Real progress is being made on the road to Huntington’s disease (HD) treatments, but in today’s fast-moving digital world, it can be harder than ever to separate genuine breakthroughs from overhyped headlines or flat-out misinformation.

That’s why HDBuzz has updated our Ten Golden Rules to help you decide whether a piece of news about HD research offers real promise, or whether its claims should be taken with a healthy pinch of salt.

If this article seems familiar, that’s because it is! Ed and Jeff wrote a version of these rules back in 2011. But over the past 14 years, the way we consume news in the age of social media and clickbait-focused news websites has changed a lot. So we hope this updated article provides some clarity and helpful guidelines for navigating research news in 2025.

Snowflakes and glaciers

At HDBuzz, we love science. We like to imagine all the world’s scientific research as a flurry of snowflakes, gently settling on a mountaintop and gradually, over months, years, and decades, compacting into a huge, unstoppable glacier that can carve entire mountains.

No single snowflake could do that, but combined, over time, the power of science to change the world – and improve the lives of people with HD – is immense.

The search for treatments and cures for HD is exactly like that. Most progress is small, incremental, and takes place behind the scenes. But step-by-step, we’re moving closer to therapies that will make a meaningful difference.

How science reaches the public in 2025

Science becomes “official” when it’s published in a peer-reviewed journal – but that’s rarely how most people first hear about it. In 2025, scientific information spreads across a sprawling ecosystem of platforms: news sites, press releases, blogs, Facebook, YouTube explainers, Reddit threads, and increasingly, short-form video on platforms like TikTok and Instagram.

That’s not necessarily a bad thing – more access to information is a win. But it comes with risks. Short videos and viral posts are often created for clicks and engagement, not accuracy. Many creators aren’t scientists, and even well-meaning ones can misunderstand or oversimplify complex findings. Sometimes, content is misleading or, worse, just plain false.

At the same time, researchers and institutions are under more pressure than ever to promote their work and secure funding. Teams will often issue press releases that highlight the long-term potential of early-stage research or niche studies, even when those applications are years (or decades) away or only give insight to a narrow aspect of HD research.

One way to excite people about this type of research is to get them to imagine the whole glacier, rather than just the snowflake. When those press releases are subsequently re-written into news articles or turned into social media snippets, nuance can be lost. A promising experiment in cells or mice can easily become “Scientists close to curing Huntington’s disease!” – even if human trials are a long way off.

What’s the harm?

It’s easy to feel hopeful, and we should! But when stories exaggerate the readiness or relevance of early-stage science, people in the HD community can end up misled, confused, or disappointed. And repeated disappointments can erode trust in science altogether.
We don’t believe this is the fault of individual scientists, journalists, or creators. But in a world where misinformation spreads fast, it’s important to stay curious and critical.

We know that some folks think of us as “HDBuzzkill”, as our articles can be less enthused than other press releases or articles on other platforms. However, for our editorial team, whilst we strive to be peppy and hopeful as much as possible, we also want to prioritise managing expectations and keeping our reporting as accurate as possible as a matter of the utmost importance.

HDBuzz’s Ten Golden Rules for navigating science news

The good news? You don’t need to be a scientist to protect yourself from hype and heartbreak. So, HDBuzz has Ten Golden Rules for reading a press release or scientific news article. They’re here to help you to draw hope from scientific news where it’s warranted – and avoid being let down where it’s not.

1. Be skeptical of anyone promising a “cure” for HD now, or in the near future.
There are promising leads, but no magic bullets yet.

2. If something sounds too good to be true, it probably is.
“Breakthrough,” “miracle,” and “game-changer” are red flags if not backed by details.

3. Has the research been published in a peer-reviewed scientific journal?
If not, it might just be a preliminary result or a publicity push.

4. Is the news about actual research results? Or a new partnership, startup, or funding award?
Hope is good, and investment in HD research from different stakeholders is fantastic, but ultimately results from the lab and the clinic matter most.

5. Has the treatment been tested in people with HD?
If not, no one really knows if it works in people.

6. Has it been tested in an HD animal model?
Even if a treatment seems to have worked in mice, that’s a great first step, but a long way from working in people, and many things fail in the path to the clinic.

7. Has it even been tested in an HD model?
If the research hasn’t yet been tried in a model that mimics HD, it’s still at a very early stage.

8. Watch out for clickbait.
Articles with headlines like “Scientists Stun the World” or “This CRISPR Discovery Changes Everything” are designed to get attention – not tell the full story. Stick with sources that prioritize facts over flash.

9. Look out for overconfident or definitive language.
Be cautious if the language used is absolute – words like “always,” “never,” “guaranteed,” or “proven.” Science is careful and cautious for a reason.

10. When in doubt, ask HDBuzz!
If you’re unsure about something you read or see on social media, drop us a note at editor@hdbuzz.net or use the form at HDBuzz.net. We’re pulling double duty with day jobs as HD scientists and researchers, giving us a unique lens to translate findings from the lab for HD families. And we’re happy to investigate and contact our network of experts to help differentiate hope from hype.

