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Posted on Mon, 8 Aug 2022 21:04:03 +0000

Sad news from Novartis: dosing suspended in VIBRANT-HD trial of branaplam

The VIBRANT-HD study began in early 2022 and was a long-awaited trial of a huntingtin-lowering drug, branaplam, that could be taken by mouth. On Monday, August 8th, we learned that dosing has been temporarily suspended at the recommendation of an independent committee that is monitoring the data from the trial. This decision was made because of signs that some of the participants taking branaplam may be experiencing new problems with their nerves, known as peripheral neuropathy. Let’s talk more about what happened and what’s next.

The HD gene and the quest to lower huntingtin

Huntington’s disease is genetic, meaning that it’s passed down in families from generation to generation. The genetic mutation that causes HD occurs in a gene called huntingtin, which produces a faulty RNA recipe, ultimately producing an extra-long huntingtin protein. This protein is believed to be harmful to brain cells, causing them to become sick and eventually disappear, and this leads to the many different symptoms of HD.

Over the past decade or so, novel approaches to treating HD have focused on a technique called huntingtin-lowering, which aims to decrease the amount of harmful huntingtin protein in the brains of HD patients. So far, the ones tested in people have been pretty invasive, requiring frequent spinal injections or brain surgery to deliver. Novartis, however, had recently begun a clinical trial of a huntingtin-lowering drug that could be taken once weekly, by mouth.

Branaplam and the promise of oral huntingtin-lowering

The story of branaplam and the VIBRANT-HD trial began with a different disease, known as SMA, which affects children. SMA is also genetic; it causes worsening muscle weakness in babies and young kids and is eventually fatal within just a few years.

Branaplam was originally developed as a genetic treatment for SMA. It is known as a splicing modulator - essentially this means that it can steer the remixing of the RNA recipe for the gene involved in SMA, and restore the function of the protein. In a fascinating twist of science, Novartis discovered that branaplam could also affect the RNA recipe for huntingtin, in this case leading to less huntingtin being produced.

In the summer of 2021, as more genetic treatment options became available for kids with SMA, Novartis made the decision to stop developing branaplam for kids with SMA, and to focus its efforts on adults with HD. This decision was supported by data in HD model animals, and very early safety trials of branaplam in healthy adults. Excitement built in the HD community around the possibility of an oral huntingtin-lowering treatment, and the Phase 2 VIBRANT-HD trial began in early 2022.

This week’s sad news

The VIBRANT-HD trial was planned to involve 75 people with early symptoms of HD, at more than 20 sites around the world. The main goals of the study are to test safety and the ability of the drug to lower huntingtin measured in spinal fluid. The plan was to test high and low doses of branaplam, each taken as a liquid once weekly for four months. Since early 2022, only the first cohort of participants had begun the trial. This was approximately 25 people, around 20 taking low dose branaplam and 5 taking placebo.

We learned today that the dosing in the trial has been stopped for safety reasons. We’ll get right to the point: branaplam was showing signs that it could be toxic to the nervous system. This was determined by an independent Data Monitoring Committee (DMC), a group of evaluators that has access to the data, long before the doctors, patients, or study sponsor (Novartis) know the outcomes. This is an important and standard practice in the vast majority of drug trials and it’s exactly for this reason - to keep participants safe in the event that problems arise.

The recommendation to suspend dosing in the study was based specifically on signs that branaplam might be causing damage to nerves outside the brain and spinal cord, known as peripheral neuropathy. Evidence from neurological exams, nerve conduction studies, and assessments of HD symptoms, as well as measurements of levels of a protein called NfL in the blood, all pointed to some concerns that some patients could be experiencing new nerve damage in their limbs.

What happens next?

In the immediate term, everyone participating in the trial will stop taking the treatment they were assigned. However, they will be asked to continue having their planned study appointments, which include blood and spinal fluid collection, and tests of nerve health. Essentially, the study will continue, but without branaplam or placebo, and participants will be monitored closely for other safety signs. This will be essential to understand as much as possible about branaplam's effects on adults with HD.

