HDBuzz

DNA repair and CAG repeat instability

The effect of HTT lowering on CAG repeat expansions

Welcome to last day of the @hdfcures conference! We’ll only be sharing a few talks from today’s sessions, which focus on DNA repair. The first is from HDBuzz’s very own Jeff Carroll!

Jeff will be sharing his work on HTT lowering and how this might influence the stability of the CAG number in mouse models of HD. This is part of a process called somatic instability which we previously wrote about on HDBuzz.

Scientists have found that buildup of HTT within a cellular compartment called the nucleus, where our genetic material is stored, might be driving aspects of HD. This might be because of interactions HTT has with that genetic material – the DNA

It seems that the huntingtin protein molecule is binding to genes which we know are very important in HD. Interestingly, it looks like huntingtin is binding on to the end of genes, where expression of the gene ends. Very spooky!

When they looked to see which groups of genes huntingtin seems to be hanging out near, it looks like these are mainly genes with lower expression in HD and HD animal models. While cool, it’s not clear what this all means just yet.

Now Jeff is switching gears to look at somatic expansion in HD mouse models. His team found that when HTT levels are lowered, the amount of expansion is reduced when they looked in the liver, but in the brain, they don’t see the same effect.

It turns out that the HTT-targeting ASO causes the machinery involved in gene expression, a process called transcription, to be thrown off the DNA at the HTT gene. Scientists have found that transcription is important for somatic expansion so Jeff thinks this might be why the ASO reduces expansion.

Lowering HTT using a different tool, Jeff’s data shows that lowering only the expanded form of HTT prevents expansion of the CAG repeat – somatic instability. This is great news since there’s been a lot of talk at this meeting about the contribution of somatic instability to HD and what it could mean for therapeutic development

It turns out that the HTT lowering ASO also reduces somatic instability at other genes which have lots of CAG repeats. It’s not quite clear what’s going on just yet but Jeff and his team are on the case to follow up on this interesting data.

The role of modifiers in CAG repeat expansion

Our next talk is from Anna Pluciennik, who will be sharing her work on DNA repair and CAG expansions. Anna’s work is focused on understanding how mistakes in reading DNA can lead to additions of CAG repeats.

When the gene has lots of CAGs, like HTT, DNA slips out forming a little loop. This little DNA loop is recognized by molecular machines in the cell that can increase those repeats.

Normally, cells can repair this, but it seems in diseases like HD there are also problems with the proteins that repair these slip outs. Understanding more about these DNA slip outs at the CAGs and proteins that repair DNA could tell us something about the cause of HD.

Interestingly, many genes that modify the age of onset of HD – “modifiers” – also happen to be these proteins that repair DNA. It’s all connected!

One of those modifier proteins that Anna is interested in is called FAN1. Anna and her team can make FAN1 protein in the lab and look to see what other molecules it might be working with. They found that FAN1 interacts with DNA only when CAG slip outs are present. Her lab is doing lots of experiments to find other proteins that are required for this process.

Understanding exactly what’s going on and what proteins are involved will help the team understand if they can disrupt this process to reduce the slip outs. Ultimately, they hope this could help them reduce CAG expansions in HD.

Different forms and fragments of the HTT protein

The last talk of the conference is by Gill Bates, who will put HTT splicing into perspective for HTT-lowering therapeutics. HTT splicing is something we’ve heard a lot about lately with recent trials around PTC-518 and branaplam.

Splicing is the fancy science name for the process by which genetic messages are processed and chopped up before they get turned into protein molecules. If the huntingtin genetic message is spliced differently, then different forms or fragments of the huntingtin protein molecule will be made.

Dr. Bates’ team looked at lots of these different forms and fragments so that they could systematically ask what each is doing. Interestingly, they found that there is one particular fragment – called “exon 1” – which may be super important.

This exon 1 fragment contains the CAG repeats, but is missing much of the rest of the HTT gene. So it seems that this particular fragment may be causing much of the trouble in HD.

Since scientists like to give molecules specific names once they know they’re important, this exon 1 fragment of the huntingtin protein has been named HTT1a.

Using various tools in lab, they have shown that HTT1a is also made into a little protein fragment and can be found in different mouse models of HD. When they looked in brains generously donated from people with HD, they also found this little HTT1a fragment there.

It seems that the HTT1a protein fragment is important for beginning the formation of toxic protein clumps, called aggregates. Aggregates are a common feature in HD in both people and our animal and cell models of HD.

Dr. Bates has focused on developing tools to specifically look at the small HTT1a protein. This has been tricky because HTT protein fragments, like HTT1a, are hard to handle and make in the lab as they are rather sticky.

Interestingly, when they look in certain mouse models of HD over time, they find full length HTT levels go down as the mice age but levels of the HTT1a clumps go up. This suggests the HTT1a fragment becomes more prevalent as the HD mice get more sick.

Gill’s team is also looking at measuring the really enormous full-length HTT protein molecule. There are lots of different ways to do this but nearly all of these experiments get confused by a mixture of expanded and unexpanded HTT.

All of this work is very important because all of the HTT lowering clinical trials rely on these tests to work out if their drug is working or not by measuring changes in the HTT levels in different samples.

One important thing Gill’s work points out is that it’s really critical to measure various forms of the HTT protein – both full length and fragments that seem to be very toxic and contribute to disease.

An interesting question Gill asked was, what happens if we could make a mouse that doesn’t produce the toxic HTT1a fragment given how important it appears to be in HD?

Gill’s team have used some clever genetics tricks to make a mouse which only makes the full-length HTT protein but not the HTT1a fragment.

When they compare these mice to the same strain that DOES express HTT1a and look at protein clump formation in the brain, they find they do eventually form, just much later than expected and to a lesser degree.

While this might seem to suggest that even without HTT1a, mice can form toxic protein clumps, the caveat with this interpretation is that these mice did have a very small amount of HTT1a still present. So that small amount may be driving this pathology.

No experiment is perfect, but these results strongly suggest that a significant amount of the toxicity associated with the HTT protein is because of the HTT1a fragment.

