We received an update on June 2, 2025 from uniQure about their recent discussions with the US Food and Drug Administration (FDA) regarding the development of AMT-130 – a treatment they’re testing for Huntington’s disease (HD). uniQure announced that they remain aligned with the FDA and have received guidance on next steps, including plans for manufacturing, statistics, and a comparison control group. So what exactly did we learn from this recent update? Let’s get into it!

Laying the Tracks

We’ve been following the development of uniQure’s HTT-lowering drug, AMT-130, from its genesis in the lab, to animal studies just a few years ago, and now through to their ongoing Phase 1/2 clinical trials. 

We’ve also written about it quite a bit. To save our regular readers from repetition, we’ll link any HDBuzz newbies to previous news we’ve covered:

• Promising results from animal models, covered in April, 2021
• The announcement of the clinical trial, covered in July, 2021
• 12 month safety data, covered in July, 2022
• A short pause in the trial, covered in August, 2022
• The trial resumes, covered in November, 2022
• A promising safety profile, covered in December, 2023
• AMT-130’s potential to slow clinical progression, covered in July, 2024
• Previous alignment with the FDA, covered in December, 2024

FDA Meetings

On June 2nd, CEO Matt Kapusta shared that uniQure had two milestone meetings, called Type B meetings, with the FDA. These are formal meetings between the regulatory agency and drug companies to discuss development and advancement of a medicine. Any face-to-face meeting with the FDA is a good opportunity for a drug company, because it helps to ensure that they’re moving in a direction that the agency supports. 

During these meetings, uniQure aligned with the FDA on a plan for submitting a Biologics Licensing Application (BLA). This is the formal application a drug company puts together to request permission to market a biologic, a type of therapy derived from living organisms, such as proteins, cells, or genetic material. Unlike traditional small-molecule drugs, biologics are typically larger and more complex, and include treatments like antibodies and gene therapies. UniQure’s Chief Medical Officer, Dr. Walid Abi-Saab, shared that the FDA agreed that data collected from their ongoing trials could be used to support a future BLA. In other words, uniQure may not need to run another trial before seeking accelerated approval for AMT-130. 

The most exciting part? UniQure shared that their hope is to submit this BLA for accelerated approval during the first quarter of next year – as soon as the end of March, 2026. BUT, that doesn’t mean this is a done deal. The upcoming data, anticipated by the end of September 2025, still has to show that the drug is having the expected effect, or else the FDA won’t approve the BLA. 

For serious conditions like HD, which carry a tremendous burden with limited treatment options, regulators may greenlight earlier access to drugs that show potential.

Approval Paths

As HD drugs advance through the clinic, we’ve been hearing hopeful news about “accelerated approval.” But what exactly does that mean, and how does it differ from traditional approval?

First, the easy one – traditional approval. This means that a drug has undergone rigorous testing, is safe and well tolerated, and has improved symptoms or delayed worsening of a disease. Drugs that gain traditional approval have lots and lots of data to support their use, and they are very unlikely to be pulled from the market.  

With accelerated approval, a regulatory agency allows a drug to be made available to the general population while the drug is still being tested. There isn’t enough data yet to conclusively say that it’s having the desired effect. However, for serious conditions like HD, which carry a tremendous burden with limited treatment options, regulators may greenlight earlier access to drugs that show potential. 

The idea is that the accelerated approval path could help people in need access drugs sooner, in hopes that they will work. But drugs made available through accelerated approval could still be pulled from the market if additional testing suggests that they don’t actually benefit patients. While no one wants to take drugs that don’t work, many people accept the risk of taking drugs that might work, which is why uniQure is exploring the accelerated approval path. 

Regulatory milestones

To make sure that uniQure and the FDA are aligned on steps towards a speedy (possible) approval of AMT-130, they talked about a few key points: 

Manufacturing

Thinking ahead, the FDA wants to know if uniQure is capable of manufacturing  AMT-130 at scale for people with HD, should the data continue to look good. UniQure shared that the FDA agrees they have the manufacturing capabilities and has endorsed their production platform. This streamlines uniQure’s path toward commercial readiness and  a future BLA submission. 