There may also have been some people who were all set to begin participating in the VIBRANT-HD trial, at either a low or a higher dose - these folks will not begin the study. Current participants and doctors will stay “blinded” until the end of the study, meaning they still don’t know who was on drug or placebo.

What does this mean for branaplam…and huntingtin lowering?

Essentially, this trial suspension is a way to protect participants from further potential danger to their nervous systems. It also means that Novartis will need to take a step back, take the time to analyze and learn more from the data, and determine whether it would make sense to keep testing branaplam.

It might be that the drug is really not safe for people with HD, and moving forward isn’t an option. On the other hand, it might be possible to use lower or less frequent dosing, or it could be that branaplam may have affected some participants differently than others. This latter possibility is similar to how Roche will be running a new trial of the huntingtin-lowering drug tominersen in a specific group of people.

It’s a tremendous disappointment that branaplam looks much riskier than expected for adults with HD. This will of course be especially tough for the first brave trial participants in VIBRANT-HD. But the news affects everyone in the community who felt hopeful about the first oral huntingtin-lowering drug to be tested in people.

That said, this news is not reason to abandon hope in huntingtin-lowering - nor even in oral huntingtin lowering. Branaplam was originally designed to treat a different disease, and though it lowers huntingtin, there may be other reasons it is causing unforeseen issues, known as “off-target effects.” There is another oral huntingtin-lowering drug in clinical trials right now – it’s called PTC-518 and is being developed by PTC Therapeutics. Based on data published by the company, that drug may have more ideal drug properties, compared to branaplam. Importantly, PTC-518 shows more accumulation in the brain, compared to the rest of the body, and the brain is the primary treatment goal for HD. We look forward to updates from PTC after they digest the branaplam results, but we’re hopeful that their trial can continue, if experts feel it’s likely to be safe.

Gratitude and moving forward

Beyond these oral drugs, there’s a wide field of folks working on various approaches to huntingtin lowering, and ongoing clinical trials are being conducted by uniQure and Wave, with Roche’s next study in planning stages. There are also some important HD research conferences approaching this summer and fall, and there is sure to be exciting news to share from HD clinical studies and basic research laboratories worldwide.

There’s no doubt this is a tough day for the HD community, and for those of us hopeful for Huntingtin-lowering drugs to be an effective treatment for HD. But, as we often say, science is cumulative, and if we do it right, even failures in the clinic can teach us more than we knew before we started the trial.

The entire community owes the participants in the VIBRANT-HD study a huge debt. They rapidly signed up for the study, and their participation enabled us to get to this point – disappointing as it is – as quickly as possible. Their selfless contribution will enable the design of the next study to take into account the lessons learned in VIBRANT-HD, and get us closer to a day when we have effective treatments for HD.

From: HDBuzz (English)

Posted on Mon, 11 Jul 2022 07:02:48 +0000

Updates from uniQure about their gene therapy for Huntington's disease

uniQure is a company specializing in gene therapy, and they have been working on an experimental drug for Huntington’s disease (HD), called AMT-130, that is delivered via brain surgery. This is an unprecedented genetic approach to treating HD, and safety is the top priority for the first human trials. A press release and public presentation on Thursday June 23rd announced 12-month data on safety and huntingtin-lowering, from the first cohort (group) of 10 people with HD to undergo the surgery. HDBuzz also had the opportunity to speak with Dr. Ricardo Dolmetsch, President of Research and Development at uniQure, to get some additional clarity on what was shared. Overall, the drug and surgery were well tolerated, with no major safety issues arising so far. It can be difficult to interpret huntingtin-lowering data from such a small group, but what’s there so far looks like it could be promising - let’s explore what it means and what’s next for this study.

