Research news
Posted on Fri, 23 Aug 2024 04:59:30 +0000
Mini brains grown in a dish shed light on Huntington’s disease and how we might treat it
Stem cells grown in 3D in a research lab can mimic some features of Huntington’s disease (HD). They also hold promise for transplantation studies to potentially add back cells that are lost in HD. But what would happen to those new cells? Would they get along with the cells still in the brain that have the HD gene? And what can this system teach us about ongoing clinical trials aimed at lowering the HD-causing message in only parts of the brain? Read on to find out!
The power of stem cells
Stem cells hold a certain mystique. They can either retain their “stemness”, remaining a stem cell, or to turn into something else altogether. Contained within each one is the ability to become almost any cell type in the human body. Scientists can coax them into becoming a heart cell, or a muscle cell, or even a brain cell, providing scientists with a powerful research tool that can be used to answer questions about people’s brains in health and disease.
For brain diseases like Huntington’s disease (HD), there’s a second powerful potential application for stem cells – transplantation. As a neurodegenerative disease, HD causes the gradual loss of brain cells. This primarily happens in a central portion of the brain, called the striatum, and in the outer wrinkly bit of the brain, called the cortex.
Several groups of researchers are exploring approaches that would allow them to harness the power of stem cells to replace cells that are lost over the course of HD. We recently wrote about the work Dr. Leslie Thomspon is advancing for stem cell transplants from our coverage of the Hereditary Disease Foundation conference. But what would happen to the new cells? Would they adopt features of HD?
Dr. Elena Cattaneo and her team from the University of Milan, in Italy, recently published a study aiming to answer some of these questions. Elena’s lab are world leaders in using stem cells to research HD. In this new paper, they sought to better understand the effect that cells with the gene for HD have on cells without the HD gene. This might help inform future cell transplantation studies and trials aimed at lowering the disease-causing message since those drugs are unlikely to hit every cell in the brain equally.
Mini brain in a dish
Typically, when cells are used in lab experiments, they’re grown flat on the back of a dish. But if you’ve ever seen another person, you know that people aren’t 2D! So more sophisticated technologies allow researchers to grow cells in 3D.
The fancy term for these 3D cells is “organoids”, aka “mini brains”. We’ve previously written about these lab-grown brains and what researchers have learned from them. While mini brains can adopt some of the cellular features of a brain, such as connections between different cells, they don’t actually have the ability to transmit thoughts and feelings.
While these mini brains look deceivingly unsophisticated on the outside (like a little whitish, pinkish snot to be honest!), they’re elegantly complex on the inside. The cells form intricate networks between brain cells that can be seen communicating with one another under the microscope. These mini brains give researchers a way of understanding in 3D how HD affects connections and communication between different cells.
Scientists know that in a human brain, HD reduces the ability of cells in the outer cortex to communicate with the inner striatum. This communication breakdown leads to a loss in those connections over time. When those connections go unused for extended periods of time, it can create an unhealthy environment for the brain cells, and they may eventually die.
A positive influence
Elena and her team see something similar in their mini brains that have the HD gene. At the molecular level, brain cells communicate across a very small gap called the synapse. This is where the tips of brain cells meet to send bubbles of information back and forth to one another. In HD, the number of bubbles is reduced over time. In this new paper, the team sees the same thing in HD mini brains – there is less communication at the synapse than in mini brains without the gene for HD.
A key experiment in the new paper from Elena’s lab asked what happens to cells in mini brains when cells without the gene for HD are combined with cells that have the gene for HD.
The team performed a very detailed analysis of the genetic messages contained in the mixed population mini brains, seeing that they more closely resemble the mini brains without the HD gene rather than the ones with the HD gene. This suggests that the cells without the HD gene have a positive influence on those with the HD gene. Good friends to have around!
They also looked at the synapses in these mixed population mini brains. They found the communication being sent from the synapse was greatly improved! It more closely matched the mini brains without the gene for HD. This suggests the cells without HD might be helping the cells with HD to communicate better.
The team also identified some features that weren’t totally rescued by the presence of the cells without the gene for HD. In the mixed population mini brains there were still some changes at the genetic message level. Additionally, the number of cells that died in the mixed population mini brains wasn’t totally rescued. This suggests that while cells without HD help the mixed population mini brains, they can’t overcome every feature caused by the HD gene.
Informing ongoing and future trials
Overall, this type of research can help determine the therapeutic potential for using stem cells to slow progression and treat HD. It is also informative for ongoing trials that lower levels of the disease-causing genetic message.
While the goal for some of those trials is to lower the message by about 50%, that won’t occur in every cell in the brain. Because of that, those cells with reduced HD genetic message will exist in a mixed population with cells that have more of the HD genetic message. Data from studies like those highlighted here help researchers understand exactly what may happen at the molecular level when such mixed populations of cells with and without the gene for HD exist.
An important point the research team was able to tease out in this paper is that the cells without HD have a positive influence on the cells with the HD gene. But the opposite is not true. The cells that have the HD gene don’t seem to alter programs in the cells without HD. This is important for future transplantation studies because it suggests cells without HD that are added may have a positive effect, but the cells already in the brain with HD possibly won’t have a negative effect on the new cells. A win, win!