Progress is still progress, even when it’s slow. Every study, even ones that don’t lead directly to a treatment, helps us get closer to our goal. That’s the power of the snowflake – glacier model: steady, collective progress over time.

Using the golden rules in practise

Example 1 – “New drugs cross blood-brain barrier to slow progression and even reverse symptoms of Huntington’s disease”

In this research paper, we learn that a team of researchers from the Weizmann Institute of Science in Israel have identified two small molecules that can reduce levels of the harmful huntingtin protein that causes HD. These molecules work by interfering with part of the machinery that helps coordinate how genetic message molecules are made.

In a mouse model of HD, direct delivery of these drugs into the brain improved many signs and symptoms of HD in this model. Importantly, the molecules were able to cross the blood-brain barrier, and seemed to slow disease progression without noticeable side effects.

This is a really cool study and suggests that these small molecules that target the genetic root of HD could be a promising path toward new treatments.

Unfortunately, in one of the articles covering this research paper, the story comes across quite differently. The headline alone states that these small molecules are drugs that can slow and even reverse symptoms of HD. Let’s go through the rules to see how this article fares. Here is our summary:

Rule 1. Cure claim? ⚠️ Caution – Data suggests reversal of symptoms in mice; not a human cure.
Reversing HD symptoms is akin to claiming a cure. Whilst the data in mice might support reversal of features of HD mouse models, which we use as a surrogate for HD symptoms, this is a long way from a cure for people.

Rule 2. Too good to be true? ⚠️ Caution – Promising results in mice; human applicability uncertain.
This article definitely sounds too good to be true in our opinion. These aren’t drugs, but tool molecules these folks are using in the lab. There is a long road from a tool molecule being tested in mice in the lab to a drug being tested in people in the clinic.

Rule 3. Peer-reviewed? ✅ Pass – Published in EMBO Molecular Medicine.

Rule 4. Actual results? ✅ Pass – Reports on experimental findings in mice.

Rule 5. Tested in HD patients? ❌ Fail – Not yet tested in humans.
This study has not conducted any experiments in people, not that you would know from the headline, which fails to caveat that this work was conducted in mouse models of HD. The data in the paper is supportive that these molecules might help slow symptoms, or stuff scientists can measure in HD mouse models which look somewhat like human symptoms of HD. This is an excellent start, but certainly a long way from showing this is a tractable approach to be investigated in people.

Rule 6. Tested in HD animal model? ✅ Pass – Conducted in mouse models of HD.

Rule 7. Tested in HD model? ✅ Pass – Yes, in relevant animal models.

Rule 8. Clickbait? ⚠️ Caution – Headline may overstate findings.
In our opinion, the title of this article is clickbait. The title doesn’t tally with the subsequent text which goes into more detail about what really happened in the study.

Rule 9. Definitive language? ⚠️ Caution – Language suggests more certainty than warranted.
The title of the article and some of the text therein is definitely peppered with overconfident or definitive language. Claiming to reverse symptoms of HD is a very bold statement, which we don’t believe the data definitively support.

Example 2 – “AMT-130 slows progression in early Huntington’s, 2-year trial data show”

Last July, the HD community had an exciting update from uniQure about their gene therapy drug, AMT-130, currently in clinical trials. The update uniQure provided in their press release was based on data collected from folks treated with the drug over a 2-year time period.

They found that the treatment continued to appear relatively safe, with no new serious side effects since the study was briefly paused in 2022. Most side effects so far are linked to the brain surgery required to deliver the drug. They also reported on a key brain health biomarker, NfL, which typically rises as HD progresses. After an initial spike (likely due to the surgery), people treated with AMT-130 showed a long-term decrease in NfL levels, suggesting the drug might be slowing the disease process. This trend was seen in both low- and high-dose groups at 2 years post-treatment, though the number of participants remains small.

On clinical measures, the high-dose group showed about 80% slower progression by cUHDRS, a sensitive scale that tracks HD symptoms, compared to untreated patients in a natural history study. That’s a potentially big deal, but with only 9 people in that group, we still need to interpret the results cautiously. Other individual clinical scores showed less obvious effects, and data on huntingtin protein levels or brain imaging weren’t shared in this update.

HDBuzz and many others reported on this update. One report from Huntington’s Disease News somewhat missed the mark in our opinion. Let’s go through the rules to see where this piece falls short. Here is our summary:

Rule 1. Cure claim? ✅ Pass – No cure claimed.

Rule 2. Too good to be true? ⚠️ Caution – Significant claims based on small sample sizes.
In our opinion, the article makes claims that are very bold for data from such a small number of trial participants.

Rule 3. Peer-reviewed? ❌ Fail – Data not yet peer-reviewed.
Whilst companies typically work to ensure that all of the data they share in updates on clinical trials are accurate and appropriately interpreted, their reports are not peer-reviewed. In fact these “science-by-press release” updates are often geared towards their financial investors, so will often put a positive lens on their findings. Some healthy skepticism is certainly warranted for updates from all companies in this format.

Rule 4. Actual results? ✅ Pass – Interim clinical trial results presented.

Rule 5. Tested in HD patients? ✅ Pass – Yes, in early-stage HD patients.