The first gene therapy for HD

Let’s begin with a refresher on the basics of this trial. Gene therapy is a technique that aims to permanently modify the core instructions from which living things are built. There are different targets and different methods for transporting such drugs to parts of the body and brain, but the key point is that gene therapy aims for permanence, a one-and-done delivery, to treat a genetic disease at its roots. Most HD gene therapies are focused on a technique called huntingtin-lowering, which targets the huntingtin gene or its genetic message molecule, RNA. The aim is to switch off the gene and decrease the amount of harmful huntingtin protein that builds up in the brain, with the goal of slowing the worsening symptoms of HD.

uniQure is developing an HD gene therapy called AMT-130. They are using an approach where a piece of man-made genetic material is packaged inside a harmless virus and delivered directly to the part of the brain that is most affected by HD, the striatum. This requires a single surgical procedure in which minuscule holes are made in the skull and tiny needles are used to inject the virus into six different locations deep in the brain. The drug spreads into many brain cells and sets up little factories for producing a type of genetic micro-message that tells the cell to make less huntingtin protein.

The state of uniQure’s HD clinical trials

uniQure spent several years testing their drug in different lab models and animals, including pigs that have the HD gene. Then, when it looked like they could safely achieve huntingtin-lowering in a large animal brain, they embarked in 2020 on the first trial in people, known as HD-Gene-TRX1. So far, 36 people are enrolled in different cohorts (groups) of this trial in the USA and Europe, some receiving a low dose of AMT-130, some receiving a high dose, and some receiving an imitation surgery, in which no needles are used and no drug given but the tiny holes are made.

Last week’s press release and an investor-focused presentation from uniQure shared some data, from just the first cohort of 10 participants with HD. 6 of these individuals received the low dose of AMT-130, and 4 were in the “control” group that had imitation surgery. In addition to showing that the drug and procedure were safe and well-tolerated, uniQure was able to share huntingtin-lowering data from 7 of the participants, 4 in AMT-130 group and 3 in the control group.

The very small numbers of people mean that the data is variable and should be interpreted with caution. That said, there may be reason for excitement, even with such a small group.

What was shared in the press release?

The June 23rd press release shared basic data on the side effects of the surgical procedure, levels of huntingtin after 1 year, and a protein called NfL that can act as an indicator of brain health. Essentially, what they shared addresses safety first and foremost, followed by a “biomarker” of how brain cells might be reacting to the treatment, and a measure of whether the drug is acting biologically in the way it’s meant to - this is known as “target engagement.”

Safety & Tolerability

This is the simplest piece to interpret and is solidly good news. The 10 participants were followed closely over the course of 1 year, and the main side effects they experienced were related to the surgery, which was overall very well tolerated. The surgery can take most of a day, and one person had a blood clot from being immobile for many hours, which resolved soon afterwards. Another person experienced delirium after the surgery, a period of serious confusion that happens sometimes after anesthesia, and this also resolved quickly. Those were the most serious side effects; other examples of minor ones were headaches after the surgery, and pain or dizziness after lumbar punctures to take samples of spinal fluid.

Measurements in spinal fluid

The 10 participants in the first cohort had lumbar punctures before having the surgery (“baseline”) and then 1, 3, 6, 9 and 12 months later. This was to allow uniQure to measure changes in levels of huntingtin as well as other biomarkers, like NfL, that can help to give a picture of brain health.

* Biomarkers: Temporary increase in NfL

A biomarker is something in the body that can be measured to give us a picture of an aspect of a person’s health. For a neurodegenerative disease like HD, an ideal biomarker changes reliably as things worsen, and reverts with treatment. NfL, which is released by sick brain cells, tends to increase as HD progresses, so it is increasingly being measured as part of human clinical trials. However, a short-lived increase in NfL can also indicate different types of stress on brain cells, such as that caused temporarily by an invasive brain surgery. As expected, the HD-Gene-TRX1 participants who received the drug had an increase in NfL that went up right after the surgery and slowly returned to baseline levels. For those who had sham surgery and no needles or drug, NfL levels stayed around the same over that time period.