Moving treatments forward
While stem cells and mini brains are super cool, there are some limitations to their use. Firstly, they don’t truly mimic what’s happening inside a human brain in a living person. Nothing in a lab dish can. This is why it’s important to study potential treatments in a functioning brain, like in a mouse, and eventually run clinical trials in people.
Additionally, the mini brains that contained cells with and without the gene for HD were mixed before they were made. Meaning the mixed population was there from “birth”. In the case of a person with HD, the cells or treatment would be added after the person had a fully formed brain.
Despite the caveats, this work represents a cool approach for better understanding how cells without the gene for HD may act if they were added to a brain with HD. It also sheds light on what may happen in a brain when some cells have the gene for HD while others have less of that message.
The human brain, both inside a lab dish and out, is incredibly complex, so knowing as much as possible about how HD affects cellular and molecular features will help move treatments forward.
The power of stem cells
Stem cells hold a certain mystique. They can either retain their “stemness”, remaining a stem cell, or to turn into something else altogether. Contained within each one is the ability to become almost any cell type in the human body. Scientists can coax them into becoming a heart cell, or a muscle cell, or even a brain cell, providing scientists with a powerful research tool that can be used to answer questions about people’s brains in health and disease.
For brain diseases like Huntington’s disease (HD), there’s a second powerful potential application for stem cells – transplantation. As a neurodegenerative disease, HD causes the gradual loss of brain cells. This primarily happens in a central portion of the brain, called the striatum, and in the outer wrinkly bit of the brain, called the cortex.
Several groups of researchers are exploring approaches that would allow them to harness the power of stem cells to replace cells that are lost over the course of HD. We recently wrote about the work Dr. Leslie Thomspon is advancing for stem cell transplants from our coverage of the Hereditary Disease Foundation conference. But what would happen to the new cells? Would they adopt features of HD?
Dr. Elena Cattaneo and her team from the University of Milan, in Italy, recently published a study aiming to answer some of these questions. Elena’s lab are world leaders in using stem cells to research HD. In this new paper, they sought to better understand the effect that cells with the gene for HD have on cells without the HD gene. This might help inform future cell transplantation studies and trials aimed at lowering the disease-causing message since those drugs are unlikely to hit every cell in the brain equally.
Mini brain in a dish
Typically, when cells are used in lab experiments, they’re grown flat on the back of a dish. But if you’ve ever seen another person, you know that people aren’t 2D! So more sophisticated technologies allow researchers to grow cells in 3D.
The fancy term for these 3D cells is “organoids”, aka “mini brains”. We’ve previously written about these lab-grown brains and what researchers have learned from them. While mini brains can adopt some of the cellular features of a brain, such as connections between different cells, they don’t actually have the ability to transmit thoughts and feelings.
While these mini brains look deceivingly unsophisticated on the outside (like a little whitish, pinkish snot to be honest!), they’re elegantly complex on the inside. The cells form intricate networks between brain cells that can be seen communicating with one another under the microscope. These mini brains give researchers a way of understanding in 3D how HD affects connections and communication between different cells.
Scientists know that in a human brain, HD reduces the ability of cells in the outer cortex to communicate with the inner striatum. This communication breakdown leads to a loss in those connections over time. When those connections go unused for extended periods of time, it can create an unhealthy environment for the brain cells, and they may eventually die.
A positive influence
Elena and her team see something similar in their mini brains that have the HD gene. At the molecular level, brain cells communicate across a very small gap called the synapse. This is where the tips of brain cells meet to send bubbles of information back and forth to one another. In HD, the number of bubbles is reduced over time. In this new paper, the team sees the same thing in HD mini brains – there is less communication at the synapse than in mini brains without the gene for HD.
A key experiment in the new paper from Elena’s lab asked what happens to cells in mini brains when cells without the gene for HD are combined with cells that have the gene for HD.
The team performed a very detailed analysis of the genetic messages contained in the mixed population mini brains, seeing that they more closely resemble the mini brains without the HD gene rather than the ones with the HD gene. This suggests that the cells without the HD gene have a positive influence on those with the HD gene. Good friends to have around!
They also looked at the synapses in these mixed population mini brains. They found the communication being sent from the synapse was greatly improved! It more closely matched the mini brains without the gene for HD. This suggests the cells without HD might be helping the cells with HD to communicate better.
The team also identified some features that weren’t totally rescued by the presence of the cells without the gene for HD. In the mixed population mini brains there were still some changes at the genetic message level. Additionally, the number of cells that died in the mixed population mini brains wasn’t totally rescued. This suggests that while cells without HD help the mixed population mini brains, they can’t overcome every feature caused by the HD gene.
Informing ongoing and future trials
Overall, this type of research can help determine the therapeutic potential for using stem cells to slow progression and treat HD. It is also informative for ongoing trials that lower levels of the disease-causing genetic message.
While the goal for some of those trials is to lower the message by about 50%, that won’t occur in every cell in the brain. Because of that, those cells with reduced HD genetic message will exist in a mixed population with cells that have more of the HD genetic message. Data from studies like those highlighted here help researchers understand exactly what may happen at the molecular level when such mixed populations of cells with and without the gene for HD exist.