Statistical Plan

During the meeting, the FDA and uniQure also talked about the type of data they want to see and how those data should be analyzed. Previously, the FDA agreed that positive data for the composite Unified Huntington’s Disease Rating Scale, or cUHDRS, could be used to decide whether the drug is working. They also discussed a  biomarker called NfL, which increases as HD progresses. They agreed that if AMT-130 reduces NfL, it could be  taken as a positive sign that the treatment is working.

This is exciting news because it sets the bar for what needs to be achieved to have the FDA approve a drug for HD. UniQure’s announcement confirmed that the FDA is still in support of using these metrics to help decide whether an HD drug is working. 

They’ve also agreed on exactly what types of statistical tests should be used to analyze the data. It’s great to know that the FDA and uniQure are aligned on the nitty gritty, but we’ll spare you those mathematical details here! 

Control Group 

Another important point the agency agreed on was which dataset uniQure should use to compare their trial results. While the first cohort included people who received a mock surgery, the ongoing AMT-130 studies don’t include a traditional placebo group of participants who did not receive the drug. Since this a long-term study being conducted over several years, it was instead designed to compare people receiving AMT-130 to participants in a natural history study. 

In a natural history study, no drug is given. It’s designed to follow people who have the gene for HD and to observe them as they naturally live and age to see how HD progresses. These types of studies give us a wealth of information.

UniQure were previously comparing AMT-130 recipients to those who participated in the TRACK-HD, TrackOn-HD, and PREDICT-HD studies. They’re now also incorporating data from Enroll-HD – the world’s largest observational study for HD families. The Enroll-HD dataset will be used for the primary analysis, and data from TRACK-HD and TrackOn-HD will be used for additional analysis. 

This change was made because the Enroll-HD dataset is significantly larger, at almost 33,000 people enrolled (wow!), many of whom fall into the inclusion criteria for the AMT-130 trials. This gives a better comparator when looking at the data and increases the chances of seeing a stronger effect of AMT-130.

They’ll be presenting this data publicly during the third quarter, so we should have a much better idea of AMT-130’s 3-year effectiveness by the end of September, 2025. After that, they plan to meet again with the FDA in the fourth quarter of 2025, to prepare for submitting their BLA in the first quarter of 2026.

The Track Ahead

On the June 2nd investor call, uniQure gave us a date for when they would stop collecting data to send over to the FDA – June 30. That cutoff will include data from people who were given AMT-130 3 years ago, so it’s quite a long-term follow up. 

They also shared that they’ll be presenting this data publicly during the third quarter, so we should have a much better idea of AMT-130’s 3-year effectiveness by the end of September, 2025. After that, they plan to meet again with the FDA in the fourth quarter of 2025, to prepare for submitting their BLA in the first quarter of 2026. At that meeting, uniQure will request that the FDA make their review a priority.

To continue laying the track to reach an HD gene therapy, the data must continue to be positive. In the meantime, we’ll be standing on the platform, waiting to let you know when the whistle blows!

TL;DR Summary

• A recent meeting between the FDA and uniQure continues to show alignment
• cUHDRS and NfL lowering continue to be agreed upon metrics for success
• UniQure got a green light from the FDA on their manufacturing platform
• Statistical plans for data analysis were discussed and agreed upon
• Enroll-HD will be used as the natural history control group for primary analysis
• Next data update – Q3 2025, which will include 3 year follow up data
• Q4 2025 meeting with the FDA to discuss accelerated approval
• Plan to submit Biologics Licensing Application for accelerated approval in Q1 2026

Learn More

UniQure’s June 2, 2025 webcast.

UniQure’s June 2, 2025 press release.

We’re pleased to announce the 2025 HDBuzz Prize! This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition. Training the next generation of passionate Huntington’s disease (HD) researchers is directly in line with the HDF’s mission. The HDF understands the importance of having future key opinion leaders that can communicate their work to the global HD community in easy-to-understand language. They aim to ensure that we continue to have an abundant pipeline of talented researchers focused on HD – something we can all agree is critical for advancing HD research!

What Is The HDBuzz Prize?