Rule 6. Tested in HD animal model? ✅ Pass – Preclinical testing conducted.

Rule 7. Tested in HD model? ✅ Pass – Yes, in HD models.

Rule 8. Clickbait? ⚠️ Mild Caution – Headline somewhat overstates conclusiveness.
For this particular write up, the title clearly overstates the conclusions of the updates released by the company. AMT-130 certainly seems to be moving things in a positive direction, but to write that it absolutely slows HD progression is an overstatement in our opinion.

Rule 9. Definitive language? ⚠️ Caution – Some overconfident phrasing present.
As laid out with the previous rule, much of the language in the article is too definitive in our opinion. The article claims “Treatment with AMT-130 high dose slowed disease progression 80%”. This is in fact based on data from one clinical measure, cUHDRS, with data derived from just 9 people. The data are encouraging, but this phrasing seems to overstate the facts we have so far.

Example 3 – “AAN 2025: Pridopidine Shows Sustained Benefits on Progression, Cognition, and Motor Function in Patients With HD”

Recently, at the prestigious 2025 American Academy of Neurology Annual Meeting in San Diego, there was a presentation about pridopidine, a drug that activates a brain-protective protein called the sigma-1 receptor. Often, the abstract from talks at meetings like this are published in journals so that there is a record of the meeting and folks can see what research was presented.

From this abstract, we learnt that researchers studying pridopidine had scrutinised over 100 weeks of data to see how pridopidine might affect everyday function (TFC), disease progression (cUHDRS), movement, cognition, and quality of life. They found that for people not taking antidopaminergic medications (like VMAT2 inhibitors or antipsychotics), pridopidine seemed to outperform placebo across all measures, with some benefits lasting over a year. Based on this, the authors suggest that pridopidine could be a promising and safe, long-term treatment for HD.

This abstract was picked up and written about in this article. The HDBuzz team thinks this article falls short of conveying the complete picture. Let’s use the rules to help us work through where this article misses the mark. Here is our summary:

Rule 1. Cure claim? ✅ Pass – No claim of a cure.

Rule 2. Too good to be true? ⚠️ Partial fail – Subtle overhyping.
This article provides little context of the long and complicated journey the drug pridopidine has taken in clinical trials in HD. In its most recent trial, PROOF-HD, pridopidine failed to show benefit in people with HD and did not meet its endpoints. The news article does not provide this historical context and the title of the abstract does not accurately portray the facts of the study.

Rule 3. Peer-reviewed? ❌ Fail – Conference data only.
The conference abstract, although published in the esteemed journal Neurology, is not peer reviewed. This is stated in the abstract itself, but not the news article. This means that no external scientists have scrutinised the study to see if the claims made in the abstract are really supported by the underlying data and should be interpreted with caution until they are.

Rule 4. Actual results? ✅ Pass – Real clinical data, though limited to a subgroup.

Rule 5. Tested in HD patients? ✅ Pass – Phase 3 trial.

Rule 6. Tested in HD animal model? ✅ Pass – Not mentioned but detailed in published literature.

Rule 7. Tested in HD model at all? ✅ Pass – Preclinical work exists.

Rule 8. Clickbait? ⚠️ Borderline – Sensational phrasing in the absence of context.
The article uses phrases such as “Sustained benefits” and “Significant benefits on progression, cognition, and motor function” that imply more certainty than the subgroup analysis supports, and could be deemed clickbait by omission.

Rule 9. Definitive language? ❌ Fail – Overstated benefits not clearly qualified.
There are examples in this article of overconfident or definitive language which lack in our opinion appropriate qualifiers such as “suggests,” “trended toward,” or “needs further validation,” which are standard in cautious scientific reporting.

Final thoughts

In a world flooded with content, from traditional news stories to snappy TikToks, it’s more important than ever to know how to spot good science. At HDBuzz, we’re here to help. We believe in sharing clear, accurate, and hopeful information with the HD community.

With that in mind, don’t forget Rule 10 – if you’re unsure about something you read or see on social media, drop us a note at editor@hdbuzz.net or use the form at HDBuzz.net. We’re happy to investigate!

Science is slow, but it’s moving. And we’re moving with it. Let’s keep learning, questioning, and pushing forward – together.

This week, we heard an update from Roche about their huntingtin-lowering therapy, tominersen, currently being tested in the GENERATION HD2 trial. An independent data monitoring committee (iDMC) that regularly reviews all of the data from the trial recently held their scheduled meeting and made a recommendation to modify the trial design. To cut to the chase and set everyone’s mind at ease – the trial is continuing and there are no major safety concerns. Tominersen still appears to be well tolerated but there are some changes to the trial in regards to the dosing of the drug that the community should know about. Let’s get into it.

Recap – what is tominersen and how does it work?

Tominersen is an experimental drug developed by Roche that is designed to treat Huntington’s disease (HD) by targeting the root cause of the condition: the huntingtin (HTT) gene. People with HD inherit a version of this gene with a mutation at the beginning that leads to the production of a faulty version of the HTT protein. Making this faulty protein is thought to cause damage to brain cells, leading to the progressive symptoms of HD.