An important point the research team was able to tease out in this paper is that the cells without HD have a positive influence on the cells with the HD gene. But the opposite is not true. The cells that have the HD gene don’t seem to alter programs in the cells without HD. This is important for future transplantation studies because it suggests cells without HD that are added may have a positive effect, but the cells already in the brain with HD possibly won’t have a negative effect on the new cells. A win, win!
Moving treatments forward
While stem cells and mini brains are super cool, there are some limitations to their use. Firstly, they don’t truly mimic what’s happening inside a human brain in a living person. Nothing in a lab dish can. This is why it’s important to study potential treatments in a functioning brain, like in a mouse, and eventually run clinical trials in people.
Additionally, the mini brains that contained cells with and without the gene for HD were mixed before they were made. Meaning the mixed population was there from “birth”. In the case of a person with HD, the cells or treatment would be added after the person had a fully formed brain.
Despite the caveats, this work represents a cool approach for better understanding how cells without the gene for HD may act if they were added to a brain with HD. It also sheds light on what may happen in a brain when some cells have the gene for HD while others have less of that message.
The human brain, both inside a lab dish and out, is incredibly complex, so knowing as much as possible about how HD affects cellular and molecular features will help move treatments forward.
From: HDBuzz (English)
Posted on Fri, 16 Aug 2024 15:46:17 +0000
Buckle in: Gene therapy AMT-130 appears to slow down signs of Huntington’s disease in Phase I/II clinical trial
New data from uniQure, who developed a one-and-done gene therapy for Huntington’s disease (HD) called AMT-130, indicates that the drug is relatively safe and might be able to slow down signs and symptoms of HD. AMT-130 is currently under investigation in Phase I/II clinical trials in Europe and the US which are mainly focused on drug safety. These hot new data are very encouraging, so let’s dive into what it all means!
What is AMT-130?
Developed by uniQure, AMT-130 is the first gene therapy for HD. Like many of the other therapies being tested in the clinic right now, it aims to reduce the levels of the HD protein, huntingtin, in the brain. What makes it a bit different, however, is that AMT-130 is a one-and-done gene therapy; you are only given one dose of the drug ever in the course of your life.
AMT-130 is made up of a harmless virus packaged with genetic material that contains the instructions to reduce the amount of huntingtin in each cell that the virus infects in the brain. The drug is given to people with HD by a very specialised type of brain surgery.
All of this was obviously rather daunting back when AMT-130 was first developed and we didn’t know how safe the drug might be. The one-and-done nature of the drug means that effects of the drug, good or bad, can not be undone.
uniQure did a huge number of studies before they tested AMT-130 in people, which took place over years using many different types of HD animal models. Even when uniQure began testing AMT-130 in people in 2019, they did so very slowly, starting with just a few brave folks who selflessly signed up to test this innovative therapy. Only when things looked ok following these first surgeries did they begin giving the drug to more people.
HD-GeneTRX-1 and HD-GeneTRX-2 - two trials for AMT-130 on two continents
There are in fact two clinical trials testing AMT-130 in people with HD; HD-GeneTRX-1 in the US and HD-GeneTRX-2 in Europe. Together, 39 participants of the trials were given either a high dose of AMT-130, a low dose of AMT-130, or a sham surgery, which means that participants underwent surgery but no drug was given. All people in the trial are then tracked for 4 years after their surgery, where all sorts of clinical, biomarker, brain imaging, and other measurements are taken.
The key aim of both trials is to investigate whether AMT-130 is safe in people. In addition to this, lots of other data are collected along the way which might hint at how well AMT-130 is working and how it might impact signs and symptoms of HD.
Since the trials began, AMT-130 has had a bit of a bumpy road. In the first people treated, everything seemed to be going ok but in August 2022, serious side effects were reported for some people who received the high dose of AMT-130. Fortunately, things got back on track after a 3 month pause in enrollment into the trial, and uniQure shared the good news that their trial will continue as planned, with new safety measures in place.
Since the brief trial pause, uniQure has reported steady progress with signs that this drug appears safe. There were also some hints of trends in the data they collected from all of the study participants that seemed to suggest that the drug might be having an effect on some symptoms of HD, although this was just a signal and is not conclusive.
Some things to keep in mind with this latest update
It’s important to note that the two trials are not over, the most recent data is an interim update. There are still 2+ more years of data to be collected for most folks. In fact, only 12 people who received the low dose (out of 13 in this group) and 9 people who received the high dose (out of 20 in this group) are at the 24 month mark.
Given the arduous way this drug is delivered, it takes a long time for everyone to get their surgery, even after they are enrolled. This means that the numbers of people from which the data comes from in this release are very tiny, so we should be very cautious in how we interpret the findings - we don’t yet know how this will play out in a bigger pool of people over a longer period of time.
Another important thing to note is that all comparisons in this data release are against natural history data, not placebo controls. Natural history data tracks people with HD over the course of their lives to see how their symptoms, brain imaging, biomarkers, and other clinical measurements change over time. This is very different to a placebo group who undergo the same procedures as the folks receiving the drugs, the only difference being they don’t actually receive the drug. The placebo effect can be very powerful so if we are using natural history data as our baseline, we should be cautious in the direct comparisons we draw. This decision was taken as there is only complete data for people in the sham surgery group up until 12 months.
