated changes in genes that are turned on and off, leading to toxicity in the cell, and eventually death of those cells.

The model Bob is proposing is somewhat in contrast to data published by other scientists, many of whom are in the room – but this is what conferences are for, to discuss these hot topics and see how the collective evidence shakes out, to move the science forward.

Interestingly, when they dig into the data to see which genes are turned off in neurons from the striatum (the very center of the brain) they’re genes associated with “cell identity”. This means the cells, in a way, lose their ability to tell what kind of cell they are.

Bob and the team also looked at the protein clumps that they see in the brain and how these change over time. Their modelling and analysis suggest that this is a late feature of HD, happening in just a subset of cells in the brain.

Overall, the model Bob proposes suggests why HD might take decades to develop and they hope it can be used to develop better therapeutics for HD, or to track how new drugs might slow or halt HD.

Different disease, similar effects

Up next is Harry Orr, who works on a different CAG repeat disease called spinocerebellar ataxia 1 (SCA1). While there are similarities with HD, there are also differences. SCA1 typically has adult onset, causes movement changes, and problems with thinking. Also like HD, there is no treatment.

One major difference is the primary cell type affected. While HD primarily affects neurons of the striatum, SCA1 primarily affects a different type of brain cell called a Purkinje cell in an area of the brain called the cerebellum.

Harry’s lab has been working on developing mouse models of SCA1 to better understand this disease. They are using these models to look at somatic expansion in different parts of the brain

It seems ongoing CAG expansion isn’t unique to HD, but may be a common feature in several diseases, including SCA1. As we’ve heard already at this meeting, a rising tide lifts all ships – finding treatments for one brain disease could have implications for others, including HD.

Location, location, location

Our last talk of day 2 is from Longzhi Tan whose talk is titled, “3D genome architecture across the lifespan and in HD” – sounds like it will be high tech!

Each of our cells carries the entire genome – all of our DNA – in its nucleus. Tan analyses the shape of this DNA at the single cell level. Measuring the shape of DNA is incredibly difficult. This is because DNA shape differs cell to cell, so shapes within 2 cells aren’t the same.

Tan developed his own technique to solve these challenges and define the shape of DNA across many cells. Combining computers with microscopes gives a high-tech solution, allowing him to back calculate DNA shapes within the nucleus.

He’s showing the crowd super cool videos that have caused audible murmuring throughout the audience. There’s very cool science being done in the HD space!

Each cell uses different genes to do its job. Tan is explaining how the genes used by one cell type move toward each other in the nucleus. For HD we’re of course interested in brain cells. Tan can tell the difference between diverse brain cell types simply by looking at the position of their genes. Wow!

Tan is using his cool technology to study HD by asking if the disease affects the position of DNA within a cell and if that may alter which genes are on or off. He is currently working on these questions in mice that model HD. They have found that the biggest differences in the DNA’s 3D shape happen in the very cells that are vulnerable in HD!

Tan is also looking at how DNA shape changes when he turns off a gene associated with somatic instability, called MSH3. Turning off MSH3 rearranges the DNA location so that it more closely matches cells without HD.

Overall, Tan’s work is a super cool debut of new technology that can be used to analyze HD in very fine detail.

That’s all from us for day 2 of the conference! We’ll be back for day 3 to share updates about cells other than neurons, somatic instability, and DNA repair. Stay tuned!

The stormy trial updates that hung over the Huntington’s disease (HD) field in 2021 have certainly parted, making way for the bright and clear forecast we’ve had so far in 2024! Close on the heels of recent positive trial news from Sage Therapeutics, PTC Therapeutics, Wave Life Sciences, and uniQure, we’ve received more encouraging results from another company, Skyhawk Therapeutics, about their drug SKY-0515. Since there are a lot of trials going on right now in the HD space testing various drugs, let’s break down how SKY-0515 works, what we’ve learned so far from this Phase 1 trial, and how it differs from other drugs being tested.

How does SKY-0515 work?

SKY-0515 is designed to lower huntingtin (HTT), the molecule that ultimately causes HD. While we all have the HTT gene, folks who go on to develop HD have an extra stretch of genetic message within their HTT gene. The good news is that since we know the exact genetic cause of the disease is within the HTT gene, it gives us a very reasonable target to go after. That’s why Skyhawk, along with many other companies, have focused on developing drugs that lower HTT.