* Target engagement: decreased huntingtin levels

The goal of uniQure’s therapy, from a biological standpoint, is to target the genetic “message” created by the huntingtin gene, so that less huntingtin protein is made in brain cells. So for AMT-130, “target engagement” means lower levels of huntingtin. They were only able to make accurate before-and-after measurements in a subset of participants, but despite this roadblock, it already looks like AMT-130 may be lowering huntingtin protein. For people who received the drug, they found that huntingtin levels dropped over time, and by 12 months they were about 50% lower on average. The people in the sham surgery group had lots of variability in the levels of huntingtin in their spinal fluid but looked fairly steady. Again, the numbers are way too small to talk about statistical significance, but overall it looks like the drug is doing what it is designed to do.


The trials and tribulations of measuring huntingtin

Ideally we would have a clever way to look directly in the brain at huntingtin levels before and after treatment, and scientists are working on tracers which would allow us to do just that, but these are not ready to use in drug trials just yet. Instead, scientists measure the very small amounts of huntingtin protein found in spinal fluid as a proxy, and these measurements are a technical challenge for the entire field of HD research. Of the 10 people in this part of the uniQure study, the researchers were only able to get reliable huntingtin-lowering data from 7; 4 people who received the drug and 3 who received the sham treatment. This means we are looking at data from a very small number of people so, whilst things look to be going in the right direction, we should still be cautious.

Another consideration is that uniQure’s drug lowers both healthy and harmful huntingtin, based on this data, by around 50% in people who received the low dose of AMT-130. Questions came up in the public presentation around whether longer exposure or higher doses could lead to “too much” lowering of huntingtin, but this seems unlikely for several reasons.

The work that uniQure have published in animal models shows that higher doses of the drug are safe and well tolerated over the course of several years. In people, the data so far show the levels of huntingtin getting lower and lower over time, but uniQure expects the lowering to level off after 12 months, as they have seen in their animal model experiments. They also show that higher doses of the drug don’t lower huntingtin levels much more than low doses; instead, the drug is able to spread to more parts of the brain, so the same level of lowering is seen in more areas, which they think will be beneficial.

Finally, there are several trial participants in the USA and Europe who have already received high doses of AMT-130, and none of them have had major dangerous side effects thus far.

So what’s next for AMT-130?

Although this early data is encouraging that AMT-130 is doing what scientists hoped - lowering huntingtin levels - there is still a long way to go before this could be a drug to treat HD. A number of scenarios are possible, all of which hinge on the outcome of the results uniQure is due to publish in the second quarter of 2023.

In the best case and probably unlikely scenario (but we can hope!), the next data release will have extremely positive findings, which could prompt uniQure to pursue accelerated approval of the drug to start treating people with HD as soon as possible. What is more likely, but still wishful thinking at this stage, is that the next data update holds up the tentative conclusions we have drawn so far - the drug appears safe, engages the target by lowering huntingtin and, perhaps, might show some indications of improving symptoms or slowing down the progression of HD. In such a scenario, uniQure would likely launch a much larger phase 3 study with over 100 patients enrolled and divided into control and treatment groups, to determine in a larger population whether the drug is really doing what the scientists hope - slowing or halting the progression of HD.

However, we must prepare for the possibility that the results in 2023 are not what we hope. One possibility is that the drug continues to be safe, but that huntingtin levels are not lowered. This may not be as bad as it seems, it could be that it takes some time to see a measurable effect of AMT-130, we just don’t know what to expect at this stage. The worst case scenario is that signs of HD in people who receive the treatment could appear to progress faster - similar to the results of the tominersen trial. In that case, uniQure would need to go back to the drawing board.

All that speculation aside, uniQure are taking concrete steps to improve upon the surgery, as well as planning for access to AMT-130, should the results of this trial prove favourable. One drawback for this “one-shot” therapy is that the procedure itself takes all day. In a third cohort of patients, uniQure are planning to test a much shorter version of the surgery which would only take half a day to complete.

All in all, uniQure's preliminary safety and huntingtin-lowering results are encouraging. We are grateful for the brave participants in this unprecedented gene therapy trial, and eagerly await the next data release.

From: HDBuzz (English)

Posted on Tue, 21 Jun 2022 07:32:46 +0000

Huntington’s disease therapeutics conference 2022 - Day 2

Good morning and welcome to Day 2 of HDBuzz coverage of the CHDI HD Therapeutics conference!