Keeping all that in mind, this update is still rather exciting, so buckle in!
What’s the latest news about AMT-130?
Safety
The good news is that AMT-130, at both the low and high dose, appears to be relatively safe. There are manageable effects which we would expect to see following brain surgery, like headaches and pain associated with the procedure. However, the important part is that no new serious side effects were reported since the trial was paused back in August 2022, which is good news.
NfL - insights to brain health
An important measurement for tracking general brain health is the biomarker neurofilament light, often called NfL. Because HD has a detrimental effect on brain health, NfL levels go up over time as HD progresses. Therefore, NfL measurements can tell us two things: Firstly, whether the therapy might be causing harm, and secondly, whether the therapy might be slowing down disease progression, and therefore slowing the rate at which NfL levels go up over time in someone with HD.
We learned in previous updates from uniQure that there’s an initial spike in NfL levels. This is to be expected for any treatment requiring brain surgery, since the surgery itself will temporarily reduce overall brain health. What’s important is that this is short-lived - the initial spike is followed by a rapid decline in NfL levels over the next 6-8 months after surgery. Looking at NfL levels after the initial spike is where the juicy details are - this is what will tell us if AMT-130 is improving brain health and slowing HD progression.
In the last data release in December of 2023, only 6 people in the low-dose group and 2 people in the high-dose group had made it to the 24 month time point. Now, there are 12 people from the low-dose group and 9 people from the high-dose group that have reached the 24 month mark. Having data from more people helps give us a clearer picture of the effect AMT-130 is having on NfL 2 years after treatment.
Excitingly, the new data show that people treated with both the low- and high-dose of AMT-130 have NfL levels significantly below what would be expected, suggesting their decline in brain health is slowed compared to folks who have not been treated with AMT-130. While this sounds incredibly exciting, this is still a very small dataset so we shouldn’t get our hopes up too high.
Clinical measures
uniQure also looked at clinical measures to get an idea of the effect that AMT-130 might have on slowing or stopping symptoms of HD. Specifically, they looked at the Composite Unified Huntington's Disease Rating Scale, or cUHDRS. This is a collection of tests that measures the ability of someone with HD to carry out daily tasks, movement control, capacity to pay attention, and memory. Overall, the cUHDRS is known to be the most sensitive way to measure clinical progression of HD.
At the end of the day, clinical measures will be the most important readout. Having a drug that is effective at slowing or stopping progression of clinical signs and symptoms of HD is what we all want. Compared to a natural history study, disease progression was slowed by around 80% in people on the high dose of AMT-130. This suggests that AMT-130 may be having an effect in slowing progression of HD as measured by cUHDRS. Again, this is only data from 9 people, so it must be interpreted with caution.
cUHDRS is actually made up of many different clinical measures including Total Function Capacity (TFC) and Total Motor Score (TMS). Looking at these individual measures, the effect of AMT-130 is less obvious although there is a suggestion of a trend of things heading in the direction of slowing HD symptom progression. Not to be a broken record, but again, the tiny number of folks whose data is being analysed at this stage means we have to be careful in drawing too strong conclusions.
Other measures uniQure didn’t report this time
Interestingly, this update included no new information about whether huntingtin protein levels are being lowered by the drug, the effect we expect this drug to have in the brain. We also didn’t learn any new information about what brain imaging might tell us about how AMT-130 is working. Hopefully, uniQure gives us updates on both of these measures the next time they share data.
What does this all mean?
Overall, this update is exciting, positive and certainly cause for very cautious optimism. That said, this does not mean that AMT-130 is a cure for HD, there is still a long road ahead. We need more data from more people over longer timeframes to be sure of the effect this drug is really having on slowing down symptoms of HD. Nonetheless, the fact that the drug appears relatively safe and there are positive signs in how it might be helping slow down symptoms is good news for the HD community.
What’s next for AMT-130?
Recently, the FDA granted AMT-130 Regenerative Medicine Advanced Therapy (RMAT) designation - the very first time this has happened for an HD therapeutic. This gives them more frequent interactions with the FDA and priority review of their data, so that if the time comes that they’re ready to file for regulatory approval, they can hit the ground running to get accelerated approval.
uniQure have disclosed that they expect to meet with the FDA in the second half of 2024 to continue their discussions about the development of AMT-130. In those conversations, they hope to define a path for getting approval of AMT-130 for HD.
Lot’s of things to be thankful for
Sometimes when it rains, it pours! We have had what feels like a deluge of positive and encouraging news about HD clinical trials lately, and certainly at HDBuzz, we are feeling thankful. It was not so long ago that the news deluge was delivering a very different and much more difficult message, that many drugs just weren’t working as we had hoped.
So, what’s changed? Well it’s important to remember that even when clinical trials don’t give us the results we had hoped for, there is still so much to be learnt from the wealth of data that is collected. All of the selfless hours in the clinic from the folks with HD who sign up for these trials count for a huge amount. The rich datasets they help generate have a huge impact in how scientists understand how different therapies might work in people, and what they can change and improve to give us the best chance of success. Their contributions have gotten us to this exciting point where we still have lots of irons in the fire and are edging closer to disease-modifying therapies.