That’s all for our reporting from the @hdfcures conference! HDBuzz looks forward to tweeting future HDF symposia. We hope you all enjoyed following along and we look forward to sharing more HD research with you soon!

To learn more about the Hereditary Disease Foundation, visit their website. To learn more about the science discussed at #HDF2022, tune into a live webinar on September 15th at noon EST! Register here You can also follow HDF on Facebook, Instagram, and Twitter to ensure you don’t miss future webinar updates.

Pre-clinical work moving toward trials

New tools to lower HTT showing promise in animal models

Welcome back! The first talk we will be tweeting about today is from Anastasia Khvorova, who will be telling us about her teams work on lowering of Huntingtin using technology called RNAi.

One of the problems in studying drug delivery to the human brain is that animal models, even large ones, all have much smaller brains than us! Mouse and even monkey brains are tiny by comparison, so Anastasia’s lab use sheep as they have fairly large brains. In these sheep brains, the Khvorova lab can measure how drugs are able to spread and work across the different regions of the brain.

Similar to the approach Wave Life Sciences are taking, the drugs Anastasia and her collaborators are testing target small genetic signatures which means they can lower just the toxic form of the huntingtin protein. However, one of the problems about being so specific in which form of huntingtin you are targeting, is that you need more drug to see the same effect.

We’ve talked a lot about huntingtin protein clumping up in cells, but Anastasia is looking at the huntingtin message – the recipe – forming clumps in the cell’s nucleus. She thinks this could contribute to the lengthening of CAG repeats that can cause cells to become sick.

The toxic huntingtin actually comes in a long and short form. The shorter form is thought to be responsible for the toxic clumps that we see in HD models. Anastasia tells us that we have to be careful when looking at these clumps, because they differ between models and people.

Anastasia and her team have identified compounds which are able to reduce the amount of the short form of the toxic huntingtin. They have added this to their toolkit of compounds which change the levels of important targets in HD including total huntingtin, toxic specific and MSH3, a genetic modifier of HD.

Anastasia thinks this toolkit is an excellent portfolio of different options for targeting HD, which may also help us unpick exactly which protein or protein form is important in the disease progression.

Cell replacement treatment options using stem cells

The next talk we’ll cover is by Anne Rosser from Cardiff University. As a part of the Stem Cells 4 HD initiative, she’ll give an overview of how stem cells are being used to study and potentially treat HD. Stem cells can be used in HD research for various purposes: either as a tool to understand more about HD or, perhaps, as a therapy. Anne’s talk focuses on the latter.

The overall goal of using stem cells as a therapy would be to 1) replace cells that have been damaged by disease and 2) release biological factors like chemicals or proteins that might have been lost during disease, to try and keep other cells in the brain healthy.

The cells that researchers have been interested in using for this cell replacement therapy come from “pluripotent stem cells.” These can be made from the cell of an adult, like a skin cell or blood cell, and they can be turned into almost any type of cell in the body.

We know from older studies using a different type of stem cell that cells transplanted to the brain do a good job of integrating into their new environment. This would be great news for HD, where they hope that cells added to damaged areas will form connections with other parts of the brain

Anne mentions that there are several HD labs moving this technology forward toward clinical trials. However there are challenges with such an invasive approach, including exactly which cell type to use for transplants and how to create a comparison group.

To deeply consider all of these challenges before moving forward, researchers have created the Stem Cells for HD (SC4HD) group, comprised of stem cell leaders from around the world.

The SC4HD group is standing on the shoulders of giants – learning lots from previous studies that transplanted fetal tissue in the HD brain, changing what didn’t work and using what did to move forward logically and safely. To ensure researchers have as much information as possible before moving forward, studies are being done to compare various ways to make striatal neurons, which are the most vulnerable cell type in HD.

There are a lot of variables to consider – controlling between different batches of cells, tracking the cells after they’re implanted, and ensuring they turn into the cell type we want once they’re in the brain. There’s still a lot to work out before we have this technology in humans for HD, but stem cells represent a very powerful source for cell replacement therapies.

It’s an action-packed morning, and we’ll be back after a break, tweeting briefly about a couple of short talks on impactful topics.

Datablitz: presentations from young investigators

Putting mouse models head-to-head: which is the best?

Sophie St-Cyr was selected to give a short talk related to the advantages and disadvantages of different types of mouse models we use to study HD.

There are dozens of models, grouped in different categories based on how they’re created and what HD-like signs and symptoms they have. Sophie compares different behavioral tests in different HD models and across sexes.

As an expert in mouse behavior, she made recommendations to the scientists in the audience about the use of different mouse models and how best to design their behavioral experiments.

At-home collection of samples for NfL detection in blood

Next up is Lauren Byrne from UCL who works on a protein called NfL (neurofilament light), which is released by sick cells and can be used as a biomarker of brain damage in HD. NfL levels go up as HD progresses.

Scientists might also be able to use NfL to track whether a treatment is working, and it is increasingly being measured in clinical trials to check firstly, that there are no safety issues, but secondly, to see if the drug is helping to keep the brain healthier.

Lauren’s work has been focused on developing more practical ways to measure NfL levels. Luckily NfL is a very stable protein so Lauren has developed an at-home finger-prick test to collect blood, and then post it back to the lab through the mail for analysis.

She will be running a study called iNfLuence-HD to study NfL levels and improve methods for measurement, and is also heading up the JOIN-HD registry which aims to study juvenile HD patients from all over the world.

That’s all from this morning’s session. We are breaking for lunch now and will be back with more updates on all this exciting HD research later on this afternoon.

Genes and proteins that modify HD onset

Identifying modifiers by looking at the whole genome

Welcome back! The afternoon session will focus on genetic modifiers of HD, other genes that influence the age that HD symptoms begin. The first talk we’ll cover is by William Yang from UCLA, who studies modifiers in mouse models.

What very large sequencing studies have shown us is that many of the modifier genes that change the age of onset in HD have to do with DNA repair. The question is: how can we harness them for HD therapeutics?