It turns out that the extra stretch of genetic message that causes HD within the HTT gene can get bigger in some cells as people with HD age, like brain cells. This can cause biological functions to go awry, leading to toxicity in some cells, and eventually cell death. This perpetual increase of that extra bit of genetic code within the HTT gene is called somatic expansion, something frequent readers of HDBuzz have no doubt heard about.

Some people think if we can control somatic expansion, we could slow, or maybe even stop, the progression of HD. Interestingly, SKY-0515 also targets another molecule – PMS1 – which helps to control somatic expansion. So not only can SKY-0515 lower HTT, but it can also help prevent somatic expansion. Because of this, Skyhawk is hoping this drug will have a double impact against HD.

Phase 1 trial update

On July 10, 2024 we received a short update from Skyhawk Therapeutics about their ongoing Phase 1 trial testing SKY-0515. Ultimately, they hope that this drug will be able to modify the disease course of HD, but first they need to know if the drug is safe to take and if it can do what it’s supposed to do. Phase 1 trials are the first time new drugs are given to humans, so the primary goal is always safety.

This is a small trial being run in Australia with multiple parts. In the first part, SKY-0515 is being given to healthy people without the gene for HD. So far, SKY-0515 appears to be safe and well tolerated at all the doses that were tested in healthy volunteers.

Trial participants have received the drug at increasing doses so that Skyhawk can work out which dose would be best to carry forward in a larger trial. They’ve also found a dose-dependent lowering of HTT, meaning the more drug that they give, the more they’re able to lower HTT. This indicates that SKY-0515 is engaging the target and doing what they hoped it would do.

How is SKY-0515 different?

With HTT being the cause of HD, logically, lots of companies have designed drugs to target HTT and lower it. But not all HTT lowering drugs are the same and many require different delivery methods. Excitingly, SKY-0515 is a small molecule, which means it can be taken orally. This is obviously a much less invasive way to take a drug compared to those that would require a spinal injection or brain surgery.

SKY-0515 not only targets HTT, but also somatic expansion. While there are suggestions that other HTT-lowering drugs could also have this effect, that wasn’t specifically stated in the design of trials testing those drugs. We also don’t yet have data for the somatic expansion piece in people yet. Hopefully that will come with Skyhawk’s next data release.

An important aspect of drug design is potency – the ability of a drug to have an effect at a specific concentration. The more potent a drug is, the less of it needs to be taken to get the same effect. And, very often, taking less of a drug can mean there are fewer potential negative side effects. SKY-0515 appears to be very potent. At just 9mg (the high dose tested in this Phase 1 trial), the drug is able to lower HTT by ~70%! While we can’t say for sure that SKY-0515’s potency means that there will be fewer side effects, this is something we’ll be looking for in future updates.

Astute readers may notice that 70% lowering is a fair bit higher than the current target in other HTT lowering trials of around 50%. Currently, most companies have targeted the 30-50% range for HTT lowering drugs. If Skyhawk finds safety issues at the higher doses, they may chose to scale dose back and lower HTT less.

What’s next?

Now Skyhawk will begin the next part of their Phase 1 trial – testing SKY-0515 in people that have the gene for HD. A low and a high dose will be tested in people with early-stage HD, corresponding to people with stages 1, 2, and early 3 on the HD-ISS scale. These are people with early HD, prior to overt clinical onset in some cases. Recruitment for this part of the trial is underway and dosing is set to begin as early as this month.

If all goes well, Skyhawk plans to initiate a Phase 2 trial in early 2025. While the current Phase 1 is being conducted in Australia, we don’t yet have details about where the potential Phase 2 trial would take place.

While we’ve had a windfall of good news lately for HD clinical trials, it’s not all sunshine and rainbows just yet. We are hopefully optimistic about all this recent good news, but we have to temper that excitement with the knowledge that these are early trials with very few people. On the horizon are larger trials that will bring much more clarity over the next few years, hopefully making a clear path for getting a disease-modifying drug to market.

New data from uniQure, who developed a one-and-done gene therapy for Huntington’s disease (HD) called AMT-130, indicates that the drug is relatively safe and might be able to slow down signs and symptoms of HD. AMT-130 is currently under investigation in Phase I/II clinical trials in Europe and the US which are mainly focused on drug safety. These hot new data are very encouraging, so let’s dive into what it all means!

What is AMT-130?