The future of HD clinical trials is bright, thanks to the resiliency, fortitude, and sacrifice of so many people with HD who bravely stepped up to test these experimental drugs. We are forever thankful to them and are buckled in for the ride to see what comes next.
What is AMT-130?
Developed by uniQure, AMT-130 is the first gene therapy for HD. Like many of the other therapies being tested in the clinic right now, it aims to reduce the levels of the HD protein, huntingtin, in the brain. What makes it a bit different, however, is that AMT-130 is a one-and-done gene therapy; you are only given one dose of the drug ever in the course of your life.
AMT-130 is made up of a harmless virus packaged with genetic material that contains the instructions to reduce the amount of huntingtin in each cell that the virus infects in the brain. The drug is given to people with HD by a very specialised type of brain surgery.
All of this was obviously rather daunting back when AMT-130 was first developed and we didn’t know how safe the drug might be. The one-and-done nature of the drug means that effects of the drug, good or bad, can not be undone.
uniQure did a huge number of studies before they tested AMT-130 in people, which took place over years using many different types of HD animal models. Even when uniQure began testing AMT-130 in people in 2019, they did so very slowly, starting with just a few brave folks who selflessly signed up to test this innovative therapy. Only when things looked ok following these first surgeries did they begin giving the drug to more people.
HD-GeneTRX-1 and HD-GeneTRX-2 - two trials for AMT-130 on two continents
There are in fact two clinical trials testing AMT-130 in people with HD; HD-GeneTRX-1 in the US and HD-GeneTRX-2 in Europe. Together, 39 participants of the trials were given either a high dose of AMT-130, a low dose of AMT-130, or a sham surgery, which means that participants underwent surgery but no drug was given. All people in the trial are then tracked for 4 years after their surgery, where all sorts of clinical, biomarker, brain imaging, and other measurements are taken.
The key aim of both trials is to investigate whether AMT-130 is safe in people. In addition to this, lots of other data are collected along the way which might hint at how well AMT-130 is working and how it might impact signs and symptoms of HD.
Since the trials began, AMT-130 has had a bit of a bumpy road. In the first people treated, everything seemed to be going ok but in August 2022, serious side effects were reported for some people who received the high dose of AMT-130. Fortunately, things got back on track after a 3 month pause in enrollment into the trial, and uniQure shared the good news that their trial will continue as planned, with new safety measures in place.
Since the brief trial pause, uniQure has reported steady progress with signs that this drug appears safe. There were also some hints of trends in the data they collected from all of the study participants that seemed to suggest that the drug might be having an effect on some symptoms of HD, although this was just a signal and is not conclusive.
Some things to keep in mind with this latest update
It’s important to note that the two trials are not over, the most recent data is an interim update. There are still 2+ more years of data to be collected for most folks. In fact, only 12 people who received the low dose (out of 13 in this group) and 9 people who received the high dose (out of 20 in this group) are at the 24 month mark.
Given the arduous way this drug is delivered, it takes a long time for everyone to get their surgery, even after they are enrolled. This means that the numbers of people from which the data comes from in this release are very tiny, so we should be very cautious in how we interpret the findings - we don’t yet know how this will play out in a bigger pool of people over a longer period of time.
Another important thing to note is that all comparisons in this data release are against natural history data, not placebo controls. Natural history data tracks people with HD over the course of their lives to see how their symptoms, brain imaging, biomarkers, and other clinical measurements change over time. This is very different to a placebo group who undergo the same procedures as the folks receiving the drugs, the only difference being they don’t actually receive the drug. The placebo effect can be very powerful so if we are using natural history data as our baseline, we should be cautious in the direct comparisons we draw. This decision was taken as there is only complete data for people in the sham surgery group up until 12 months.
Keeping all that in mind, this update is still rather exciting, so buckle in!
What’s the latest news about AMT-130?
Safety
The good news is that AMT-130, at both the low and high dose, appears to be relatively safe. There are manageable effects which we would expect to see following brain surgery, like headaches and pain associated with the procedure. However, the important part is that no new serious side effects were reported since the trial was paused back in August 2022, which is good news.
NfL - insights to brain health
An important measurement for tracking general brain health is the biomarker neurofilament light, often called NfL. Because HD has a detrimental effect on brain health, NfL levels go up over time as HD progresses. Therefore, NfL measurements can tell us two things: Firstly, whether the therapy might be causing harm, and secondly, whether the therapy might be slowing down disease progression, and therefore slowing the rate at which NfL levels go up over time in someone with HD.
We learned in previous updates from uniQure that there’s an initial spike in NfL levels. This is to be expected for any treatment requiring brain surgery, since the surgery itself will temporarily reduce overall brain health. What’s important is that this is short-lived - the initial spike is followed by a rapid decline in NfL levels over the next 6-8 months after surgery. Looking at NfL levels after the initial spike is where the juicy details are - this is what will tell us if AMT-130 is improving brain health and slowing HD progression.
In the last data release in December of 2023, only 6 people in the low-dose group and 2 people in the high-dose group had made it to the 24 month time point. Now, there are 12 people from the low-dose group and 9 people from the high-dose group that have reached the 24 month mark. Having data from more people helps give us a clearer picture of the effect AMT-130 is having on NfL 2 years after treatment.