One approach being tested in the clinic currently to treat HD is HTT lowering. There are many different HTT-lowering approaches that various companies are testing out, all of which aim to reduce the amount of HTT protein produced in the brain. The idea is simple: if we can reduce levels of the harmful form of the HTT protein made in people with HD, we may be able to slow or even stop the disease’s progression.

Tominersen is a type of therapy known as an antisense oligonucleotide (ASO). These are short strands of synthetic genetic material that bind to the messenger RNA (mRNA) instructions that cells use to make the HTT protein. Once bound, the ASO causes the message to be destroyed, leading to lower levels of the HTT protein overall. Unlike gene therapy approaches, ASOs don’t permanently alter DNA, so their effects wear off over time. While this means that repeated dosing is required, it also means that the dosing of the ASO can be adjusted as needed.

How did we get here with tominersen?

Roche’s tominersen program has had a winding road. Initial trials showed encouraging signs, but a Phase 3 study called GENERATION HD1 was halted early in 2021 after an iDMC found that the safety risks outweighed any potential benefits in the group of trial participants being assessed.

However, an after-the-fact investigation of the data generated in this trial, known as a post hoc analysis, suggested that certain groups of participants, particularly younger individuals with less advanced disease and lower CAG numbers, might benefit from a lower or less frequent dose.

The best way to prove that the findings from the subgroup analysis were real was to do another trial. So even though this trial didn’t give us the results we had hoped for, this important finding sparked renewed interest in studying tominersen and the launch of a new trial called GENERATION HD2.

What was different in the new trial?

GENERATION HD2 has completed enrollment with 301 participants in total. Everyone in the trial is being dosed every 16 weeks over the course of 16+ months. The cohort is divided into three approximately equal groups who are either receiving a placebo, 60 mg, or 100 mg of tominersen by spinal tap. This is less drug, less often than folks in the GENERATION HD1 trial, who received 120 mg of drug every 8 or 16 weeks.

The trial is randomised and double blinded – this means that neither the participants nor the investigators in the clinic know who is getting which dose of the drug or the placebo. This helps to reduce bias in the way the trial is run and data are analysed. Data from people on the drug can be fairly compared to folks given the placebo as they will have all undergone the same procedures and testing.

Now, Roche has shared a new update on the program. Let’s break down what this latest update tells us, what this means for the HD community, and what comes next in the long road toward a potential therapy.

What did Roche share in this latest update?

The iDMC has recently completed a scheduled review of the data generated so far in the ongoing Phase 2 GENERATION HD2 trial. The iDMC is an impartial group that reviews the study data regularly—every 4 to 6 months—to ensure safety and scientific integrity. It’s important to note that the scientists at Roche have NOT seen any of the data yet; this is a completely independent review to make sure things are proceeding appropriately.

The good news from this review? Tominersen continues to appear safe and the trial is continuing. Based on safety and early data, the iDMC had no major concerns with folks in the trial who had received the drug—no new safety issues and no signs of worsening symptoms. This is great news since this was not the case with the very disappointing iDMC review from March of 2021 that ultimately halted the GENERATION HD1 trial.

The big piece of news in the update from Roche is that after the pre-planned interim analysis, the iDMC has recommended stopping the 60 mg dose for the rest of the study and continuing only with the 100 mg dose, which was judged more likely to result in clinical benefit. This doesn’t mean that the 60 mg dose doesn’t work, or that the 100 mg dose does work—it just means that, based on what they can see so far, the higher dose looks like a more promising dose with which to proceed.

What does the data say?

Right now, the only people that know what the data are showing are on the iDMC. While we know that Roche has collected data so far looking at different clinical progression measures (e.g., TFC), brain structure (volumetric MRI), and different biomarkers (e.g., plasma NfL), only the folks on the iDMC know what that data actually looks like. Not even the top researchers on the tominersen project at Roche have access to the data from the GENERATION HD2 trial. This ensures that the trial and the data remain unbiased until the trial concludes.

Because of this, no one knows exactly what data caused the iDMC to make the recommendation that they have to alter dosing. Everyone will have to wait until data is unblinded and released publically.

To maintain the integrity of the blinded trial, participants, researchers, and Roche staff still don’t know who’s receiving what. All participants in the trial will be told about this change, regardless of whether they were previously receiving placebo, 60 mg of drug, or 100 mg of drug. Everyone will be asked whether they consent to carrying on with the amended plan. Those in the placebo group will remain in that group and those on the 60 mg dose will now be moved to the 100 mg dose in a blinded and seamless transition.

What does this mean for the HD community?

While any study change can understandably elicit concern, particularly for those participating in the trial, this is actually a reassuring and encouraging update—and an important one for the HD community. First and foremost, the study is continuing with no major safety red flags. That’s always a critical milestone in drug development, particularly given the history of this drug in the clinic.

It’s also somewhat hopeful that one of the doses—100 mg—was seen as potentially more likely to offer benefit. While it’s still too soon to know for sure what impact tominersen is really having, the data so far are encouraging enough to continue the trial with this potentially more effective dose.