Innovative approaches for HD therapeutics

Chairing the third session of HD research talks is Dr. Michael Finley (CHDI) and Dr. William Martin (Janssen R&D, LLC) are chairing the third session of HD research talks, which will cover innovative approaches for HD therapeutics.

Our first talk is from Dr. Beverly L Davidson from The Children’s Hospital of Philadelphia & University of Pennsylvania, who will discuss her work on improving gene therapies for HD.

Improving gene therapies for HD

The Davidson lab works on making gene therapies to treat genetic illnesses like HD. She’s focused on what part of the huntingtin gene to target and how best to get drugs to the brain. Researchers want to make sure they’re doing this as efficiently as possible. As we learned yesterday, there are small toxic fragments of huntingtin that exist at the beginning of the code - exon1. The Davidson lab is focused on making sure this part of the huntingtin gene is targeted by the therapies they’re developing.

The Davidson lab is working with CRISPR - this is a very precise tool which can edit specific letters in the DNA code. The lab aims to take advantage of unique genetic signatures, called SNPs (“snips”), to target the expanded huntingtin gene. Using this approach, researchers identify SNPs that are only on expanded huntingtin. This allows their potential therapeutics to specifically target only harmful huntingtin, leaving “normal” huntingtin alone. In a mouse model of HD, they showed that their CRISPR tool reduced the levels of huntingtin protein by about 50% - the magic number researchers think we need to lower huntingtin by to improve symptoms of HD.

Next the Davidson lab focused on how to improve the way that these tools are delivered to cells. They want to make sure they’re effective and safe. The Davidson lab used a neat genetic trick to allow precise tuning to the expression level of the gene of interest, which you can think of like a dimmer switch. We previously wrote about this cool new tool here: https://en.hdbuzz.net/311

This molecular dimmer switch could be really powerful for HD research - it could allow precise control of huntingtin levels, it gets directly to the right places in the brain, and leaves the body of the mouse quickly after they stop delivering it. The Davidson lab have now refined this tool for use in HD models and showed that they can fine tune huntingtin levels - the more drug they treat with, the more the dimmer switch is lowered.

Moving forward, they’re focused on improving the way this CRISPR tool is delivered and testing it in other types of animals, including monkeys.
They delivered this tool to the monkeys through a spinal injection and found that even very low doses reached lots of different areas in the brain, including those most affected by HD.

Overall, the Davidson lab has developed an exciting new tool that targets only the expanded huntingtin copy and can reach many areas of the brain. This occurs even at low doses and can be precisely controlled. We’re excited to see where this goes next!

RNA-targeting CRISPR

Next up is Gene Yeo, from the University of California, San Diego, who will also be talking about CRISPR technology and testing genetic treatments in different animal models of HD. The Yeo lab is focused on understanding proteins that bind to the genetic message - RNA. They’re trying to target these RNA-binding proteins to develop therapeutics.

RNA-binding proteins (RBPs) can control expression of other genes. The Yeo lab wants to know where RBPs bind, and have developed tools that let them learn this in individual cells - wow!

Many experiments look at changes in whole tissues, or samples created from many cells. Looking at individual cells lets researchers zoom in on subtle but potentially important changes. A recent publication from the Yeo lab showed that they could use RBPs to bind to certain RNAs to “chew them up”. This would be great for destroying the huntingtin message to treat HD!

Most recently, they have shown a decrease in the huntingtin message by delivering RBPs that specifically target CAG repeats. They can do this in multiple models, including human neurons created from stem cells. When the CAG repeats in the huntingtin message were destroyed, they were able to reverse some changes in cells caused by HD! One change they noticed was that expression of genes associated with brain cell health went back to normal. But they wanted to know what happens when they use this therapy in mice - does destroying the CAG repeats with their cool tool make the HD mice better?

Yes! The mice did better on performance tests, had reduced huntingtin protein clumps, and improvements in brain structures seen by MRI. Also important, this genetic approach didn’t seem to affect other genes. This cool new tool still needs some validation but has lots of promise for many diseases, most excitingly, for HD!