The HDBuzz prize is an opportunity for early-career HD researchers to get involved in communicating HD science to the global community, see their work published and shared through our online channels, and win US $200 – woohoo for you! 

The prize was designed to diversify the voices that bring you content on HDBuzz. Not every researcher interprets data the same, so having multiple viewpoints represented here helps ensure that our readers are getting HD news content that spans the varied perspectives of the HD field.

Calling All HD Scientists

We’re looking for young scientists with a gift for communicating research news clearly and imaginatively.

The HDBuzz prize is open to anyone with an active involvement in any aspect of Huntington’s disease research. We’re particularly keen on the fresh take that PhD students and postdocs provide and are actively seeking researchers with clinical experience. So if that’s you, hit us up!

Full articles will include a piece of around 1,000 words, suitable for publication by HDBuzz, about a recent HD research paper that we haven’t covered yet.

In addition to the article, full article submissions will contain:

• a catchy title
• a front-page summary of no more than 100 words
• a social media post of no more than 250 characters, including spaces
• two in-text image suggestions and a cover photo suggestion
• at least one reference to a peer-reviewed article forming the subject of the piece

The HDBuzz prize is an opportunity for early-career HD researchers to get involved in communicating HD science to the global community, see their work published and shared through our online channels, and win US $200 – woohoo for you!

How To Apply

Entrants should submit a short pitch, of ~200 words detailing what they wanted to write about and why they thought it was important for HD families to know about, all in HDBuzz-style language. We will review all of the article pitches to screen ideas and writing styles before inviting full articles to be written. Our goal is to save everyone time! We want HD researchers to be able to spend as much time working on their science.

The closing date for entries for the article pitches is Tuesday 1st July at 5pm Eastern Standard Time.

All entries must be written in English. We regret that entries in other languages will not be considered.

Prizes!

The pitch winners will be announced throughout the Fall (or autumn, if you’re feeling fancy – or just British to be honest) of 2025.

Winning articles will be published on HDBuzz, translated into various languages, and syndicated to dozens of HD community sites worldwide.

Winners will also receive US $200!

Public engagement is important for every scientist’s training, so apart from the cash, this would enhance the CV of any eager young HD researcher.

Tips For Successful Writing

1. Take a look at several HDBuzz articles before you start, to get a good feel for our tone and style.
2. If in doubt, simplify.
3. Assume that your reader is interested in HD and willing to learn, but has no formal scientific training.
4. Explain anything beyond high-school science, in bite-sized steps. Then go back and explain the high-school science.
5. Apply metaphor, analogy, humor, and silliness generously.
6. Remember to explore the limitations of what you’re writing about and try to explain what needs to happen next for it to bring HD treatments closer.
7. Avoid pictures that contain text for full article submissions, as this causes translation problems.
8. Avoid studies we’ve already covered, publications with which you’re affiliated, and any pre-print articles.

The Fine Print

The editors’ decision is final and correspondence will not be entered into. By submitting an entry, you are agreeing to allow editing of your article for style and content, and its publication via HDBuzz.net and release under the Creative Commons Attribution-ShareAlike 3.0 Unported License including translation and unlimited syndication. Winners agree to be named at HDBuzz.net. All entries will be scrutinized for plagiarism and disqualified if it is found. 

Public engagement is important for every scientist’s training, so apart from the cash, this would enhance the CV of any eager young HD researcher.

Help Us Spread The Word!

Whether you’re a Principal Investigator (that’s ‘head honcho’ in laboratory-speak) or an HD family member, chances are you know a young scientist with a neat turn of phrase and a gift for communication.

If so, please put them in touch with us or send them to this article, so they can think about entering the prize.

So, fellow science nerds – get in touch and get cracking!

May was a month packed with exciting research, and we’ve got the highlights ready for you – no lab coat required! From genetic mysteries to vision changes and dental awareness, researchers uncovered some fascinating stuff about Huntington’s disease (HD) this month. And we heard an exciting clinical trial update from PTC Therapeutics. Buckle up for an abbreviated tour through the latest discoveries that are helping us learn more about HD and getting us closer to a treatment. 

