Posted on Tue, 23 Jun 2020 06:18:59 +0000
Researchers have known for quite some time that HD causes a progressive loss of neurons. But what if we could find a way to fill their place? In a new report, researchers used an intriguing strategy in living mice to do just that – they converted a different type of brain cell into neurons, with very promising results.
Neurons aren’t alone
In HD research we spend a lot of time talking about neurons. And understandably so! Neurons are the cell type in the brain most affected by HD, and they are the cells that exchange messages to drive our movements, moods, and memories. You can think of neurons like the computer programmers of the brain – they convert information into action.
In particular, neurons in an area of the brain called the striatum – striatal neurons – tend to be most vulnerable to the mutation that causes HD. Right now no one knows exactly why those cells are especially vulnerable. But researchers know that many of the symptoms of HD are related to the loss of neurons in this area of the brain.
But there are lots of different types of cells in the brain. In fact, the most abundant cell type in the brain isn’t neurons – it’s a cell type called glia. Glia is a general term that describes several kinds of cells in the brain and spinal cord that provide support, insulation, and protection. You can think of glia like the body guard of the brain – they make sure other cell types have the support they need to function.
One type of glia are brain cells called astrocytes. A lot of the nervous system is made up of astrocytes – 30% in fact! Because astrocytes are everywhere in the brain, they’re also present in the areas where neurons degenerate due to HD – the striatum. And unlike neurons that stop dividing when they’re fully mature, glia continue to divide.
Recently, scientists took advantage of the abundance of glia in the brain and their ability to reproduce. They used an experimental technique in the brains of mice to turn astrocytes into new, functioning neurons. So to stick with our analogy, they encouraged the body guards of the brain to change jobs and become computer programmers.
A neuron by any other name
The work was led by Dr. Gong Chen, a former professor at Penn State University, who is now leading the Institute of CNS Regeneration at Jinan University in China. His team took advantage of a technique to turn cells that aren’t neurons into neurons – something called direct conversion.
This technique allows researchers to coax different cell types, such as astrocytes, into becoming neurons, by adding chemical cocktails to boost the action of genes that influence a cell’s role. This is a bit like changing the job description of a certain cell type - but this has been done before. Many times in fact. It’s old news that scientists can take one cell type grown in a laboratory dish and directly turn it into a neuron.
So what did this report add, and why was it worthy of publication in the prestigious journal Nature Communications? Because these authors did direct conversion inside the brains of living mice! They used a harmless virus to deliver their chemical cocktail that gave a genetic nudge to the astrocytes, encouraging them to change jobs and become neurons. In this way, they were able to turn abundant astrocytes into potentially valuable striatal neurons– a very cool accomplishment!
We know what you may be thinking – “Did you just say virus?!” We all get a little weary when we hear that word, especially in the days of COVID-19! But rest assured, this is a very harmless method used frequently in biology.
It’s actually just the outside of the virus that’s used, without any of the inside bits that typically make viruses so harmful. Similar to a letter in an envelope – researchers here are repurposing an envelope and adding something new inside. So the old message is removed, and the envelope is sent with new instructions that body guards should change jobs and become computer programmers!
Changing jobs within your company vs, going to a new company
An important finding from the paper was that the overall number of astrocytes didn’t decrease over time. This is related to the point we made above about astrocytes – they continue to divide. So even though the researchers turned some of the astrocytes into neurons, the astrocytes that remained produced more astrocytes to replace them. This approach provided a source of new striatal neurons for these HD mice without affecting the astrocyte population! And because these astrocytes are already located in the striatum, the intervention occurs in the exact area of the brain that could use more neurons.
Chen and colleagues also showed that these new neurons in the striatum fired signals just like native neurons. They also connected with other areas of the brain, just like native neurons. Most compellingly, with the addition of these new neurons in the striatum, the HD mice performed better on movement tests and had an extended lifespan. All very exciting and promising results!
The idea of adding back lost neurons in HD isn’t new. The big difference is that previous studies have added new cells through surgery, performing what’s called cell transplantation. So while direct conversions, like the experiments performed by Chen and his team, are like changing jobs within the same company, cell transplantations are like getting a job at a new company.
Several research groups have experimented with cell transplantation as a therapy for HD, and some of these options are moving toward clinical trials. More recently, cell transplantations have been done with immature cells known as stem cells or neural progenitor cells that haven’t fully committed to becoming a specific cell type yet. The benefit of using immature cells is that they can obtain cues from the surrounding environment, letting them know what cell type is needed.
Cell transplantations have shown promise, but can come with some risks. There’s no guarantee that the cells will become exactly the type of neuron you want. And there’s no guarantee that the cells will survive long-term because that’s not their native environment.
Chen’s group got around these issues by triggering specific biological machinery to convert astrocytes into striatal neurons. The researchers knew exactly what type of neuron they were going to get in the end. And because the astrocytes they targeted were already present in the striatum, they knew the new neurons would be in exactly the right place!
Ready for prime time?
One thing to keep in mind with this approach is that the astrocytes used to make the neurons come from the HD mouse. That means the new striatal neurons also contain the genetic error (mutation) that causes HD. Researchers don’t yet know what that means for the lifespan of those neurons.