Dr. Yang uses mice to study how we might be able to use these modifiers for treatments in HD. His team has created many of the mouse models that have become the standard in the field.

Dr. Yang’s lab has compared these different models at different timepoints to understand how HD changes within each model over time. In particular, he has done a deep dive on gene expression changes – how levels of genetic “recipes” go up and down.

Another key feature they examine are clumps of the HTT protein, also known as protein aggregates. This is a unique feature caused by expanded HTT that seems to occur mainly in brain cells called neurons.

The Yang lab has recently created a new mouse model that can be used to study different aspects of HD, like problems with sleep, CAG repeat expansion, and damage to specific brain areas. One of the questions they want to answer with this new model is whether genetic modifiers of HD can influence these features, like changes in gene expression or protein aggregation.

A relatively recently identified feature of HD is somatic instability – expansion of the CAG repeat in certain cells or tissues over time. This happens frequently in neurons and might be contributing to why certain types of cells become sick and die in HD.

Adding or removing certain modifier genes in these HD model mice can cause symptoms and features of HD to improve or worsen. This strengthens the case for targeting these genes with drugs in people.

Dr. Yang’s lab has found that altering levels of a specific modifier, FAN1, in HD mice can affect their behaviors, like sleep patterns and ability to walk on a rotating rod. There is also a change in protein aggregation

It seems that just targeting FAN1 alone might not be the answer to HD, but interestingly, when they also target another modifier in these mice, called MSH3, the mice get better in most of the metrics they looked at.

These types of controlled genetic experiments in mice can help to identify and confirm the right targets for drugs that could delay HD onset.

Alfy as a modifier of HD

The next presentation we’ll talk about is from Dr. Ai Yamamoto of Columbia University, who works on a protein called Alfy, that is also a genetic modifier of HD.

Large scale human studies found that tiny genetic changes in Alfy can cause the onset of HD symptoms to be much later. Ai’s lab created a specialized mouse model to study this rare genetic variation in more depth, and these mice also had delayed onset of symptoms.

Alfy is involved in breaking down clumps of harmful huntingtin protein. In both humans and mice, the Yamamoto lab has found that higher levels of Alfy can have positive effects on symptom onset.

They are now finding that Alfy’s role in clearing toxic proteins is highly important in conditions of stress, including in HD and other brain disorders.

The effect of HD on connections between different parts of the brain

This afternoon we’ve got a very exciting session about BRAINSSSS!! The talks focus on different aspects of brain function, measured with very cool new techniques.

First talk is from Dr. Lynn Raymond, of @UBC. She studies how brain cells called neurons communicate. These communicating cells are the ones that die in HD, so understanding how they start to dysfunction can give us clues about how HD arises.

While the HD gene is expressed in nearly every cell of the body, it’s neurons that cause most of the symptoms of HD. And in fact, not all neurons are impacted in the same way. The most impacted include a set of structures within the brain, deeply connected to each other, called the “cortex” and the “striatum”.

Dr. Raymond’s lab has long studied the details of how these two parts of the brain communicate using mouse models of HD. She sees very clear changes in how the HD mice learn to do new movements, something like the problems that happen in HD patients

Dr. Raymond’s lab is using existing new “deep learning” or “artificial intelligence” software tools to analyze the behavior of mice in detail that was not previously possible (@deeplabcut).

To link changes in behavior to changes in brain function, Dr. Raymond uses live, real-time, microscopes that allow tracking of brain activity in HD mice doing specific HD-relevant movements. This is a good example of why we need mice, and other models of HD – there’s no way we could record this level of detail of how brain cells talk to each other in humans with HD.

In HD mice, the cortex, an outer bit of the brain critical for our thinking ability, is hyper-excitable. There’s a lot more activity accompanying movements in HD mice, compared to controls. So it’s as if the brains of the HD mice have to work a bit harder to achieve the goal of the movement. This might be a hint for why some types of movements, and the learning of those movements, are hard for HD patients

That’s all from us for today! We’ll be back tomorrow afternoon to share a few other talks before the close of the
@hdfcures symposium. Tune back in then!

To learn more about the Hereditary Disease Foundation, visit their website. To learn more about the science discussed at #HDF2022, tune into a live webinar on September 15th at noon EST! Register here You can also follow HDF on Facebook, Instagram, and Twitter to ensure you don’t miss future webinar updates.

We’re back for day 2 at @hdfcures! This morning’s talks will be focused on clinical trial planning and therapeutic updates from clinical studies. The sheer number of talks related to human trials compared to previous years is so encouraging!

Updating metrics for clinical trials

A better system for disease categorization

The first talk of this session is from Jeff Long from the University of Iowa, who will be talking about clinical trial planning using the Huntington’s disease Integrated Staging System (HD-ISS). We talked about this last night, and in a recent Buzz article.

Dr. Long is recapping the different stages (0-3) of the HD-ISS, and showing how brain areas, biomarkers, and neurological tests change over the newly defined stages of HD.

Dr. Long also recapped what stages patients were in for various trials. For the tominersen GENERATION-HD trial, and most other trials, patients have been in stage 3. Running trials of people in Stage 1 is likely not feasible right now because of the limited changes observed in this group. It seems stage 2 might be the sweet spot – it’s feasible to run clinical trials with people in this stage with current trial outcomes, and they seem to be earlier in disease.

Dr. Long uses statistical models to go through an example of participants required to run a trial, based on what we know about progression in stage 2. It’s very important that enough people participate in different arms of trials to provide the study with enough “power”. This allows researchers to draw definitive conclusions.

He points out that developing these models to design better trials requires thousands of data points, each of which comes from a different person in an observational HD trial. Without participation in Enroll-HD, PREDICT-HD, TRACK-HD, and other studies, none of this work is possible.

Using computers and robots to understand HD biology

Our next talk is by Dr. Steve Finkbeiner, who will be talking about using artificial intelligence (AI) to look at HD in patients and different animal models. HDBuzz recently wrote about AI and how it can change the game for understanding HD.