Assembly Line Breakdown: Protein Production Problems in Huntington’s Disease

New research put a spotlight on the world of protein production – and how things go a bit haywire in HD. A new study revealed that the mutant huntingtin protein doesn’t just misbehave on its own – it also messes with the cell’s entire protein-making factory. 

Imagine a broken part clogging up the assembly line, causing chaos everywhere! In HD, even a little bit of this rogue protein can throw off the cell’s finely tuned quality control systems. The researchers also uncovered a tiny control switch in the HTT gene that might crank up the dysfunction even further. The big idea? Instead of just focusing on the toxic proteins themselves, maybe we can fix the machines they’re jamming up.

What’s Good for Your Heart is Good for Your Brain: New Study Links Cardiovascular Health to Brain Aging

There seems to be a connection between heart health and brain health. A new study revealed that following the American Heart Association’s “Life’s Simple 7” guidelines – like eating well, exercising, and managing blood pressure – not only benefits your heart but also tracks with lower levels of neurofilament light (NfL), a protein that tracks with brain health, can indicate brain cell damage and has become an important biomarker in HD research. 

Specifically, participants with better cardiovascular health had significantly lower NfL levels, suggesting less neuronal damage. Over a decade, those with high heart health scores experienced a slower increase in NfL levels compared to those with lower scores. While the study didn’t find a similar connection with another biomarker, total tau , the findings underscore the potential of heart-healthy habits in protecting brain health, especially for those at risk of neurodegenerative diseases like Huntington’s.

Excitement and Anticipation as PTC’s Huntington’s Disease Drug Clears a Major Hurdle to Sprint Home

Perhaps the most exciting update from the month was the buzz-worthy news from the world of HD clinical trials! PTC Therapeutics’ daily pill, votoplam (formerly PTC-518), showed promising results in the Phase 2 PIVOT-HD clinical trial. The trial met its primary goal by effectively lowering levels of the huntingtin protein, a key strategy being explored in the clinic to treat HD. Importantly, votoplam demonstrated a favorable safety profile, with no serious adverse events reported. 

Additionally (and certainly most excitingly!), early data suggest potential benefits in slowing disease progression, particularly in individuals with Stage 2 HD, as measured by some biomarkers and clinical assessments. While further analysis is needed, these findings advance hope for a new, convenient potential treatment option for the HD community.

The next steps here are for PTC to dig into the data more, then go over it with their new partner, Novartis. It’s not clear yet if they’ll use data they already have to seek accelerated approval from regulatory agencies or dive into a larger Phase 3 trial for votoplam. We’ll be watching closely and keep you updated as we learn more!

From genetic mysteries to vision changes and dental awareness, researchers uncovered some fascinating stuff about Huntington’s disease (HD) this month.

Navigating the Genetic River: How Tiny Variants Could Shift the Course of Huntington’s Disease

New work this month took us on a journey down the genetic river of the HD gene. Researchers discovered that tiny changes – like missing or duplicated genetic “dams” in the DNA sequence – can dramatically alter the river’s flow, potentially shifting the onset of HD symptoms by over a decade. These rare variations, known as Loss of Interruption (LOI) variants, affect the stability of the CAG and CCG repeat regions in the HTT gene. 

While these genetic quirks are uncommon, they offer valuable insights into why some individuals develop HD earlier than expected, especially those in the diagnostic “gray zone” with intermediate repeat lengths between 27 and 29 CAGs. This research underscores the complexity of HD genetics and highlights the importance of understanding these subtle variations as we navigate toward more precise diagnostics and treatments.

Red Light, Green Light: How Huntington’s Disease Influences Genetic Traffic Lights

This month we took us on a ride through the genetic intersections of HD, revealing how the disease throws the cellular traffic system into chaos. Normally, our genes are regulated by epigenetic “traffic lights” – chemical signals that tell genes when to stop (red) or go (green). 

In HD, these signals malfunction, causing some genes, especially those involved in early brain development, to get stuck on green when they should be red. This misregulation leads to neurons acting like they’re in a perpetual developmental phase, potentially accelerating brain aging and dysfunction. 