While the results from this study are very exciting and potentially provide another tool in our belt to combat HD, this study was done as a proof-of-concept and still has a long way to go before it reaches the clinic. But so far, even though the new neurons carry the HD mutation, the direct conversion technique seems to improve HD-related symptoms in the mice.
Follow up studies are likely to try this technique in larger animals or to test it in combination with huntingtin lowering, which will undoubtedly provide interesting results. We’ll be eagerly waiting!
From: HDBuzz (English)
Posted on Wed, 27 May 2020 06:24:45 +0000
A new study headed up by Dr. Sarah Tabrizi, a pioneer in HD research, assessed pre-manifest HD young adults many years from predicted symptom onset with a battery of clinical tests. The goal of this study was to identify a sweet spot – a time when HD participants weren’t experiencing any observable symptoms, but when markers of disease progressing begin to show the earliest changes. This was a challenging task, but the HD researchers rose to the occasion!
Young Adult Study – assessing patients 24 years from predicted HD onset
As HDBuzz readers are undoubtedly aware, there is a bewildering array of trials of HD drugs planned and underway. A number of these drugs target the mutant HD gene, or the protein made from it, directly. To see if these approaches work, researchers need to find the right window of time in which to test their drugs.
The key question researchers are interested in understanding is: When is the best time to treat HD? Some researchers think that the best time to treat may be at the very earliest stages of HD – before any brain cells begin to die and before there has been any functional decline. But since we know emotional and psychiatric changes can occur even 10 to 15 years before symptom onset, no one was sure when the healthy baseline began to cross over into symptomatic onset – until now!
An team led by Dr. Tabrizi set out to try and identify the very earliest stages of HD – when patients are functioning at full capacity, but there’s some measurable marker of decline. That last bit is super important. There needs to be some sort of measurable change so that when therapeutic strategies effectively improve HD progression, researchers will be able to measure improvement even in the very earliest stages of HD.
The name of Dr. Tabrizi’s study is the Young Adult Study, or HD-YAS. This study examined over 130 young adults that included HD gene carriers as well as individuals without HD, that were on average 29 years old. The participants that carry the HD gene were predicted to be about 24 years from onset. That makes this one of the earliest comprehensive assessments of pre-symptomatic HD gene carriers ever.
All participants were assessed using many, many tests designed to assess both cognitive and psychiatric components of patients. A few of these tests included brain imaging, blood collection, spinal fluid collection, assessment of cognition (planning, attention, memory), and psychiatric assessment (depression, anxiety, behavior). So these participants were quite thoroughly examined!
Cognitive and psychiatric function are preserved, but NfL is increased
The first major component of the study they described was the cognitive and psychiatric assessment. What they found was amazing: Of all the cognitive and psychiatric tests performed on HD gene carriers and individuals without HD (and there were lots of different tests), none of them showed any difference – wow! This means that no matter how hard we look at people carrying the HD mutation this far from onset, there really is a time in which even the most sensitive tests don't reveal any changes, compared to people without the mutation.
This study also examined the sizes of various parts of the brain to determine how early changes in these regions may be occurring. One of the primary areas of the brain affected by HD is the striatum, which is made up of two halves called the putamen and caudate. These areas of the brain shrink as HD progresses due to the loss of cells that occurs in these regions over time.
While there was no change in caudate size, there was a reduction in putamen size in the people carrying the mutation, called the preHD group. But this difference was small and didn’t match with predicted years from onset in the preHD group, which means further study is needed to understand what this change means. No other brain regions that were assessed showed size differences.
The last major component of this study looked at biomarkers – measurable markers in samples from patients that change with disease progression. Identifying biomarkers in HD patients is critical for tracking disease progression and for measuring the effects of treatments.
Currently, one of the most reliable biomarkers we have for HD is changes in the levels of a protein called neurofilament light, or NfL. While it can be measured in blood plasma, examining levels of NfL in CSF appears to be more sensitive and accurate. We've written about NfL, and what role it might play in future HD trials here.
HD-YAS found that NfL levels in both blood and spinal fluid were increased in the preHD group. Since NfL levels increase with injury to brain cells, this indicates that there is some level of stress on the brain occurring in the preHD group, even this far from symptom onset.
While this may seem like a negative finding, it’s actually really good! Even though NfL levels are elevated, study participants aren’t experiencing any cognitive of psychiatric effects because of it. This means that a timepoint has been established where HD mutation carriers have totally normal function, but there are biomarker tests that can still be measured to determine if therapeutics would be effective. This is exactly what HD-YAS set out to determine!
What do these findings mean for the field and future trials?
Overall, HD-YAS was able to conclude that NfL levels in the spinal fluid may be the earliest detectable event in HD before symptom onset. These researchers also found that movement, cognitive, and psychiatric function remain unchanged, even up to 24 years from predicted onset – amazing news!
When this study is combined with other large studies, like TRACK-HD, PREDICT-HD, and ENROLL-HD, a comprehensive, predictive map begins to take shape. Thanks to HD-YAS, and studies that came before it, we now know that the earliest, subtle, functional changes begin sometime between 24 to about 15 years from symptom onset.