Steve attempts to capture the great complexity of the biology of HD by applying mathematical and computer modeling to the many changes observed in cells growing in a dish.

Steve’s team also used AI to predict which cells would die and when based only on their shape and some markers. They found their computers were far more accurate than when the same predictions were made by people! The computers also found new ways to predict if cells would live or die based on some of their structural features which scientists hadn’t even thought of or discovered yet!

These models can distinguish between healthy and Parkinson’s disease cells, and between healthy and Alzheimer’s disease tissue, with up to 97% accuracy – something that might be impossible even for a trained pathologist. AI tools like these could be huge game changers for diseases like Parkinson’s that have spontaneous cases. But Steve’s group is very keen on applying his tools to HD to learn more.

Since AI can see things people can’t, Steve wonders if we could harness AI to learn and even plan experiments! His most recent endeavor focuses on “how to make a sick cell healthy” – can his computers develop a model of HD and an effective treatment?

Biomarkers in HD research

Next up is our own Dr. Ed Wild! Ed will be talking about HD biomarkers – things we can measure to get a picture of where a person is in the progression of their HD.

Naturally, Ed started his talk with British pudding…noting that desserts prove themselves when eaten. HD scientists have been searching for an HD biomarker – “making the pudding” – for a long time. Ed detailed a timeline for how long the field has been working on a biomarker for HD. It’s taken about 20 years to get to the point where we’re really at the precipice of reliable biomarkers for HD.

He talked about the challenge of looking at levels of huntingtin in the brain, which must be measured indirectly in spinal fluid or blood. It has thus far been very difficult to distinguish between the expanded and non-expanded forms.

Ed also detailed recent challenges in the field with current trials. While there have been several recent disappointments, they’ve all failed or faced roadblocks for different reasons. The Wave PRECISION trials didn’t “engage the target”, meaning they didn’t lower HTT. The uniQure trial engaged the target, but the low numbers of patients so far make the data variable. And as we recently learned, the higher dose arm of the trial is on pause.

Now Ed is detailing work on NfL – neurofilament light – a biomarker that was touched on during yesterday’s talks. In every test thus far, NfL is turning out to be an excellent biomarker for HD in both CSF and blood. While NfL isn’t currently included in trials as an official biomarker, everything suggests we’re headed in that direction. To help get us there, samples are being collected in many current trials to track NfL levels. Great news for sensitively tracking progression of HD!

Ed also touched on imaging biomarkers, like brain scans, and digital biomarkers, taken from smartwatches and smartphones. These currently have complex results, but are being studied and developed in full force.

To wrap things up, Ed brought back his pudding analogy – he thinks it’s time to eat the pudding, i.e. that we’re ready to start applying all these strategies to clinical trials, and to continue learning as much as we can from existing human samples.

After a short panel discussion, we’re breaking for lunch, but we will be back this afternoon for updates from LOTS of different pharma companies on current HD clinical trials. Stay tuned!

Updates from ongoing clinical trials

The first part of this afternoon’s session will involve short talks about current HD clinical trials.

Triplet Therapeutics – SHIELD-HD natural history study and clinical development of TTX-3360

First, Dr. Irina Antonijevic from Triplet Therapeutics will be talking about the SHIELD-HD trial, a natural history study which is following people with HD to learn more about the expansion of CAG repeats over time.

Triplet’s approach is different to many of the other companies making HD therapeutics. They are not targeting HTT-lowering, but instead a genetic modifier which they believe might slow or delay the onset of symptoms. Before they can test a drug, they are studying people in a two-year observational study called SHIELD-HD, which will help them to develop the most effective ways to measure changes in early HD.

SHIELD-HD is spread across 9 sites in 5 countries with about 70 participants enrolled. They are looking at different biomarkers of disease including brain imaging, CSF analysis, and other measures. About half of participants in SHIELD-HD have completed the trial, and Triplet expects to be able to analyze the early participants’ data in the first quarter of 2023.

Triplet have measured the level of a genetic modifier, a protein called MSH3, after treatment with their drug called TTX-3360 and have shown in HD models that the drug appears to be lowering levels of MSH3, as they hoped. Irina also presented data which suggests that MSH3 levels might be higher in patients at more advanced stages of HD, which is important to know about if this is the target of their drug.

uniQure – Trials related to AMT-130

Next up is Ricardo Dolmetsch from uniQure who will be giving us an update on AMT-130, a gene therapy for HD which aims to lower levels of HTT.

AMT-130 is a harmless virus which is injected into a part of the brain called the striatum by brain surgery. From there the special genetic instructions encoded in the virus are incorporated into each cell, so they are able to make the HTT-lowering molecule themselves.

The clinical trial is being run in the US and in Europe and participants in the trial are either receiving a high or a low dose of the drug, and some participants are receiving a sham surgery with no drug. After the surgery, the participants are tracked for 3-5 years to measure lots of different biomarkers and different HD signs and symptoms they might be experiencing, and how these are progressing.

Keep in mind that this is a very small trial (26 people in the US and 15 in Europe) and the major goal is to look at the safety of AMT-130 and whether it can lower huntingtin – looking at its effectiveness for slowing symptoms will come later on.

For the patients who received the low dose of the drug, no serious side effects were observed. However, for those who received the high dose, 3 folks experienced serious side effects. Fortunately, all 3 are no longer hospitalized and 2 have completely recovered, and the other has substantially recovered. This has meant that dosing with the high dose of the drug has been temporarily suspended and the patients in this part of the study will be very carefully monitored moving forward.

Additional announcements about the status of these trial participants, other adverse events associated with the high dose group, and a decision about moving forward, will come later this year, likely around October. Immediately after the participants received the drug, levels of a biomarker called NfL did spike, but seem to be returning to baseline over time, and are not significantly higher than the control group.

Giving the scientists at uniQure hope is the fact that it seems like the levels of the toxic huntingtin protein are decreasing over time after treatment. However, it is early days and the numbers in the trial are still very small. We are hopeful that the high dose group of this trial may resume with new safety measures in place – already 14 out of 16 participants planned for this group have received the surgery.