Another point to note is that Roche has taken special care to inform those involved with the study first. Roche communicated the study update earlier this week to investigators so that they could start informing study participants under their care, prior to the broader HD community learning of this update.

What’s next for tominersen?

As mentioned above, all study participants currently on the lower dose will be moved to the higher dose (100 mg to be given every 16 weeks), and everyone will remain blinded to their treatment. Because some participants will be switching doses midway through the study, the final data analysis will need to account for this. But there are well-established statistical methods to ensure the data remains valid and meaningful.

Even with these changes, we still expect the study to end in 2026. So this update to transition everyone to the 100 mg dose is not expected to cause any delays. Roche is working quickly to implement this change to get everyone on the right track as quickly as possible. The iDMC will continue to monitor data from the trial every 4 to 6 months as planned as things proceed forward.

In short: while we don’t yet know if tominersen will work to treat HD, we know that the study is continuing, the higher dose appears to look more promising than the lower dose, and everyone involved is doing their best to move this effort forward responsibly and transparently.

If you are a participant in the GENERATION HD2 study and you have questions, please reach out to your study site directly. Questions from those not in the study can be directed to your neurologist.

Huntington’s disease (HD) is caused by extra repeats of the DNA letters CAG within the genetic code of the huntingtin gene. We used to think that those CAG lengths were stable in most tissues, but we now have a growing understanding that CAG instability contributes to HD. Somatic instability is the concept that CAG repeats expand over time in some types of cells, particularly cells that are vulnerable in HD. Many scientists think this process might play a role in speeding up the development of symptoms.

A current paper delves into some of the machinery behind this phenomenon, asking how CAG expansion is connected with disease, and how science could harness DNA repair genes as a treatment for HD.

From people to animals… and back to people

Our current understanding of the phenomenon of CAG repeat expansion stems from huge human studies in which participants with HD donated samples and clinical data. Their contributions enabled scientists to link subtle differences in people’s genetics with the age when they developed HD symptoms. These studies, known as genome-wide association studies, or GWAS, (pronounced ‘gee-wass’) showed that certain DNA variations could greatly hasten or delay the onset of HD.

Many of the genes identified in these studies that warranted further research belong to a family of genes that help repair DNA. The past few years have seen a flurry of activity leading us to some new conclusions about HD and expansion of CAGs. Here’s a brief recap before we dive into some novel data around this topic:

• The DNA repair machinery can slip up when trying to “correct” extra-long CAG repeats – accidentally making them longer and longer!

• This does not happen in the vast majority of cells, but seems to occur a lot in a part of the brain called the striatum, which controls mood, movement, and motivation. Studying CAG expansion in the striatum could lead us closer to understanding why these cells are so vulnerable in HD.

• Some studies have found that there is a threshold of around 150 CAG repeats at which damage to the cell starts to speed up.

• Experimental “knockout” or genetic removal of DNA repair genes known to make mistakes on CAGs can slow down or even stop CAG repeat expansion in lab models of HD.

• Some of these genes, like Msh3, are the targets of human HD therapies in development – but we still need to understand more about how they influence HD biology, and what are the consequences (positive and negative) of knocking them out.

Setting up the experiment

The authors of a recent paper, led by X. William Yang at The University of California, Los Angeles (UCLA), took a direct and thorough approach to exploring the connection between DNA repair genes, CAG expansion, brain cell health, and even behavior.

They chose a set of nine genes identified in the human GWAS studies and which form part of the machinery that performs a certain type of DNA repair, the kind that drives the “oops” of CAG lengthening. Then they made use of specialized mouse genetics and breeding schemes to create HD mice missing one or both copies of these DNA repair genes.

In each of these HD mice, missing genes like Msh3, Pms1, Mlh1, and others, they could learn more about how messing with DNA repair might affect CAG expansion, RNA message production (the lab’s specialty), toxic huntingtin buildup, and other features of HD. They were surprised to learn that some knockouts had profound positive consequences, whilst others had no effect at all. What they learned is valuable for our understanding of HD biology and the development of therapeutics.

Reversing RNA changes

Our DNA is read or “transcribed” by specialized machinery to make RNA messages, which are eventually used to make proteins, the building blocks of life. There is a whole branch of science that explores the location and amount of RNA message made from different genes – this is the field of transcriptomics.

Scientists can define a healthy mouse “transcriptome” by looking at thousands of genes and asking which are normally turned on and off in different cells, and how much of each RNA message is present. Then they can look at how this changes in an HD mouse over time, or experiment to see what might help restore the mouse’s RNA levels to normal.

The Yang lab was working with one type of mouse that models HD that shows major changes in its transcriptome compared to regular mice. Lots of genes are producing more or less RNA than they are meant to, especially within medium spiny neurons, the cells that are most vulnerable in HD. When the Yang lab “knocked out” half of the Msh3 and Pms1 in their HD mouse model, they saw a partial reversal of the RNA changes in medium spiny neurons. With Msh3 or Pms1 fully gone, the RNA changes were almost fully reversed, often lasting up to a year (half a lifetime for a lab mouse!). Knocking out a couple of other genes – Msh2 and Mlh1 – also had some reversal effects, but these were more moderate. Some gene knockouts had no effect at all.