SHIELD HD - supporting clinical and biomarker development!

Our next speakers are Drs. Irina Antonijevic & Peter Bialek from Triplet Therapeutics. They’ll be discussing the SHIELD HD trial, a study that followed HD patients over time to try to find clinical differences and identify biomarkers.

Triplet is researching therapies to combat the expansion of CAG repeats in brain cells over time, a process known as somatic instability. This may be an important driver of symptom onset in people with HD. By looking at data from all the genetic information from individuals with HD, researchers identified changes in genes that control somatic instability that modify the age that HD patients develop HD. One of those genes is called MSH3. While Triplet is developing a therapy that targets MSH3, they are also keen to better understand when best to treat patients and which patients would benefit most from the MSH3 targeting therapy.

To better understand how CAG repeat expansion relates to HD symptoms, we need to follow people over time. SHIELD-HD is known as a natural history study - it does not involve a drug, but it is monitoring people with the HD gene who have very early symptoms.

They followed HD patients for over 2 years and took various samples, including blood and CSF. They also analyzed the patients’ brains using MRI scans.
They found that different regions of the brain, called the caudate and ventricles, changed their size over time during the 48 week period of the SHIELD-HD study. This is as we would expect as symptoms progress in people with HD.

The study also looked at another measurement called the total motor score to see how this changed over time in people in the trial. As expected, this also decreased over time, and more so for patients at the later stages of HD. While these changes are expected in HD patients, the SHIELD-HD trial provides researchers with a comprehensive dataset that can be used to better make predictions about the course of HD. These types of datasets could help expedite finding the right type of clinical trial for patients based on where they are during their disease.

Next, Triplet will share updates about their drug that targets the gene MSH3. They did experiments in monkeys to see how reducing MSH3 levels affected their CAG repeats. By lowering MSH3 by 50% in the monkeys, they found that somatic expansion was stopped! If this translates to HD patients, this might significantly delay the age at which patients start to develop symptoms.

Triplet is also interested in measuring MSH3 levels to track HD disease progression and how well the treatment is working. But they ran into a challenge since it’s difficult to detect this gene in brain tissue. To get around this problem, the team at Triplet looked at expression of MSH3 in spinal fluid from participants with HD who were in the SHIELD-HD trial. They had to develop a very sensitive technique. They are continuing to experiment with different ways to collect samples from the spinal fluid and brain in monkeys, as well as testing the drug they are developing, called TTX-3360.

They looked at levels of MSH3 in the CSF of patients at various disease stages. They found no difference in these levels between individuals without HD and those with HD who had no symptoms or were very early in their disease. This finding is important because it gives researchers at Triplet a baseline reading of MSH3 to follow for when they move TTX-3360 to a Phase 1 clinical trial and look to see how the levels of MSH3 change with treatment.
Observational trials like SHIELD-HD not only collect lots of valuable data from HD patients over time, but they also allow researchers to develop new potential treatments like those described by Triplet today. Cool stuff!

Time for a break! We’ll be back shortly for the rest of this mornings presentations. Stay tuned!

New biological insights

Next up is Dr. Beth Stevens from Boston Children’s Hospital and the Broad Institute, who will be talking about her research that could provide insight for moving treatments toward the clinic. Dr. Stevens studies yet another specialized brain cell, called microglia, which act as the immune system of the brain, protecting it from invaders, and helping clean up debris left over from damaged brain cells.

Microglia are tiny (thus the “micro”), and make up about only about 10% of the cells of the brain. But when they encounter damage, or invading bacteria, they get activated and go to work cleaning up the mess. This activation of these key helper cells is normally a good thing for the brain, but in a range of diseases - including HD - it has long been thought that they might be a little too active.

Stevens is a world expert on the role of microglia in health and disease. Stevens has shown that one of the roles of microglia in the brain is to eat up synapses - the bulb-like links between communicating brain cells called neurons. Synapses are good, but need to be cleared to to encode new information into the brain.