PTC Therapeutics – Updates for the PIVOT-HD trial testing PTC-518 for HTT lowering

Next up, we have Amy-Lee Bredlau from PTC Therapeutics who will be telling us about their HTT-lowering drug called PTC-518 which is a splicing modulator – it can alter how the huntingtin message is processed, leading to lower levels of huntingtin protein.

PTC have shown that treating HD mice with their drug reduces levels of the huntingtin message molecule in the blood as well as the protein molecule in the brain.

PTC scientists have also shown that the drug is showing promise in people. They found that the more PTC-518 they give to patients, the more the levels of huntingtin are decreased. They also show that the effects of this drug are reversible. The good news is that this means that PTC met their phase I trial objectives in healthy individuals, so this drug has moved forward to the next stage of clinical trial testing.

Now they are running a Phase II study in people with HD. PTC will be looking at safety of the drug in a much larger number of participants (162) and they will also be monitoring how well the drug lowers huntingtin levels in this group. This trial will be giving 2 different doses of the drug and will also have a control placebo group. Depending on how the data from these 2 dose groups looks, there may be an additional dose group later on.

To be recruited in this trial, participants must be 25+ years old and have a CAG number between 42 and 50. However, participants must have perfect scores in clinical metrics called TFC and UHDRS which measure day-to-day function and movement symptoms of HD.

PTC acknowledges that this might be frustrating for patients as the criteria are strict and a bit complicated. However, they hope that by having a very specific patient population in the trial, they will be able to enroll a much larger Phase III trial later on which will be open to a broader range of people with HD.

PTC-518 is an oral huntingtin lowering drug that differs from the Novartis drug branaplam. Despite the suspension of the branaplam trial, there is hope that PTC-518 could still be successful.

Wave Life Sciences – WVE-003 for selective lowering of expanded HTT in SELECT-HD trial

Next up is Danlin Xu from Wave Life Sciences who will be talking to us about WVE-003, an ASO huntingtin-lowering therapy which specifically targets only the toxic form of the huntingtin protein.

WVE-003 targets a specific genetic signature which is only found in the expanded huntingtin gene, so it could potentially lower just the toxic form of the protein. Not every person with HD has this signature, so if successful this drug would only be able to treat a subset of people with HD.

WVE-003 is an ASO delivered spinally, like Roche’s drug tominersen. However, Wave uses a different kind of chemistry to make their ASO’s which they believe makes them work better as drugs to target specific genetic messages.

Wave’s previous ASOs didn’t pan out as we had hoped – they didn’t make people any worse but they didn’t actually lower huntingtin levels. One problem was that they couldn’t test their drugs in HD mouse models previously because existing mice didn’t have the right genetic signature. However, Wave now has a mouse model they can test their drugs in.

In this mouse model, they have showed that WVE-003 lowers only the toxic form of the huntingtin protein, not the healthy huntingtin protein. After treatment, they could see this huntingtin lowering effect lasted for at least 12 weeks.

Now Wave are enrolling HD patients into their new trial, SELECT-HD, which is testing WVE-003 in people. It is taking place in Australia, Canada, and Europe. Everyone recruited to the trial needs to have a test to make sure they have the genetic signature that WVE-003 targets.

To make sure their drug is acting as it should and only targeting the toxic form of the huntingtin protein, Wave have developed a special test to measure the levels of just the healthy protein and make sure it is unaffected by the drug. The trial will run with an adaptive design which means that the dose level and frequency may change during the trial based on participant data.

Annexon Biosciences – ANX-005 to treat molecular breakdown between brain cells

Ellen Cahir-MacFarland from Annexon will be talking next to tell us about their complement C1q targeting therapy, ANX-005.

Annexon is targeting a protein called C1q. This is an important protein in a part of the body’s immune response, called the complement system. C1q is an interesting target because we know that people with HD experience neuroinflammation, which Annexon believes is caused by complement.

When our bodies are growing, C1q plays an important role in making sure all of our brain circuits are properly formed, by “pruning” improper connections within the growing “tree” that is our nervous system. This process seems to be improperly reactivated in diseases like HD, and C1q activation is linked to neuroinflammation seen in patients.

ANX005 was tested in a clinical trial and it seems to be doing its job targeting the complement system. Annexon also looked at participants’ HD symptoms, and in a subgroup of the participants, it seemed like the progression of symptoms was slowed which is good news. This suggests that there is a sub-population of people with HD who might benefit from treatment with ANX005. Annexon will likely conduct a larger Phase 2 trial to confirm these results.

However, it is important to note that levels of NfL, a biomarker for neurodegeneration, were not improved with drug treatment, so the picture is not entirely clear just yet and more work remains to be done.

SAGE Therapeutics – SAGE-718 for treatment of cognitive symptoms

Now we will hear from Aaron Koenig from SAGE. Their drug called SAGE-718 aims to improve the cognitive symptoms that people with HD experience.

Cognitive symptoms in people with HD can have a really big impact on their quality of life. While it is important that we have drugs which aim to target the root cause of HD, we also need to target symptoms of HD, which might improve patients everyday lives.

A molecule called 24S-HC which targets special nerve cell receptors is reduced in people with HD. SAGE-718 aims to target these same receptors so they might work properly again which SAGE hopes will alleviate cognitive symptoms in people with HD.

In SAGE’s PERSPECTIVE program, they will run 2 studies – one called DIMENSION and the other called SURVEYOR.

DIMENSION is a Phase 2 trial which will test SAGE-718 in people with HD. SAGE will measure how their symptoms change or evolve during the study, particularly cognitive ones. The SURVEYOR study, another Phase 2 trial, will also test SAGE-718, but the study involves additional measures of function in day-to-day life, like ability to go grocery shopping or perform in a driving simulator.

SAGE is using standard HD cognitive tests but have also developed a new measurement called the Hi-DEF scale. This includes measurements on how well participants are able to do day-to-day tasks, including driving, grocery shopping, and so forth.