Excitingly, the new data show that people treated with both the low- and high-dose of AMT-130 have NfL levels significantly below what would be expected, suggesting their decline in brain health is slowed compared to folks who have not been treated with AMT-130. While this sounds incredibly exciting, this is still a very small dataset so we shouldn’t get our hopes up too high.
Clinical measures
uniQure also looked at clinical measures to get an idea of the effect that AMT-130 might have on slowing or stopping symptoms of HD. Specifically, they looked at the Composite Unified Huntington's Disease Rating Scale, or cUHDRS. This is a collection of tests that measures the ability of someone with HD to carry out daily tasks, movement control, capacity to pay attention, and memory. Overall, the cUHDRS is known to be the most sensitive way to measure clinical progression of HD.
At the end of the day, clinical measures will be the most important readout. Having a drug that is effective at slowing or stopping progression of clinical signs and symptoms of HD is what we all want. Compared to a natural history study, disease progression was slowed by around 80% in people on the high dose of AMT-130. This suggests that AMT-130 may be having an effect in slowing progression of HD as measured by cUHDRS. Again, this is only data from 9 people, so it must be interpreted with caution.
cUHDRS is actually made up of many different clinical measures including Total Function Capacity (TFC) and Total Motor Score (TMS). Looking at these individual measures, the effect of AMT-130 is less obvious although there is a suggestion of a trend of things heading in the direction of slowing HD symptom progression. Not to be a broken record, but again, the tiny number of folks whose data is being analysed at this stage means we have to be careful in drawing too strong conclusions.
Other measures uniQure didn’t report this time
Interestingly, this update included no new information about whether huntingtin protein levels are being lowered by the drug, the effect we expect this drug to have in the brain. We also didn’t learn any new information about what brain imaging might tell us about how AMT-130 is working. Hopefully, uniQure gives us updates on both of these measures the next time they share data.
What does this all mean?
Overall, this update is exciting, positive and certainly cause for very cautious optimism. That said, this does not mean that AMT-130 is a cure for HD, there is still a long road ahead. We need more data from more people over longer timeframes to be sure of the effect this drug is really having on slowing down symptoms of HD. Nonetheless, the fact that the drug appears relatively safe and there are positive signs in how it might be helping slow down symptoms is good news for the HD community.
What’s next for AMT-130?
Recently, the FDA granted AMT-130 Regenerative Medicine Advanced Therapy (RMAT) designation - the very first time this has happened for an HD therapeutic. This gives them more frequent interactions with the FDA and priority review of their data, so that if the time comes that they’re ready to file for regulatory approval, they can hit the ground running to get accelerated approval.
uniQure have disclosed that they expect to meet with the FDA in the second half of 2024 to continue their discussions about the development of AMT-130. In those conversations, they hope to define a path for getting approval of AMT-130 for HD.
Lot’s of things to be thankful for
Sometimes when it rains, it pours! We have had what feels like a deluge of positive and encouraging news about HD clinical trials lately, and certainly at HDBuzz, we are feeling thankful. It was not so long ago that the news deluge was delivering a very different and much more difficult message, that many drugs just weren’t working as we had hoped.
So, what’s changed? Well it’s important to remember that even when clinical trials don’t give us the results we had hoped for, there is still so much to be learnt from the wealth of data that is collected. All of the selfless hours in the clinic from the folks with HD who sign up for these trials count for a huge amount. The rich datasets they help generate have a huge impact in how scientists understand how different therapies might work in people, and what they can change and improve to give us the best chance of success. Their contributions have gotten us to this exciting point where we still have lots of irons in the fire and are edging closer to disease-modifying therapies.
The future of HD clinical trials is bright, thanks to the resiliency, fortitude, and sacrifice of so many people with HD who bravely stepped up to test these experimental drugs. We are forever thankful to them and are buckled in for the ride to see what comes next.
From: HDBuzz (English)
Posted on Fri, 16 Aug 2024 14:15:05 +0000
Steady progress from uniQure - promising data to end the year
With the holidays approaching, welcome news arrived on December 19th in a press release from uniQure. The latest data from the HD-GeneTRX studies of AMT-130, an experimental huntingtin-lowering gene therapy, shows that the drug still appears to be safe over the course of a few years. Since the number of participants is very small, we cannot yet draw conclusions about the effectiveness of AMT-130 to treat HD, but there are early, promising signs that AMT-130 holds potential to stabilize some symptoms. This means that the trial can safely continue and will hopefully expand in future.
A refresher on the HD-GeneTRX trials
First, let’s talk about the history of the first gene therapy for HD. Developed by uniQure, AMT-130 involves a harmless virus packaged with genetic material that is designed to lower the amount of huntingtin protein in the brain. We’ve covered a bit more on the science of this in a 2019 article. It was first thoroughly tested in many different animal models of HD before the current human safety studies, known as HD-GeneTRX-1 and HD-GeneTRX-2, began in 2020.
AMT-130 is delivered via a single surgery into the brain, with the goal of permanently lowering levels of huntingtin in nerve cells. Across the two studies in Europe and the USA, there have been 39 participants who underwent surgery. We’ve talked more about the different groups involved in the study in a previous article. Overall, most have received AMT-130, with some receiving a low dose, some a high dose, and a few undergoing a “sham” surgery as a control. After 1 year some of those in the “sham” surgery group also received a high dose of the drug.