Developed by uniQure, AMT-130 is the first gene therapy for HD. Like many of the other therapies being tested in the clinic right now, it aims to reduce the levels of the HD protein, huntingtin, in the brain. What makes it a bit different, however, is that AMT-130 is a one-and-done gene therapy; you are only given one dose of the drug ever in the course of your life.

AMT-130 is made up of a harmless virus packaged with genetic material that contains the instructions to reduce the amount of huntingtin in each cell that the virus infects in the brain. The drug is given to people with HD by a very specialised type of brain surgery which delivers it into the fluid-filled spaces of the brain, known as the ventricles.

All of this was obviously rather daunting back when AMT-130 was first developed and we didn’t know how safe the drug might be. The one-and-done nature of the drug means that effects of the drug, good or bad, can not be undone.

uniQure did a huge number of studies before they tested AMT-130 in people, which took place over years using many different types of HD animal models. Even when uniQure began testing AMT-130 in people in 2019, they did so very slowly, starting with just a few brave folks who selflessly signed up to test this innovative therapy. Only when things looked ok following these first surgeries did they begin giving the drug to more people.

HD-GeneTRX-1 and HD-GeneTRX-2 – two trials for AMT-130 on two continents

There are in fact two clinical trials testing AMT-130 in people with HD; HD-GeneTRX-1 in the US and HD-GeneTRX-2 in Europe. Together, 39 participants of the trials were given either a high dose of AMT-130, a low dose of AMT-130, or a sham surgery, which means that participants underwent surgery but no drug was given. All people in the trial are then tracked for 4 years after their surgery, where all sorts of clinical, biomarker, brain imaging, and other measurements are taken.

The key aim of both trials is to investigate whether AMT-130 is safe in people. In addition to this, lots of other data are collected along the way which might hint at how well AMT-130 is working and how it might impact signs and symptoms of HD.

Since the trials began, AMT-130 has had a bit of a bumpy road. In the first people treated, everything seemed to be going ok but in August 2022, serious side effects were reported for some people who received the high dose of AMT-130. Fortunately, things got back on track after a 3 month pause in enrollment into the trial, and uniQure shared the good news that their trial will continue as planned, with new safety measures in place.

Since the brief trial pause, uniQure has reported steady progress with signs that this drug appears safe. There were also some hints of trends in the data they collected from all of the study participants that seemed to suggest that the drug might be having an effect on some symptoms of HD, although this was just a signal and is not conclusive.

Some things to keep in mind with this latest update

It’s important to note that the two trials are not over, the most recent data is an interim update. There are still 2+ more years of data to be collected for most folks. In fact, only 12 people who received the low dose (out of 13 in this group) and 9 people who received the high dose (out of 20 in this group) are at the 24 month mark.

Given the arduous way this drug is delivered, it takes a long time for everyone to get their surgery, even after they are enrolled. This means that the numbers of people from which the data comes from in this release are very tiny, so we should be very cautious in how we interpret the findings – we don’t yet know how this will play out in a bigger pool of people over a longer period of time.

Another important thing to note is that all comparisons in this data release are against natural history data, not placebo controls. Natural history data tracks people with HD over the course of their lives to see how their symptoms, brain imaging, biomarkers, and other clinical measurements change over time. This is very different to a placebo group who undergo the same procedures as the folks receiving the drugs, the only difference being they don’t actually receive the drug. The placebo effect can be very powerful so if we are using natural history data as our baseline, we should be cautious in the direct comparisons we draw. This decision was taken as there is only complete data for people in the sham surgery group up until 12 months.

Keeping all that in mind, this update is still rather exciting, so buckle in!

What’s the latest news about AMT-130?

Safety

The good news is that AMT-130, at both the low and high dose, appears to be relatively safe. There are manageable effects which we would expect to see following brain surgery, like headaches and pain associated with the procedure. However, the important part is that no new serious side effects were reported since the trial was paused back in August 2022, which is good news.

NfL – insights to brain health

An important measurement for tracking general brain health is the biomarker neurofilament light, often called NfL. Because HD has a detrimental effect on brain health, NfL levels go up over time as HD progresses. Therefore, NfL measurements can tell us two things: Firstly, whether the therapy might be causing harm, and secondly, whether the therapy might be slowing down disease progression, and therefore slowing the rate at which NfL levels go up over time in someone with HD.