Prilenia Therapeutics – PROOF-HD trial to test pridopidine

The last talk of this session will come from Michael Hayden from Prilenia, who is also a professor at UBC. He will be talking to us about pridopidine which is being tested in the PROOF-HD clinical trial.

Pridopidine is a drug, taken as a pill, which is thought to target a protein called the sigma-1 receptor. This protein is found in areas of the brain important in HD. More and more data in HD models has confirmed pridopidine’s effect on sigma-1.

There are a number of studies which have now been published that show that there seems to be a neuroprotective effect and better nerve cell connections when different HD models and systems are treated with pridopidine.

The PRIDE-HD clinical trial tested pridopidine in people, but it did not meet its clinical endpoints. However, there seemed to be a glimmer of hope when the scientists at Prilenia looked after the fact at a particular measurement called TFC.

Remember, these after-the-fact analyses, known as post hoc analyses, ask questions of the clinical trial data that the trial was not designed to answer, so we must be cautious when interpreting these conclusions.

In this analysis, it seemed that levels of NfL stabilized following pridopdine treatment. Together with the possible improvement in function (TFC), Prilenia set out to run another Phase III trial for this drug called PROOF-HD.

This study is now fully recruited and many participants are now entering the open-label extension, where they can continue to take pridopidine if they choose to. We should get some data updates in the second quarter of 2023 so watch this space for more news on pridopidine.

It’s now time for a break so we can all have a much needed cup of coffee! But we will be back with more tweets for you soon as we move to the next session – systems biology approaches to study HD.

Interactions between neurons and other cells in the brain

There will be a few other talks during the afternoon session, but we’ll only focus on a talk by Dr. Michelle Gray from the University of Alabama at Birmingham, who will tell us about her work on the interaction between different cell types in the brain.

Michelle and her lab work on astrocytes – a type of brain cell which are thought to be very important in nervous system function and specifically in HD. It seems that in HD, astrocytes behave strangely and they are more likely to die quickly in the HD brain compared to control models and systems.

Michelle’s team is able to lower the levels of the huntingtin protein just in astrocytes in a HD mouse model, and this seems to improve signs and symptoms of HD in these animals. When HTT levels are lowered in these astrocyte cells, there are significant changes in the levels of molecules that brain cells use to communicate, in particular, one called GABA.

Changes in GABA levels suggest that astrocytes might be working differently in this model. Michelle wanted to work out why there were changes in GABA and they found that a group of proteins which have important jobs in transport, are responsible.

Interestingly, we know that GABA signaling is changed in HD mouse models, particularly in cells called medium spiny neurons, which often die early in HD brains. Michelle and her research team wanted to work out if these two findings are linked.

Changes in the levels of GABA can have important implications for how brain cells communicate with one another. Michelle and her collaborators made measurements of electrical impulses in the brains of HD mice and confirmed that this signaling was altered.

She concludes that astrocytes can contribute to imbalances in brain cell signaling in ways that were previously undiscovered.

That wraps up the talks for today. We will be back tomorrow to bring you more exciting updates on the latest and greatest HD research from all of the speakers @hdfcures!

To learn more about the Hereditary Disease Foundation, visit their website. To learn more about the science discussed at #HDF2022, tune into a live webinar on September 15th at noon EST! Register here You can also follow HDF on Facebook, Instagram, and Twitter to ensure you don’t miss future webinar updates.

Hello and welcome from the HDBuzz team who are currently at the Hereditary Disease Foundation (@hdfcures) 2022 Milton Wexler Biennial Symposium in Boston! It’s the dawn of an exciting new era for HDBuzz. Due to our new partnership with @hdfcures, we are now able to live tweet many of the talks from this meeting which was previously closed to social media.

Huntington’s disease orientation

Two talks will kick off the meeting tonight, discussing when to treat HD and understanding treatment effects of the huntingtin-lowering drug, tominersen.

The ideal time to treat HD

The first talk of the meeting is from Sarah Tabrizi from UCL. Sarah will be talking to us about when it might be best to treat people with HD. Sarah begins her talk by reminding us that we can test for HD with a genetic test, long before we might see signs and symptoms of the disease in patients.

Thanks to many studies that HD families have participated in, like PREDICT-HD and ENROLL-HD, we know a lot about the timing of when HD begins. The HD Young Adult Study (HD-YAS) aimed to establish when biomarkers of HD first become detectable in participants who had a positive test for HD but many decades away from having symptoms. HDBuzz wrote about HD-YAS when it was first published by Dr. Tabrizi’s lab group.

Lots of different measurements were taken from all of the participants in this study including many types of brain scans and imaging. The scientists in the study looked at how these different measurements changed with participant age, CAG number, and other factors.

Many of the measurements, including thinking and psychiatric testing, showed no difference between the participants without HD and those with the HD gene expansion. Out of 8 brain regions, only a part of the brain most affected by HD (called the putamen) was slightly smaller in the group with HD compared to the controls.

Interestingly, the levels of a biomarker called NfL (neurofilament light), were significantly increased in the HD group compared to controls. However, the levels were still very low, indicating that there was probably not much neurodegeneration yet. Many other biomarkers from spinal fluid were assessed (about a dozen!), and only NfL levels indicated there was a change in people with and without HD.

Overall, this is great news. People born with the HD gene expansion have brains and biomarkers which are indistinguishable from people without HD. Even 24 years from predicted onset of symptoms, there were no obvious changes in thinking, in the size of most brain regions, and in many biomarkers.

BUT there were detectable changes in NfL levels, which means researchers do have a biomarker they can look at during the very beginning stages of HD, before obvious symptoms appear. This very subtle detectable change associated with HD may indicate the best time to treat to prevent loss of brain cells – people with HD are completely healthy by almost every measure, but there’s a biomarker (NfL) that allows researchers to determine if they could get better.

Next Dr. Tabrizi talked about using the HD Integrated Staging System (HD-ISS) to streamline recruitment for clinical trials which we wrote about a few months ago.