As the trial has unfolded, uniQure has periodically shared data along the way. HDBuzz covered these releases, discussing positive 12-month data in 2022, a [safety hiccup]https://en.hdbuzz.net/329 that led to a pause in high-dose surgeries, and then the resumption of the trial late last year. In mid-2023, the trial was continuing to proceed smoothly with some positive data emerging. Today, some of the participants have been followed up to 30 months, and the data continues to look promising.
The latest data release
uniQure issued a press release and held an investor call to share the latest data from the trial. Let’s break down the news into digestible chunks related to AMT-130’s safety, potential impact on participants’ symptoms, and biomarkers.
Safety
This is a small study that is designed mainly to test safety and how well people tolerate AMT-130. There are definite risks following a major brain surgery, which we saw with the study pause last year. But with longer monitoring after the surgery and the prescription of anti-inflammatories, these risks are now better controlled.
Additionally, bloodwork, vital signs, heart rhythms and other measures of health were largely normal. Overall, this means that for up to 30 months after the surgery, AMT-130 seems to be safe and well tolerated at the low dose, and there are good options for managing potentially dangerous side effects.
Impact on symptoms
Although this study wasn’t designed to determine if AMT-130 can actually slow or stop symptoms, there are many clinical measurements built into the study that can begin to give us a picture of whether this drug can change the course of HD. Because the control group for the HD-GeneTRX studies is so tiny, uniQure also used data that was collected separately through a big observational study that did not involve a drug, called TRACK-HD. They were able to compare data from those who got AMT-130, with data from people at a very similar disease stage who didn’t receive the drug. These observational study participants were also followed over the course of at least 30 months.
The studies involved tests that measured movement, day-to-day function, ability to switch thinking tasks, and more. The main positive takeaway here is that those who received the high dose of AMT-130 seem to retain their functional and movement abilities for 18 months, as they performed better on all the tests than the TRACK-HD participants who didn’t have the surgery. The data for the low dose extends to 30 months, and these participants showed preservation of movement and function on some measurements.
All that said, much of this data describes a trend and the statistics don’t yet allow uniQure to draw a definite conclusion about how well AMT-130 works to slow or halt the signs of HD. There are too few people so far to tell - just 5 or 6 in the low dose group have reached the 30 months mark after their surgery.
Biomarkers
Another important thing that uniQure shared was measurements made in the spinal fluid of participants. Neurofilament light (NfL) is a protein released from brain cells when they are damaged. This is one measurement that scientists use in HD drug studies to get a clearer picture of whether the treatment could be helpful or harmful. After a brain surgery, NfL levels naturally go way up, but the hope is that they return to normal or “baseline” after a while (sometimes this takes quite a long time). If NfL levels dip even lower, that is one sign that the drug is safe and could even be helping to preserve brain health.
The latest NfL data from this study show that after the surgery, there is a big spike in this biomarker, but in the group that got a high dose of AMT-130, the levels seem to have returned to baseline after 18 months. In the low dose group, NfL levels are below baseline at 30 months - a good safety sign and one piece of the puzzle to show a possible benefit for the brain. Once again, we’re looking at trends in data from a very small group of people.
Since AMT-130 is designed to lower huntingtin, uniQure also wants to understand whether the treated participants have lower levels of huntingtin - but this has proven to be very tricky, not only in this study, but across the HD research field. They weren’t able to get reliable measurements from the spinal fluid for many of the study participants. Scientists at uniQure also suggested that it’s not yet clear whether looking at levels of huntingtin in spinal fluid is the most accurate way to measure the effects of a drug delivered directly to the brain. Still, any positive clinical signs will always outweigh measurements of a biomarker.
What can we take away from the latest data?
Above all, it’s important to remember that this study was designed to test safety and not efficacy, and so far it seems that AMT-130 is safe and tolerable for up to 30 months. It’s also a very tiny data set, and the comparison group was taken from a separate, observational study.
Despite all these caveats, there is reason for some excitement around the latest data shared by uniQure. This is the first time ANY HD study has shown genuine positive signs that a drug has the potential to stabilize symptoms, with safety and side effects that appear to be manageable.
Overall, this is what uniQure hoped to see at this point in the study. There is reason for it to move forward, and to hope that a larger study will be designed to test efficacy. So - no miracles, but a solid body of data that continues to grow. We expect another data release in around six months, in mid-2024.
HD is a slowly progressing disease, and for an unprecedented gene therapy like AMT-130, it’s about the long game. Ensuring that a novel approach is safe and effective can be frustratingly slow, but we are encouraged by the latest data and we will continue to report on any new results that are shared.
In the meantime, we are doing a cautiously optimistic happy dance, and we wish all HDBuzz readers a happy and healthy holiday season.
A refresher on the HD-GeneTRX trials
First, let’s talk about the history of the first gene therapy for HD. Developed by uniQure, AMT-130 involves a harmless virus packaged with genetic material that is designed to lower the amount of huntingtin protein in the brain. We’ve covered a bit more on the science of this in a 2019 article. It was first thoroughly tested in many different animal models of HD before the current human safety studies, known as HD-GeneTRX-1 and HD-GeneTRX-2, began in 2020.