The usual molecular “traffic cops,” PRC1 and PRC2, which are supposed to help maintain order, seem to be overwhelmed or replaced by less effective versions, making the problem worse. Understanding this epigenetic traffic jam opens new avenues for potential therapies aimed at restoring proper gene regulation and slowing disease progression.

Unlocking the Mind’s Eye: How Huntington’s Disease Changes How We See and Process the World

Another study zoomed in on something we often take for granted: how our brains make sense of what we see. For people with HD, recognizing faces, reading a book, or even navigating a grocery store can get surprisingly tricky. Researchers in Spain ran a bunch of clever visual thinking tests, like drawing shapes from memory, to find out when and how these challenges pop up. 

The plot twist? Subtle changes in visual memory might show up even before classic HD symptoms appear. This offers a chance for earlier diagnosis and better planning. Because it’s not just about what the eyes see, but how the brain interprets it. Spotting these shifts early could encourage people to use helpful visual reminders that could make a big difference in daily life.

DNA Repair in Huntington’s Disease: Not Up to Par?

More and more evidence is showing that HD influences DNA repair. A new study from Dr. Ray Truant’s team shows that expanded HTT slows production of a key DNA repair molecule called PAR, which usually flags damaged DNA. Without enough PAR, HD cells let damage pile up, possibly fueling the expansion of those nefarious CAG repeats that drive the disease.

The good news? Fixing the fixer might help. Getting HD cells up to par – by increasing PAR – could give cells the repair boost they need to fight back against disease progression. It’s early days, but this glitch in the repair crew might just point to a new way to keep Huntington’s in check.

Perhaps the most exciting update from the month was the buzz-worthy news from the world of HD clinical trials! PTC Therapeutics’ daily pill, votoplam (formerly PTC-518), showed promising results in the Phase 2 PIVOT-HD clinical trial.

Mind Your Mouth: Huntington’s Disease and Oral Health

HD can wreak havoc on oral health. A recent review reveals that people with HD face many dental challenges: movement issues make brushing a chore, dietary changes favor cavity-causing foods, and many dentists are unprepared for the unique needs of HD patients. Add in anxiety, financial strain, and mobility hurdles, and it’s no wonder dental care often gets sidelined. 

But there’s hope! The article emphasizes that with the right knowledge and preparation, dental professionals can make a significant difference. By understanding HD’s impact and adapting care strategies, they can help patients maintain healthier smiles and improve their quality of life. The fact that this review was published is evidence that the word about HD is spreading amongst the dental community. So, let’s give a shout-out to those dentists ready to tackle HD’s dental dilemmas head-on – because everyone deserves a reason to smile.

Seeking dental care and adhering to recommended routines is tough for lots of folks, even under the best of circumstances. Throw Huntington’s disease (HD) into the mix, and oral health can get even tougher. A recently published review paper in the journal Special Care in Dentistry covers some of the challenges faced by HD families with keeping our chompers healthy. It also discusses research into oral health in HD, and recommends strategies for dental professionals caring for people with HD. When specialists care enough to prepare and publish a formal article about improving quality of life through oral health for people with HD, we think that’s worth mouthing off about!  

Barriers to Dental Care 

The authors of this paper, Dr. Hanad Duble and Dr. Aviv Ouanounou, describe HD for their readers (dentists) who are unfamiliar with the disease, and outline common barriers to accessing dental care for people with HD. Some of these may seem obvious to the HDBuzz readers – those who are affected by HD, live with someone who is symptomatic, or are tuned into HD research. Here are some of the main barriers the authors identify: 

• Fear: A lot of folks dread the dentist, and that anxiety can be exacerbated for people with HD. Shame and stigma can compound this as well. 
• Finances: HD can create a financial strain for many reasons, including job loss and accompanying lack of insurance, and it can be hard to financially prioritize dental care.
• Mobility and motivation: Behavioral symptoms and movement challenges can make it difficult to get to a dental office, keep appointments, or maintain a routine at home.
• Oral changes: Involuntary movement (chorea), stiffness, or muscle weakness make it more challenging for dentists to examine, clean, and operate on the mouth. 
• Lack of training: Many dental professionals don’t have experience working with people with HD (this article is a step towards providing guidelines!)