Members of the Yang lab are world experts in studying HD transcriptomics, and they used multiple cutting-edge laboratory techniques as well as different statistical approaches to confirm their results. They examined RNA levels across many cells, down to the level of single cells, and also looked at how tightly the DNA was wound around its “spool,” known as chromatin. In all cases, knocking out Msh3 and Pms1 seemed to reverse the HD-related changes.

Calming CAGs and clumps

In parallel, the Yang lab measured the amount of somatic instability – the lengthening of CAG repeats – in different parts of the brain and body. In this type of HD mouse, CAG repeats get longer over time, especially within the cells of the striatum. In fact, this group used statistics to define the rate at which CAGs expand in these vulnerable mouse brain cells: it’s about 8.8 CAG repeats per month. (These rates of expansion do NOT apply to humans – these mice start out with 140 repeats and are designed for experimentation.)

The exciting finding is that when the mice had less or no Msh3 or Pms1, that rate went way down. In fact, removing both copies of Msh3 slowed that rate down to 0.3 extra CAG repeats per month, all the way up to 20 months old – that’s basically a stable repeat length, in an old mouse!

At the same time, Yang and colleagues observed that HD mice with half or no Msh3 or Pms1 also had far fewer clumps of huntingtin protein in the striatum. The buildup of these clumps is a classic feature of HD that many scientists suspect could be toxic to brain cells. Removing Msh3 prevented the formation of huntingtin clumps in other areas of the brain as well. The amount of clumped-up huntingtin seemed to correspond with the amount of abnormal RNA changes they’d previously seen.

Furthermore, they were able to confirm results from other labs showing that there seems to be a threshold of CAG repeats – around 150 – above which the cell begins to experience more stress. They connected this threshold to higher levels of RNA changes: CAG expansion speeds up and worsens that stress.

Preventing brain and behavioral changes

We love math and multi-panel rainbow graphs, but it’s even cooler to see a link between genetics and behavioral health. One way in which this work represents a step forward is that the authors show how knockout of the genes that prevent CAG expansion can also have effects on brain cells and mouse movement.

This type of HD mouse tends to show changes in the connections between neurons, known as synapses, as well as enlargement of support cells called astrocytes. The mice also have problems with their gait and movement. However, when the researchers knocked out Msh3, they no longer observed any of these HD-related changes in the mice. This is even further evidence for Msh3’s role in HD, and suggests that it is a good drug target.

Note that this wasn’t a main focus of the paper – they only looked at a few features of brain health and one behavioral task – but it’s still a promising link.

Small steps power future treatments

You have likely noticed that HDBuzz has been harping on somatic instability (loudly and frequently) for a while now, and that we’ve presented lots of similar messaging: CAG repeat expansion seems to be contributing to HD, and scientists have identified some ways to combat it. This work is no exception; once again, genes like Msh3 and Pms1 are culprits that can be “knocked out” to great benefit in the brains of one type of HD mouse.

All these individual advances may appear to be small, but publications like this one represent years of collaborative work among a large team, shaped by frequent input from an international community of HD scientists. We chose to highlight this particular paper because it connects the dots between CAG expansion, abnormal RNA messages, and changes in brain health and behavior.

The authors caution that we need much more information to truly understand the link between Msh3 and Pms1 and the symptoms of HD. They also acknowledge, as we always do, that mice are not people. These mice in particular begin life with 140 CAGs in every cell of their body, which is much higher than even most cases of human juvenile HD. CAG repeats are not expanding anywhere near as quickly in humans as they do in these experimental mice.

Nevertheless, their data, along with that of other labs working tirelessly to understand HD, makes a strong argument for developing therapies based around Msh3 and Pms1. And these efforts are indeed under way!

We often think of the adult brain like a completed jigsaw puzzle—once all the pieces are in place, that’s it. If a few pieces go missing, as happens in neurodegenerative diseases like Huntington’s disease (HD), there’s not much we can do except try to slow the loss. But new research is challenging that idea in a big way. A new study has shown that it may be possible to grow new brain cells in the adult brain—and not just any cells, but the exact pieces that HD takes away. Even more amazing? These new cells can connect with the brain’s existing networks, as if finding their place in the puzzle and clicking right into place. This discovery opens the door to a bold new goal: not just slowing the loss, but rebuilding the puzzle itself.

What Gets Lost in Huntington’s Disease?

To see why this study matters, let’s start with the pieces that go missing in HD. The disease causes progressive damage to an area of the brain called the striatum. The striatum sits almost exactly in the center of the head and helps control movement, emotions, and decision-making. The specific puzzle pieces lost here are called medium spiny neurons, or MSNs.

MSNs are essential connectors in the brain’s motor circuit. They help organize and relay instructions for smooth, coordinated movement. As HD progresses, these cells die off, breaking key links in the puzzle. The result: jerky movements, trouble thinking clearly, and emotional changes.

For a long time, scientists believed that once MSNs were lost, they were gone for good. But what if the brain has more pieces in the box—just waiting for the right signals to grow and fit into place?