The HD-ISS stages people with HD from 0 to 4, much like the way the cancer field stages patients. This new system will allow HD researchers and clinicians to compare results between trials. Importantly, it is hoped that this new symptom will help HD researchers conduct clinical trials in patients at much earlier stages of the disease.

People with HD won’t need to know their stage and it won’t influence day-to-day life with HD or care. It will only be used behind the scenes for organizing clinical trials.

The scientists who came up with this new system did a large-scale systematic assessment of the different landmarks which could be measured to indicate disease stage. Over 20,000 data points were analyzed! This created a very robust, objective dataset from which the HD-ISS was created. For a person with a particular CAG number, scientists can predict how HD signs and symptoms might progress over that person’s lifetime.

Currently, trials have been done in people with later stages of HD. The HD-ISS staging system sets up a framework that can be used to recruit trials designed for people before they have symptoms of HD. While we’re not quite ready for trials in people with the earliest stages of HD, some HD patients are eager to see this happen and the HD-ISS sets up the system to allow this.

Sarah rightly highlights that this work was only made possible by HD research participants and families who contributed to the many studies which informed the design of the HD-ISS.

Update from Roche on the tominersen trial and moving forward

Next up is Peter McColgan from Roche. Peter will be talking to us about the huntingtin-lowering drug, tominersen, the trial of which was halted early last year.

Peter is going to tell us about some of the additional analyses Roche have done regarding the findings from the halted GENERATION-HD1 trial. He rightly thanks the commitment and dedication of HD families who participated in the trial. Without them, we wouldn’t have data or knowledge from one of the first HTT lowering trials.

In this Phase III trial, participants were either dosed with 120mg tominersen every 8 weeks or every 16 weeks or were given a placebo. Although the drug lowered the levels of the huntingtin protein, patients did not get better. In fact, patients who received the drug did worse than placebo.

Over the course of the treatment, levels of NfL did not change that much but alarmingly the changes in volume to a part of the brain called the ventricles were worse in participants who received the drug compared to placebo.

Now Peter will cover new data from the trial! Roche is interested in understanding the mechanism behind what happened. One question they’re interested in exploring is if they can maintain reduction of HTT while avoiding some of the negative effects they observed.

Peter shows new data from Roche which suggests there is a correlation in the amount of toinersen drug in the CSF and the lowering of HTT levels in the CSF. However, it seems that there is no correlation between the changes in CSF HTT levels and clinical measures.

Next Peter detailed data that looked at increases in CSF NfL they saw with tominersen dosing. They found there was no relationship. Remember that NfL levels go up with damage to brain cells. So if it’s not tominersen, what is driving the early spike in CSF NfL?

The scientists at Roche looked at exposure to the drug i.e. how much drug is actually in the CSF, and the levels of NfL they observed in the early spike. Highest levels of exposure to tominersen had the biggest NfL spike and the largest amount of HTT lowering.

Next they looked to see if increases in volume of the ventricles influenced the clinical outcomes. They found there was no relationship. However the scientists wanted to try and work out why this brain volume measurement changed more in patients who received the drug.

Increase in the volume of the ventricles correlates with an increase in the amount of immune cells, like white blood cells called leukocytes. Interestingly there is no change in overall brain volume, even though the ventricle volume is increasing. Peter suggests this means there is no brain atrophy in these patients.

Based on the data Roche currently have, they’re unable to tease out the effects that are coming from “on-target” and “off-target” effects of tominersen – meaning effects they want and expect from the drug vs those that they don’t. What they do know is that some of the negative changes that they see related to increased size of the ventricles is likely due to inflammation in the brain.

Now Peter moves on to the “post hoc analysis” – the analysis of the data that was done after the trial was over that split people treated with tominersen into different groups to see if the drug had a positive effect on some. It’s important to note that a post hoc analysis tries to ask questions of the data collected in the trial which it was not designed to do – so all of this is to be taken with a pinch of salt

In the younger patients in the trial with a lower CAG number, Roche believe that there is some hope for tominersen and perhaps there was some clinical benefit. Note that these findings are NOT statistically significant. Roche is using this analysis to guide the design of the new study, which they’re using to
target people with HD with symptoms that are less advanced and those that have lower CAG repeat sizes.

This new Phase 2 study will also test a lower dose of tominersen to “explore the full therapeutic range of tominersen”. Since they already have data on the effects of higher doses, this lower dose will fill in a gap in their data. They plan to only give participants the drug every 16 weeks and will be using lower doses of 100 mg and 60 mg. From the GENERATION-HD1 trial, Roche knows that dosing every 16 weeks was well tolerated in the patient sub group that they’re targeting in the new trial i.e. younger folks with less severe symptoms of HD.

Overall, Roche feels their data support further exploration of tominersen as a therapeutic for HD. While the road to get to this conclusion had disappointment, Roche believes the data suggests there is hope and supports additional trials for tominersen.

That’s a wrap for the kick-off session of the meeting. We’ll be back tomorrow morning for interesting updates on various clinical trials. Stay tuned!

To learn more about the Heredtiary Disease Foundation, visit their website. To learn more about the science discussed at #HDF2022, tune into a live webinar on September 15th at noon EST! Register here. You can also follow HDF on Facebook, Instagram, and Twitter to ensure you don’t miss future webinar updates.

Last month, we relayed positive news from uniQure’s trial testing AMT-130, a gene therapy delivered via brain surgery to lower huntingtin (HTT). Data released by uniQure in June suggested AMT-130 was safe and well tolerated in the small group of people that were treated with a low dose of the drug. Now we’re back to provide an update on findings from the group of people treated with a higher dose of AMT-130. This new set of data shows that the higher dose of the drug may be causing serious side effects. This doesn’t necessarily mean AMT-130 doesn’t work and won’t move forward, but it does mean that we need to take a pause, really look into what the data are telling us, and work out a safe plan to move forward for people being treated with the drug.