There may be other barriers to proper oral care for individuals from HD families – no one experiences HD in the same way. The vast majority of dentists are unlikely to see more than a few HD patients over a lifetime of practice, so it’s encouraging when knowledgeable professionals write about the challenges of HD for their peers. 

Seeking dental care and adhering to recommended routines is tough for lots of folks, even under the best of circumstances. Throw Huntington’s disease (HD) into the mix, and oral health can get even tougher.

Common Oral Health Challenges

The authors also lay out common oral challenges for people with HD and how they affect dental care. They drew from their own practice as well as from the scientific literature, including clinical studies, case reports, and past reviews. It’s a lot to sink your teeth into, but important to know what might arise as symptoms progress. 

Cavities (caries) and gum disease: 

• Chorea: movements of the body, face, and tongue can make it more difficult for a person with HD or their companion to brush and floss, and dentists may have trouble using specialized tools or finding safe and comfortable positions. 
• Diet: a person’s eating habits might change to accommodate chorea, difficulty with chewing and swallowing, or weight loss. Softer foods, liquids, higher frequency of meals, and foods with more sugar and carbs can affect tooth and mouth health.
• Dysphagia: the medical term for difficulty swallowing, which is very common in HD. This can mean that more food gets stuck in the teeth, mouth, and throat.
• Mood and motivation: symptoms like apathy and depression can make it more difficult to prioritize oral care at home or make dental appointments.

Medication challenges 

• Side effects: some of the drugs used to manage HD symptoms, like antidepressants and mood stabilizers, can cause dry mouth, drooling, or increase the risk of mouth infections. Other medications can cause increased likelihood of fainting or dizziness, which is important for a dentist or hygienist to be aware of when using a reclining chair or choosing anesthetics. 
• Drug-drug interactions: some medications prescribed to treat dental pain, anxiety, and infections can interact negatively with common treatments for HD.
• Anesthesia: general anesthesia can lead to complications, especially with chronic disease, so specialists may choose sedation over “putting someone under.” 

Dysarthria (difficulty speaking) 

• Home care and appointments: also known as dysarthria, when someone has a hard time communicating, it can be difficult to let a loved one or dentist know what is causing them pain or discomfort on a daily basis or during an appointment.
• Placement of devices or prosthetics: muscle weakness in the face and tongue that causes difficulty with speech can also make it difficult to keep safety devices or prosthetics (false teeth) in place. 
• Consent: some people might want to request or deny aspects of routine care or invasive procedures, and communication challenges can make these discussions slower or impossible. 

Strategies for dental care

This paper provides recommendations for dentists who are treating people with HD, based on a thorough understanding of published evidence, as well as the authors’ years of collective experience in this field. It may be helpful for families to “brush up” on what special precautions, procedures, and work-arounds are available.  

• Compassion and presence (duh!): the authors urge dentists not to discriminate against HD patients, and they note that a good rapport, emotional support, and care partner involvement can be especially helpful to ease anxiety and motivate a routine.

• Planning for dental care: making a longer-term plan for dental care early on can be helpful to discuss concerns and wishes around diet, role of a care partner, and how to approach daily care or procedures when communication becomes more difficult. 

• Extra prevention:
  • The paper recommends that dentists assign an oral hygiene plan and emphasize caregiver involvement and education. 
  • Dentists might consider fluoride or varnish treatments for adults, though they are normally given to kids. 
  • Consuming products with xylitol (a sugar substitute in some types of candy, mouthwash, and toothpaste) can be good for teeth
  • Mouthguards can relieve grinding pressure due to chorea. 
  • More frequent visits (every 3 or 6 months) if possible may help to keep teeth healthier and adjust care plans as needed. 

• Comfort and safety:
  • If a person is taking medications that cause a sudden drop in blood pressure when sitting or standing, the authors recommend avoiding reclining the dental chair past 45 degrees, and not sitting them up too fast.
  • Pain control: choosing acetaminophen (paracetamol) over ibuprofen is safer for those taking SSRIs.
  • Dentists can consider using medications that keep the patient awake but relaxed to minimize pain or control chorea for long appointments or procedures. 
  • Dental offices might have (or may be able to order) special chairs, restraints, biting devices, or pillows that help to keep someone comfortable and stable and their mouth positioned safely during an exam, cleaning, or procedure.