There’s a cell-to-cell communication system called the “complement system” that tells microglia to eat, or not to eat, a given synapse or cell. Years ago, Stevens’ team discovered that this complement system is used in the brain by microglia to decide which brain bits need to be digested. In many brain diseases - including HD - this complement system becomes over-active, eating bits clearly labeled with a “don’t eat me” signal for the complement system. The team is interested in understanding whether the complement system plays a key role in the loss of synapses known to happen in HD.

They’ve developed very sophisticated microscope tricks to identify specific populations of synapses in brain regions impacted by HD. In HD mice, there’s a very specific pattern of synapse loss that worsens during aging. Similar changes are seen in HD patient brains. As they’d seen in other diseases, these same vulnerable synapses were decorated with “eat me” signals for the complement system. That suggests that microglia in HD mice and patients might help remove these critical synapses from the brain, potentially contributing to disease progression.

In brains donated by HD patients, Stevens’ team found clear evidence of angry, activated, microglia. They then turned back to mice, where they can manipulate this system to see what role it plays in disease progression. A company - Annexon Biosciences - has developed a drug that blocks complement activation. This allows us to ask whether blocking this hyper-active “eat me” activity contributes to the development of HD-like symptoms in HD model mice. Treating HD mice with this drug did what it was supposed to do - it reduced the “eat me” label from being placed onto critical brain regions. This allows us to ask whether this synapse removal is good or bad in diseases like HD. Using another approach - a genetic change to the mice to fully block the complement system - the team is studying the relationship between complement activation and symptoms. Excitingly, they see protection from some HD-like symptoms in HD model mice.

But what about HD patients, do similar things happen in the brains of real patients? Using Clarity, the team was able to get access to cerebrospinal fluid from HD patients. This fluid, which bathes the brain, can be a non-invasive way to sample brain proteins. Consistent with their predictions, there were clear signs of increased activation of the complement system in the spinal fluid from HD patients. A small human study in HD patients is being conducted currently by Annexon.

Very cool to see how seemingly very basic biological studies can be quickly translated to trials in HD patients!

Stem cell research!

Dr. Leslie Thompson, from UC Irvine, is up next. Thompson has been a long-time leader in the field using stem cells to understand and treat HD. Stem cells are very special cells that can be coaxed to become any other cell type in the body, including the brain cells that are vulnerable in HD.

Historically, these cells had to be isolated from human embryos, but more recently researchers have learned to coax regular cells from adult humans to become stem cells. These “induced pluripotent stem cells” are an amazing tool, allowing researchers to generate real brain cells in the lab.

Dr. Thompson represents a large consortium - called Stem Cells for HD (SC4HD) - who are coordinating efforts to develop potential cell-replacement treatments for HD. They’ve carried out huge studies to develop stem cell lines as a potential source for transplant studies into people with HD. Cells are complicated! The team has carried out a huge amount of standardization to make a very well-characterized source of donor cells.
They’re using these human stem cell lines in experiments in HD mouse models to see whether transplanting cells into the brain improves HD-like symptoms in mice. Excitingly, transplantation of human stem cells leads to significant improvements. This is a proof of concept to show that implanting stem cells can lead to some improvements in HD-relevant symptoms in mice. Understanding the underpinnings of these improvements might allow the team to predict what symptoms to go after in HD patients.

Long-term mouse studies show quite striking improvement in the movement symptoms of an HD mouse model treated with human stem cell transplants. Excitingly, the team has been able to refine their procedures to increase the survival of transplanted cells.

Thompson outlines the consortium’s clinical studies to meet all the requirements of regulators for trials in humans. An obvious concern with stem cells is making sure they don’t grow into unexpected cell types, or cause tumors. These enabling studies are underway - including testing the surgical approaches needed to implant stem cells into the right place in the HD brain. We don’t want transplants into the wrong spot!

That wraps up an exciting series of talks focused on novel treatments for HD. This afternoon is a featured speaker, David Baker, from the University of Washington. We’ll not tweet that talk - so stay tuned for more exciting updates tomorrow!

From: HDBuzz (English)