Making New Pieces

That’s exactly what this new study from the lab of Dr. Steve Goldman at the University of Rochester set out to test. The researchers tried something bold: encouraging the adult mouse brain to grow new neurons. Not just any neurons, but the right kind—the ones that fit the MSN-shaped holes in the HD puzzle.

They used two special proteins to create the right environment. One, called BDNF (brain-derived neurotrophic factor), acts like fertilizer for neurons, helping them grow and survive. The other, called Noggin, guides stem cells toward becoming neurons rather than other cell types.

Think of BDNF and Noggin as puzzle guides: one boosts the brain’s ability to make new pieces, and the other makes sure those pieces are shaped correctly. When these were delivered to the brains of adult mice, something remarkable happened: the brain started creating new neurons that looked and acted like MSNs.

Lighting Up the New Pieces

To track these new cells, the researchers used a clever genetic trick that made newborn neurons glow under the microscope. This let them see exactly where new pieces were forming—and whether they matched the shapes of the ones lost to HD.

In mice that received BDNF and Noggin, glowing new cells filled in the striatum. Many of them had the molecular markers scientists know are specific to MSNs. Even more encouragingly, they produced the same kinds of receptors MSNs use to communicate—essential for locking into the brain’s circuitry. It wasn’t just random growth. These were puzzle pieces that actually looked like they belonged.

Connecting the Dots

But pieces alone aren’t enough. For a puzzle to make sense, the connections between pieces matter just as much as the pieces themselves. The brain is no different. So, the next big question was: do these new MSNs actually connect with the right parts of the brain?

Using a safe, specialized version of the rabies virus (yes, really), the scientists traced incoming connections to the new neurons. They found that these newborn cells were receiving signals from all the right brain areas—the motor cortex, thalamus, and more.

Then, they flipped the direction and looked at where the new neurons were sending signals. Sure enough, they were linking up with the globus pallidus, a region of the brain that relies on MSN input to control movement. The puzzle wasn’t just getting new pieces—it was starting to fit back together.

Functional, Not Just Decorative

For the brain, even a puzzle with the right shapes won’t help if the pieces just sit there. To really matter, these new neurons had to be active and firing correctly. So the scientists used high-tech tools—like optogenetics and electrical recordings—to see if the new MSNs were actually sending signals and responding.

The answer? Yes. These weren’t passive bystanders—they were live, working parts of the brain. They could receive and send electrical signals. They acted like mature MSNs. In other words, they functioned.

This is crucial. It means the new pieces didn’t just look right and fit—they helped complete the picture.

Moving the Needle on Symptoms

The final and most important test: could these new neurons make a difference in how the mice moved?

The researchers used a technique called chemogenetics to selectively activate the newborn MSNs. When they did, the mice that model HD—who typically move very little—became more active. Turning on these cells improved movement.

That’s a big deal. It’s like putting a few critical pieces back into a jigsaw puzzle and suddenly seeing the image take shape again. The effect wasn’t just cosmetic; it made a real difference in behavior.

A Piece to Remember

While this work is incredibly exciting for HD families, it’s important to remember that these new cells have the same genetic makeup as the rest of the cells in the brain. So for someone with the gene for HD, that means the new cells will also have the gene for HD. Which means they’ll likely start to show signs and symptoms of the disease eventually too.

The good news is that the newly created MSNs would be developmentally “younger” than the MSNs initially created during brain development. Since HD has a delayed effect, we could expect that the same might be true in the new MSNs. In people, that delayed onset could provide the sort of time to improve health span and extend lifespan.

The less good news is that this means that this type of approach would very likely require multiple treatment rounds to compensate for the continued loss of the new brain cells. But, from where we stand right now, that would be a welcome problem!

Another positive piece of news to keep in mind is that these studies were done in adult mice using a pretty severe HD mouse model. This shows that even in more advanced cases, the right cell population may still be around and able to respond to treatment by BDNF and Noggin. While mice aren’t a one-to-one comparison for people, that’s great news!

What It Means for HD Families

This study doesn’t offer a treatment—not yet. But it completely reimagines what might be possible. For decades, scientists have worked to slow or stop the loss of brain cells in HD. Now, they’re asking: what if we could replace them?

The idea that the adult brain can grow new, functional MSNs—and integrate them into circuits that matter—is a seismic shift. It gives researchers a new strategy. And for people and families affected by HD, it offers something else: hope.

The puzzle isn’t finished. Pieces are still missing. But now we may have found a way to craft new ones—and click them into place. As always, we’ll be following this story closely at HDBuzz, keeping you updated as the picture comes more clearly into view.

Imagine battling a disease that not only affects your body but also causes your mind to lose touch with reality, making it hard to see the world as it really is. This is the heartbreaking reality for many people living with Huntington’s disease (HD) who also experience symptoms of psychosis. Professor Clement Loy and his inspiring team of researchers from the University of Sydney investigated how psychosis symptoms in HD may affect the lives of these people.