• Less invasive care:
  • Brushing/flossing alternatives exist to make care easier, like water flossers, floss picks, or different types of brushes. 
  • Preventing damage: if someone with HD has many small cavities that might require a lot of fillings, the authors recommend that dentists consider painting teeth with Silver Diamine Fluoride, which can kill bacteria and stop existing cavities from worsening. 
  • Filling material: there are different substances that dentists use to fill cavities. One recommendation in this paper for treating people with HD is the use of a filling made of Glass Ionomer (GI). This is often used on baby teeth, or as a temporary solution in adults. It doesn’t last many decades the way a metal or composite filling can, but it is easier to apply and releases fluoride. 

Extra care and planning early on can help delay the need for tough conversations and complex procedures later.

Lots to chew on

First and foremost, the existence of this publication is encouraging. It’s a new reference that consolidates information and practical advice, with the goal of helping professionals better understand HD-specialized dentistry. However, we are not presenting medical advice! Please consult with your own dentist before embarking on any new oral health regimen. The more info they have about other aspects of your health and medical history, the better individualized care they can provide. 

That said, the authors of this paper stress prevention and early communication. Extra care and planning early on can help delay the need for tough conversations and complex procedures later. They recommend that dentists caring for people with HD consult with each patient’s neurologist, understand the side effects of common HD medications, and provide comfort measures and plans tailored to the individual. You may be able to help jump-start those important conversations and connections.  

Above all, we encourage each member of every HD family to take care of their pearly whites and to advocate for their needs – healthier mouths make for louder voices!

Learn More

Original research article, “Huntington’s Disease and Dentistry: A Review of Its Etiology, Clinical Presentation, Symptomatic Pharmacotherapy, and Dental Management” (open access).

Scientists are working to understand some of the earliest changes to DNA repair caused by Huntington’s disease (HD) – insights that could help uncover new therapeutics and new ways to target somatic expansion, a key driver of disease progression. A molecule that helps fix DNA damage – called PAR – is lower than expected in people with the HD gene. This suggests that cells may struggle to properly repair their DNA  from the natural wear-and-tear damage that happens everyday to DNA. These findings could have implications for changes in the DNA repair process that drives somatic instability. The discovery could help researchers explore new ways to protect brain cells by boosting the cell’s natural repair systems.

Genetic Mutations and Repairs

The term genetic mutation gets thrown around quite a bit, but what does it actually mean? In short, a genetic mutation is any change to the letters of DNA – the cell’s instruction manual for building proteins. These changes can alter how the genetic code is read and used by cells, sometimes disrupting the function of proteins, the cell’s molecular machines. One striking example are mutations in the HTT gene, which significantly disrupts the activity of its coded protein, leading to HD. 

While the mutation that causes HD is inherited at birth, our cells also collect new mutations as we age. The consequence of these random age-related mutations is difficult to predict, but generally speaking, they contribute to age-related diseases like cancer and neurodegeneration. Fortunately, these age-related mutations are normal and are mostly repaired and fixed before they cause problems. 

But unfortunately, this process is not working right in HD. Previous studies have noticed that cells from people with the gene for HD tend to build up more mutations over their lives, likely a result of faulty DNA repair machinery. Faults with the DNA repair machinery lead to somatic expansion, a biological process that increases the CAG repeat length in the HTT gene in some cells over time. A new study led by Dr. Ray Truant and his team at McMaster University investigated how the HD mutation disrupts DNA repair and identified a prime suspect: defective PARylation. 

A Broken Spell Checker

Cells are equipped with sophisticated systems to fix DNA damage, and one key pathway is PARylation. PARylation involves building long chains of a molecule called PAR (Poly-ADP-Ribose) on regions of damaged DNA. These long chains act like molecular handles for DNA repair enzymes to latch onto and begin fixing the DNA. In this way, PAR chains are like the red squiggly lines in a Word document highlighting spelling errors. However, like a broken spell checker, HD cells are missing many of these red squiggly lines despite having more mutations. 