AMT-130 is delivered via a single surgery into the brain, with the goal of permanently lowering levels of huntingtin in nerve cells. Across the two studies in Europe and the USA, there have been 39 participants who underwent surgery. We’ve talked more about the different groups involved in the study in a previous article. Overall, most have received AMT-130, with some receiving a low dose, some a high dose, and a few undergoing a “sham” surgery as a control. After 1 year some of those in the “sham” surgery group also received a high dose of the drug.
As the trial has unfolded, uniQure has periodically shared data along the way. HDBuzz covered these releases, discussing positive 12-month data in 2022, a [safety hiccup]https://en.hdbuzz.net/329 that led to a pause in high-dose surgeries, and then the resumption of the trial late last year. In mid-2023, the trial was continuing to proceed smoothly with some positive data emerging. Today, some of the participants have been followed up to 30 months, and the data continues to look promising.
The latest data release
uniQure issued a press release and held an investor call to share the latest data from the trial. Let’s break down the news into digestible chunks related to AMT-130’s safety, potential impact on participants’ symptoms, and biomarkers.
Safety
This is a small study that is designed mainly to test safety and how well people tolerate AMT-130. There are definite risks following a major brain surgery, which we saw with the study pause last year. But with longer monitoring after the surgery and the prescription of anti-inflammatories, these risks are now better controlled.
Additionally, bloodwork, vital signs, heart rhythms and other measures of health were largely normal. Overall, this means that for up to 30 months after the surgery, AMT-130 seems to be safe and well tolerated at the low dose, and there are good options for managing potentially dangerous side effects.
Impact on symptoms
Although this study wasn’t designed to determine if AMT-130 can actually slow or stop symptoms, there are many clinical measurements built into the study that can begin to give us a picture of whether this drug can change the course of HD. Because the control group for the HD-GeneTRX studies is so tiny, uniQure also used data that was collected separately through a big observational study that did not involve a drug, called TRACK-HD. They were able to compare data from those who got AMT-130, with data from people at a very similar disease stage who didn’t receive the drug. These observational study participants were also followed over the course of at least 30 months.
The studies involved tests that measured movement, day-to-day function, ability to switch thinking tasks, and more. The main positive takeaway here is that those who received the high dose of AMT-130 seem to retain their functional and movement abilities for 18 months, as they performed better on all the tests than the TRACK-HD participants who didn’t have the surgery. The data for the low dose extends to 30 months, and these participants showed preservation of movement and function on some measurements.
All that said, much of this data describes a trend and the statistics don’t yet allow uniQure to draw a definite conclusion about how well AMT-130 works to slow or halt the signs of HD. There are too few people so far to tell - just 5 or 6 in the low dose group have reached the 30 months mark after their surgery.
Biomarkers
Another important thing that uniQure shared was measurements made in the spinal fluid of participants. Neurofilament light (NfL) is a protein released from brain cells when they are damaged. This is one measurement that scientists use in HD drug studies to get a clearer picture of whether the treatment could be helpful or harmful. After a brain surgery, NfL levels naturally go way up, but the hope is that they return to normal or “baseline” after a while (sometimes this takes quite a long time). If NfL levels dip even lower, that is one sign that the drug is safe and could even be helping to preserve brain health.
The latest NfL data from this study show that after the surgery, there is a big spike in this biomarker, but in the group that got a high dose of AMT-130, the levels seem to have returned to baseline after 18 months. In the low dose group, NfL levels are below baseline at 30 months - a good safety sign and one piece of the puzzle to show a possible benefit for the brain. Once again, we’re looking at trends in data from a very small group of people.
Since AMT-130 is designed to lower huntingtin, uniQure also wants to understand whether the treated participants have lower levels of huntingtin - but this has proven to be very tricky, not only in this study, but across the HD research field. They weren’t able to get reliable measurements from the spinal fluid for many of the study participants. Scientists at uniQure also suggested that it’s not yet clear whether looking at levels of huntingtin in spinal fluid is the most accurate way to measure the effects of a drug delivered directly to the brain. Still, any positive clinical signs will always outweigh measurements of a biomarker.
What can we take away from the latest data?
Above all, it’s important to remember that this study was designed to test safety and not efficacy, and so far it seems that AMT-130 is safe and tolerable for up to 30 months. It’s also a very tiny data set, and the comparison group was taken from a separate, observational study.
Despite all these caveats, there is reason for some excitement around the latest data shared by uniQure. This is the first time ANY HD study has shown genuine positive signs that a drug has the potential to stabilize symptoms, with safety and side effects that appear to be manageable.
Overall, this is what uniQure hoped to see at this point in the study. There is reason for it to move forward, and to hope that a larger study will be designed to test efficacy. So - no miracles, but a solid body of data that continues to grow. We expect another data release in around six months, in mid-2024.
HD is a slowly progressing disease, and for an unprecedented gene therapy like AMT-130, it’s about the long game. Ensuring that a novel approach is safe and effective can be frustratingly slow, but we are encouraged by the latest data and we will continue to report on any new results that are shared.
In the meantime, we are doing a cautiously optimistic happy dance, and we wish all HDBuzz readers a happy and healthy holiday season.
From: HDBuzz (English)