We learned in previous updates from uniQure that there’s an initial spike in NfL levels. This is to be expected for any treatment requiring brain surgery, since the surgery itself will temporarily reduce overall brain health. What’s important is that this is short-lived – the initial spike is followed by a rapid decline in NfL levels over the next 6-8 months after surgery. Looking at NfL levels after the initial spike is where the juicy details are – this is what will tell us if AMT-130 is improving brain health and slowing HD progression.

In the last data release in December of 2023, only 6 people in the low-dose group and 2 people in the high-dose group had made it to the 24 month time point. Now, there are 12 people from the low-dose group and 9 people from the high-dose group that have reached the 24 month mark. Having data from more people helps give us a clearer picture of the effect AMT-130 is having on NfL 2 years after treatment.

Excitingly, the new data show that people treated with both the low- and high-dose of AMT-130 have NfL levels significantly below what would be expected, suggesting their decline in brain health is slowed compared to folks who have not been treated with AMT-130. While this sounds incredibly exciting, this is still a very small dataset so we shouldn’t get our hopes up too high.

Clinical measures

uniQure also looked at clinical measures to get an idea of the effect that AMT-130 might have on slowing or stopping symptoms of HD. Specifically, they looked at the Composite Unified Huntington’s Disease Rating Scale, or cUHDRS. This is a collection of tests that measures the ability of someone with HD to carry out daily tasks, movement control, capacity to pay attention, and memory. Overall, the cUHDRS is known to be the most sensitive way to measure clinical progression of HD.

At the end of the day, clinical measures will be the most important readout. Having a drug that is effective at slowing or stopping progression of clinical signs and symptoms of HD is what we all want. Compared to a natural history study, disease progression was slowed by around 80% in people on the high dose of AMT-130. This suggests that AMT-130 may be having an effect in slowing progression of HD as measured by cUHDRS. Again, this is only data from 9 people, so it must be interpreted with caution.

cUHDRS is actually made up of many different clinical measures including Total Function Capacity (TFC) and Total Motor Score (TMS). Looking at these individual measures, the effect of AMT-130 is less obvious although there is a suggestion of a trend of things heading in the direction of slowing HD symptom progression. Not to be a broken record, but again, the tiny number of folks whose data is being analysed at this stage means we have to be careful in drawing too strong conclusions.

Other measures uniQure didn’t report this time

Interestingly, this update included no new information about whether huntingtin protein levels are being lowered by the drug, the effect we expect this drug to have in the brain. We also didn’t learn any new information about what brain imaging might tell us about how AMT-130 is working. Hopefully, uniQure gives us updates on both of these measures the next time they share data.

What does this all mean?

Overall, this update is exciting, positive and certainly cause for very cautious optimism. That said, this does not mean that AMT-130 is a cure for HD, there is still a long road ahead. We need more data from more people over longer timeframes to be sure of the effect this drug is really having on slowing down symptoms of HD. Nonetheless, the fact that the drug appears relatively safe and there are positive signs in how it might be helping slow down symptoms is good news for the HD community.

What’s next for AMT-130?

Recently, the FDA granted AMT-130 Regenerative Medicine Advanced Therapy (RMAT) designation – the very first time this has happened for an HD therapeutic. This gives them more frequent interactions with the FDA and priority review of their data, so that if the time comes that they’re ready to file for regulatory approval, they can hit the ground running to get accelerated approval.

uniQure have disclosed that they expect to meet with the FDA in the second half of 2024 to continue their discussions about the development of AMT-130. In those conversations, they hope to define a path for getting approval of AMT-130 for HD.

Lot’s of things to be thankful for

Sometimes when it rains, it pours! We have had what feels like a deluge of positive and encouraging news about HD clinical trials lately, and certainly at HDBuzz, we are feeling thankful. It was not so long ago that the news deluge was delivering a very different and much more difficult message, that many drugs just weren’t working as we had hoped.

So, what’s changed? Well it’s important to remember that even when clinical trials don’t give us the results we had hoped for, there is still so much to be learnt from the wealth of data that is collected. All of the selfless hours in the clinic from the folks with HD who sign up for these trials count for a huge amount. The rich datasets they help generate have a huge impact in how scientists understand how different therapies might work in people, and what they can change and improve to give us the best chance of success. Their contributions have gotten us to this exciting point where we still have lots of irons in the fire and are edging closer to disease-modifying therapies.

The future of HD clinical trials is bright, thanks to the resiliency, fortitude, and sacrifice of so many people with HD who bravely stepped up to test these experimental drugs. We are forever thankful to them and are buckled in for the ride to see what comes next.