The findings from HD-YAS are an important discovery for the field, indicating the time at which a healthy baseline exists in HD individuals. If researchers learn that the best time to treat HD patients is prior to any sort of symptom onset, we now have an idea of when that time would be. This will be critically important for designing future clinical trials aimed at preventing HD, rather than treating it.
Have you missed the boat?
It’s important to note that these results don’t mean that lowering HTT after symptom onset won’t have an effect. That question is still very much up in the air. The full set of results from the Phase III tominersen trials will help researchers understand if patients can regain cognitive, psychiatric, and motor function once they begin to decline. Following the progress of the brave trial participants as they continue to take tominersen will be critical in determining if follow-up trials are needed.
While we all hope that HD patients will regain functional capacity even after symptomatic onset, that’s just not something we know based on the current data. But if we discover that HD patients need to be treated before symptoms begin to appear, we now know exactly when that is based on HD-YAS. This allows researchers to stay one step ahead and hit the ground running, saving valuable time.
From: HDBuzz (English)
Posted on Wed, 13 May 2020 04:16:11 +0000
A team of scientists has recently published their findings on how our bodies are able to repair brain and spinal cord injuries. They found that the huntingtin protein plays an important role in repairing damaged nerve cells.
Repairing nervous system damage – the holy grail of medical science
It has long been the ambition of many scientists to find ways to help repair damage to the brain and spinal cord. By studying how the nervous system is able to heal, scientists hope to get clues about exactly how to reverse damage, which in turn may help develop medicines or therapies to treat those with nervous system injuries.
One of the ways we can repair damage to the nervous system is by using a type of stem cell that can readily become a brain cell. These neural stem cells develop into neural progenitor cells, or NPCs. Like other types of stem cells, these are cells which have not fully developed yet; they are growing into different types of nervous system cells but are not all the way there yet. Scientists are able to graft NPCs onto the areas of the nervous system which are damaged, in a similar way to how we transplant tissues and organs. Once grafted on, the NPCs help the other cells grow and reconnect with each other, restoring function to the damaged area of the nervous system.
Modern tools helping to answer age-old questions
Professor Mark Tuszynski and colleagues are interested in researching exactly how NPC grafts can help repair brain and spinal cord damage. In their study published recently in Nature, they investigated nervous system repair using modern neuroscience and genetic tools to look at the details of the process.
To investigate how NPCs help to repair spinal cord damage, the team studied mice with spinal injuries, and treated some of them by grafting NPCs. Then they compared the treated and untreated mice by monitoring which genes were switched on and off as they healed. Rather unexpectedly, the scientists found that the damaged cells reverted back to an embryonic state. This means that the cells had similar genes switched on and off to the nervous system cells you would find in early stages of neural development in embryos. Furthermore, when comparing recovery from spinal cord damage with and without the NPC grafts, this embryonic state is maintained for a longer period of time with the grafts.
Scientists in the team hypothesise that reverting to an immature or embryonic state helped the injured cells to regrow and promoted repair of damage. This is a neat finding which differs strongly from dogma 20 years ago that the brain was a static organ incapable of repair.
Who’s in the driving seat?
To work out what was driving the damaged cells to revert to the embryonic state, Tuszynski and colleagues looked at which genes had turned on and off during healing from the injury. Interestingly, they found that huntingtin could be playing this role.
As all you readers probably know, huntingtin is the protein which is encoded by the huntingtin gene, mutated in patients with Huntington’s disease. We still don’t have a complete picture about what this protein is doing in the cells of our bodies under normal circumstances in its non-mutated form and many scientists are working hard to figure this out.
The work by Tuszynski and colleagues suggests that huntingtin is the central player in nerve cell regeneration in their models. They found that huntingtin helped to keep damaged nerve cells in the embryonic state, promoting nerve cell regeneration. In fact, when the scientists looked at nerve damage in mouse models which had huntingtin deleted from the spine, recovery from spinal cord injury was reduced by 60% - a huge effect! This suggests that huntingtin is very important for the repair of neurons after injury.
But what does this mean for HD research?
The findings of Tuszynski and colleagues are a great step forward in terms of our understanding of the normal huntingtin protein and what its function might be in brain development. It’s tempting to speculate that the HD mutation might hinder the way our nervous systems can repair themselves and many other scientists are now certainly trying to work out if that is the case. This could underlie how neurodegeneration happens in HD patients but further research is needed to confirm this hypothesis.
For all avid HDBuzz readers, it’s important to note that the huntingtin deletion the scientists used in their mouse model is very different to the huntingtin lowering trials currently underway by Wave, Roche, and uniQure. In these experiments, the researchers deleted 100% of huntingtin in the brain and spinal areas they were studying, to better understand huntingtin’s role there. The clinical trial approaches are designed to lower huntingtin levels in the parts of the brain affected most by HD. They don’t get rid of 100% of the protein, so we would not expect the trials to affect repair of nerve damage in the same way.
This exciting new study is sure to spark a new wave of experiments in HD labs around the world; we eagerly await their findings!
From: HDBuzz (English)