Despite setbacks, HTT lowering is still considered an attractive strategy by many researchers

One advantage researchers that study Huntington’s disease (HD) have is that we know exactly what causes HD – an expansion in the HTT gene. The expanded HTT gene produces an expanded HTT message that is then processed into an expanded form of the HTT protein that causes damage in brain cells. So, in theory, reducing the presence of that expanded HTT protein could alleviate the symptoms associated with HD because it directly targets the root cause of the disease. This means that despite recent setbacks for several clinical trials designed to lower HTT levels, HTT lowering is still considered an attractive strategy for HD therapeutics by many researchers.

There are several different ways researchers are trying to lower HTT. The first horse out of the gate in the HTT lowering race were antisense oligonucleotides (ASOs). These are short sequences that bind to a specific message which then cause it to be degraded. Without the message, no protein can be produced. So while the gene remains intact, the protein is never made. This type of HTT-lowering technology is being explored by Roche with their drug tominersen that took a step back to find the right dose and patient population. Wave Life Sciences is also using ASOs to selectively lower the expanded copy of HTT with their ongoing Phase I/II trial for WVE-003, SELECT-HD.

Another way to lower HTT that’s being tested in clinical trials is through “splice modulators”. These are drugs that change how the genetic message is edited. Like a story, every gene has a beginning, middle, and end. The end is a specific sequence that tells molecules in the cell to stop reading the code for that gene. Splice modulators work by editing the message to move that ending code up, confusing the sequence of that gene. So rather than a beginning, middle, and end, the story is just a beginning and end. The cell recognizes that this makes no sense and stops producing that protein.

HDBuzz recently wrote about the splice modulator branaplam, being tested by Novartis in the VIBRANT-HD study, for which dosing was suspended due to safety concerns. Another splice modulator, PTC-518, is being tested by PTC Therapeutics. Even though PTC-518 works in a similar way to branaplam, a head-to-head comparison of these drugs suggests they are actually quite different. So bad news for one doesn’t necessarily mean there will be bad news for the other. We’re still eagerly waiting for news about the PTC-518 trial!

AMT-130 is a one-shot gene therapy approach to lower HTT

A third way to lower HTT is through gene therapy, which is the technology being used by uniQure with AMT-130. This drug works by using a harmless virus to deliver DNA instructions that will destroy the HTT message. The HTT gene still exists in its original form, but now the cell contains a new message that will prevent the production of the HTT protein. Because the cells infected with the harmless virus contain the genetic instructions, they can make the HTT lowering message all on their own. This means AMT-130 is a one-and-done approach – deliver the therapy through a single procedure, and the cells will continue to make the instructions that allow them to lower HTT. This is both exciting and nerve-wracking. While it means only one treatment is necessary, it also means any changes are likely permanent.

To get AMT-130 directly where it’s needed most – the brain – it’s delivered using brain surgery. Because brain surgery is always risky, this trial was rolled out very slowly to be as careful as possible. After the first 2 surgeries were complete, the participants were watched to make sure there were no immediate negative effects. When everything went well, surgery for the rest of the study participants continued.

The trial testing AMT-130, HD-Gene-TRX1, is a Phase I/II designed to test safety and tolerability of the drug as well as find the right dose that will work for people with HD. Because one of the primary goals of this study was finding the right dose that will work best for people with HD, 2 groups were tested: a low dose group and a high dose group. Scientists at uniQure believe that the higher dose of the drug will not necessarily lower HTT further in each cell, but that more drug will mean that more brain cells will have their levels of HTT lowered by the same amount.

36 people in total were enrolled in uniQure’s AMT-130 study: 10 that received an imitation surgery that will act as the control group, a critical part of any study, and 26 people in the treatment group. Of the 26 in the treatment group, 12 were treated with a low dose of AMT-130 and 14 were in the group for the high dose. So far, 12 of those 14 have undergone surgery.

In June we got an update from uniQure about people that were treated with the low dose of AMT-130 12 months after their surgeries, which HDBuzz wrote about. In that group, the surgeries and drug were well tolerated with no major safety issues reported. uniQure shared that preliminary data indicating that HTT seemed to be lowered more in the group treated with AMT-130 than the control group. While this is exciting news because it means AMT-130 appears to be doing what we want it to do – lowering HTT – this was reported in a very small group of only 4 participants.

Some participants in the AMT-130 study have suffered serious side effects

In early August, uniQure made an announcement about participants from the high dose group in the AMT-130 study. Three participants (out of 14) from this arm of the study were found to have severe adverse reactions by an independent safety review committee. Two people that underwent surgery in Europe reported swelling and a third person, treated at a U.S. location, reported a severe headache and related symptoms shortly after surgery. While this is very upsetting and disappointing news, importantly, all three patients have either fully or substantially recovered and have now been released from the hospital.

What’s next for AMT-130?

There are many theories as to why these patients suffered these side effects, including some form of immune response. However, there is no clear or definitive explanations just yet and we must wait for further information before jumping to conclusions.

While the safety review committee doesn’t suspect the effects observed in the high-dose group of the trial are due to the drug itself, surgeries for the remaining 2 participants in this arm of the study have been halted for now. The low-dose arm is proceeding as planned and all trial particiants – in both the low- and high-dose groups – will continue to be followed for the duration of the trial. uniQure still expect to report data from the trial according to the originally planned schedule and we will be hearing further updates from the company about this trial in early 2023.

What does this mean for HTT lowering as an approach to treat HD?

The HD community has received disappointing news from many of the HTT lowering trials now and it is easy to feel like perhaps this is not a good strategy to keep pursuing to try and treat people with HD. It is important to keep a few things in mind though as all is not lost just yet. All of these trials have suffered very different problems and we only really have theories for why they haven’t panned out as we hoped, all of which might be unrelated to HTT lowering itself. All of these trials are also treating people with HD who are already showing symptoms and perhaps these folks are more vulnerable to potential side effects from these drugs. It’s important to note that none of these trials have given us a definitive answer as to whether HTT lowering in people with HD will improve symptoms or change the course of the disease. As the uniQure trial continues, we hope that the next data release might shed some light on this important question.