Breaking the Silence

HD can cause symptoms across three main areas: mood, mind, and movement. For some people with HD, one of these areas may be more impacted than the others. What’s important to remember is that each person with HD has their own unique journey, much like how every star in the sky is unique. Symptoms and progression can vary from one person to the next.

For some people with HD, mood and mind symptoms can be more intense, and this can sometimes lead to a set of symptoms known as psychosis. A person struggling with psychosis symptoms may experience hearing voices that aren’t there, having hallucinations, believing things that aren’t true, or feeling confused about what is real and what is not.

This can add an extra layer of difficulties for someone who is already struggling with other symptoms associated with HD. Psychosis can be a sensitive topic for some, but by opening up discussions around psychosis, it is hoped that the topic will become more widely understood and talked about.

Shining a Light

An important study by Professor Loy and his team investigated how psychosis symptoms may impact daily life and the progression of HD. They aimed to better understand the challenges faced by people with HD, who also suffer from psychosis symptoms. Beyond the mental toll, the researchers concluded that psychosis appears to have an impact on particular movement symptoms in HD.

The researchers gathered information from people who tested positive for the gene that causes HD – both individuals displaying movement symptoms, as well as individuals who were not yet displaying any movement symptoms.

Over 1,000 participants were invited to complete questionnaires and assessments to measure mood, mind, and movement symptoms, every year, for 5 years.

• Movement symptoms were measured by participants performing different motor tasks, such as walking in a straight line.
• Mind symptoms were measured through an interview with a researcher. This involved remembering and repeating words and following simple instructions.
• Mood symptoms were assessed through a questionnaire. Questions focussed on assessing mental health and behaviour in participants. For example, do they feel sad, nervous, or frustrated?

Different Stars, Different Paths

Around 1 in 6 people with HD, about 18%, in this study experienced psychosis symptoms at some point during their lives. In those people, the researchers found that they had less independence and ability to carry out day-to-day tasks, reduced cognitive ability, and increased behavioural symptoms. This is perhaps unsurprising given the intense effect that psychosis can have on a person’s ability to function, think, and behave.

One of the more surprising findings in this research was that people with HD who experienced psychosis symptoms appeared to experience less uncontrollable jerky movements or uncontrolled twitching. These very common movement symptoms – known as chorea – are often seen in people with HD.

To make sure there weren’t external factors contributing to reduced chorea, the scientists adjusted for the use of some medications, like antipsychotics and tetrabenazine, that can affect movement symptoms associated with HD. However, the authors acknowledge that a limitation of this study is the lack of detail around dose and duration of the use of these types of medications. Even still, this finding highlights how some people with HD will experience very different levels of mood, mind, and movement symptoms. This enlightening research by Professor Loy and his team, reflects back to how unique each person with HD is.

This research has raised interesting questions: Could those who experience psychosis symptoms in HD have different brain chemistry or genetics compared to those who do not experience psychosis symptoms? This is because those with psychosis symptoms did not seem to follow a similar pattern for movement symptoms, compared to those who do not experience these symptoms. Although this study did not provide definitive answers, it does support the idea that HD does not follow a ‘one-size-fits-all’ approach.

Guiding the Way

For individuals and families affected by HD, the presence of psychosis symptoms can be particularly distressing. Caregivers may struggle to understand the sudden paranoid thoughts or when their loved-one is hearing or seeing things that aren’t really there. The person with HD, who is also experiencing psychosis, may feel confused, frightened, or defensive when their reality does not align with others.

If you are a person with HD or if you are a caregiver for someone with HD and relate to some of the psychosis symptoms discussed in this article, you are not alone. There are a number of coping strategies that you can try to help to manage these symptoms better, which could improve quality of life.

Potential Coping Strategies for Psychosis Symptoms

• Medication Management: Antipsychotic medications may help, though their use must be carefully balanced as they can sometimes worsen movement symptoms. If you want to explore the use of antipsychotic medication, please consult a medical professional, such as your psychiatrist.
• Psychological Support: Therapy can help both people with HD and caregivers in managing distressing symptoms.
• Routine and Structure: Providing a predictable, supportive environment may help ease feelings of agitation and confusion for people with HD.
• Open Conversations: Recognising and discussing symptoms without judgment can help increase understanding and reduce stigma of psychosis symptoms.

Shattering Stigma

Psychosis, particularly when linked to a condition such as HD, remains a difficult topic to discuss. There is often fear and misunderstanding surrounding psychosis symptoms. However, studies like this remind us that mental health is just as important as physical health in HD care. By talking openly and honestly about psychosis symptoms, we empower people with HD, their loved-ones, and medical professionals to provide better support and reduce misconceptions.

HD effects both body and mind in deeply intertwined ways. As research continues to unravel the mysteries of HD, understanding the mood and mind aspects, including psychosis, will be key to providing compassionate and effective care. For people navigating the journey of HD, one message remains clear: you are not alone, and your experiences, both physical and emotional, are valid and worthy of support.

Remember, each person living with HD shines in their own unique way, like a star in the sky, adding their light to the world in ways only they can. As we continue to learn and grow together, let this article be a source of strength, compassion, and hope, illuminating the path for others facing similar challenges.