To investigate, Truant’s team first analyzed the amount of PAR chains in the spinal fluid, a substance that bathes the brain, from people with HD. Because PAR chains are produced in response to DNA damage, and people with HD have higher levels of DNA damage, they expected to find more PAR chains. 

However, what they found surprised them – people with HD had fewer PAR chains. This paradox was then examined using cells from people with HD, which did not show elevated levels of PAR chains despite having elevated levels of DNA damage. These results suggest that the machinery for building PAR chains, and thus repairing DNA, may not be able to keep up with demand!

PAR chains are like the red squiggly lines in a Word document highlighting spelling errors. However, like a broken spell checker, HD cells are missing many of these red squiggly lines despite having more mutations.

Not On PAR

Why might there be fewer PAR chains in HD cells despite having more DNA damage? To figure out why, the researchers needed to examine the underlying protein machinery. PARylation relies on two key enzymes: PARP, which builds PAR chains to initiate DNA repair, and PARG, which cuts them up once repairs are complete. 

So the researchers asked, is PARG overactive? Or is PARP underperforming? After some careful biochemistry, they found the latter seems to be true – PARP activity seemed to be reduced in HD cells, explaining the shortage of PAR chains and perhaps the increased rates of mutation. 

The team then turned their attention to HTT. Since the HTT protein acts as a scaffold, binding to lots of other proteins, they wondered if the mutated version that causes HD might interfere with HTT interacting with PARylated proteins. Because PAR chains also form on proteins in addition to DNA, they compared the proteins that HTT is known to interact with to the proteins known to be PARylated. They found that nearly half of the proteins that HTT interacts with are also PARylated.

This raises the suspicion that HTT itself could be modified by PAR. If it is, and this process is altered by mutant HTT, it might explain the differences in the PAR chains they saw in HD cells. 

HTT and PAR Chains

To test if HTT interacts with PAR chains, the team used a high-tech microscope to track where HTT and PAR chains are found in living cells. Although PAR chains and HTT did not overlap most of the time, they did overlap on chromosomes when cells divide. 

Additionally, when they turned off PAR chain production by blocking PARP activity, HTT no longer overlapped, suggesting that PAR chains might be guiding HTT to chromosomes during cell division. Although the importance of HTT and PAR chains overlapping during cell division was not investigated further, it does suggest there could be a functional interaction between them! 

To strengthen their case, the researchers used a couple more techniques to confirm the interaction between HTT and PAR chains. First, they looked closely at the molecular structure of the HTT protein and found many slots that looked like they could fit a PAR chain. Then, using a high-resolution microscope, they directly visualized the PAR chains produced by PARP with and without HTT present. They noticed PARP produced far more elaborate PAR chains when HTT was around, suggesting that HTT was stimulating PARP activity. Importantly, mutant forms of HTT did not have any stimulating effect on PARP activity, possibly explaining the reduced production of PAR chains in people with HD. 

In cells without the HD gene, HTT stimulates PARylation and promotes efficient DNA repair. However, in HD, the mutant HTT protein fails to stimulate PARP, leading to fewer PAR chains, impaired DNA repair, and an accumulation of mutations that could participate in neurodegeneration.

Implications for HD and Beyond

These findings paint a clear picture: in cells without the HD gene, HTT stimulates PARylation and promotes efficient DNA repair. However, in HD, the mutant HTT protein fails to stimulate PARP, leading to fewer PAR chains, impaired DNA repair, and an accumulation of mutations that could participate in neurodegeneration. 

These findings are exciting because they help researchers better understand the underlying defects in HD cells, but perhaps more importantly, they open up therapeutic possibilities. 

Much of the interest surrounding PARP is due to the publicity it has received in an entirely different domain of research – cancer, where dozens of molecules targeting PARP have already been teased out. Because drugs designed to modulate PARP activity have already been tested for safety, they could potentially be repurposed for HD, accelerating its path to clinical trials. Although any repurposed drugs would still need to be thoroughly tested, this research opens up exciting new therapeutic roads that may address the issue of mutations building up, a critical problem with cells in HD.

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Original research article, “Poly ADP-ribose signaling is dysregulated in Huntington disease” (Open access).