HDBuzz

This was a year that tested the resilience of the Huntington’s disease (HD) community, with 2025 being remembered for landmark highs followed by disappointing lows shadowed in confusion. Data from clinical trials produced the strongest evidence yet that we can slow disease progression, offering families concrete hope that changing the course of disease is possible. However, just 6 weeks later, the FDA reversed its regulatory guidance and blocked the originally agreed upon path to approval, delivering crushing disappointment to the HD community. Yet the community’s response was extraordinary: over 45,000 petition signatures and unified advocacy from major HD organizations demonstrated that this field won’t accept setbacks quietly.

Beyond the AMT-130 rollercoaster, 2025 brought advances across multiple huntingtin-lowering therapies, revolutionary insights into how CAG repeats expand and can be targeted, actionable health strategies backed by new research, and HDBuzz’s own transformation into an independent nonprofit. As we close out this remarkable year, we’re left with complex feelings – hope tempered by regulatory reality, scientific progress shadowed by bureaucratic obstacles, but also a community more unified and determined than ever. Let’s dive into what made 2025 so unforgettable.

The AMT-130 Story: Hope, Whiplash, and Community Response

September 24: A Moment of Hope

The HD community woke up on September 24, 2025 to news that felt transformative. UniQure announced topline results from their Phase 1/2 trials of AMT-130, revealing that the gene therapy appeared to slow disease progression based on clinical measures accepted by the FDA.

For families who have watched loved ones decline year after year with no way to intervene, this felt like vindication. After decades of research, disappointing trial results, and dashed hopes, here was real, quantifiable evidence that suggested HD’s relentless progression might be slowed.

AMT-130 is a one-time gene therapy delivered directly into the brain by surgery. It uses a harmless virus (AAV5) to deliver genetic instructions that cause brain cells to destroy the messenger RNA for huntingtin (HTT), thereby reducing production of both normal and expanded HTT protein that causes disease. The therapy is designed to last a lifetime: one surgery, one dose, and cells should continue making the HTT-lowering machinery on their own.

The topline data showed approximately 75% slowing of disease progression as measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS), which tracks motor function, cognitive performance, and daily living capacity. Additionally, participants seemed to show stabilization or improvement in neurofilament light (NfL), a biomarker of brain cell health that typically rises as HD progresses.

While there are some caveats to remember, like this data was from a small number of people and compared against a natural history control group, this was the first time any drug had shown this degree of slowing of HD progression on clinical measures in alignment with FDA standards. Families, researchers, and clinicians around the world celebrated cautiously, knowing that regulatory approval was still needed, but for the first time in a long time, hope felt tangible.

This was a year that tested the resilience of the Huntington’s disease (HD) community, with 2025 being remembered for landmark highs followed by disappointing lows shadowed in confusion.

The Road to September: FDA Alignment and Regulatory Progress

These steps forward for AMT-130 success didn’t come out of nowhere. Earlier in 2025, uniQure had been working closely with the FDA to define a pathway for accelerated approval. In June, the company announced they remained aligned with the FDA on several critical points:

1. The cUHDRS and NfL could be used as measures of therapeutic benefit
2. Data from ongoing HD-GeneTRX trials could support a Biologics License Application (BLA)
3. An external control group from Enroll-HD (a natural history study) could be used instead of requiring an additional placebo-controlled trial

This alignment was significant not just for AMT-130, but for the entire HD field. For the first time, the FDA clearly defined what success looks like, which included positive changes in cUHDRS and improvements in NfL levels.

November 3: The Rug Pulled Out

Then came November 3. In a brief press release, uniQure announced they were no longer aligned with the FDA on using an external control group to support their BLA application. The FDA, which had explicitly accepted this approach as recently as June 2025 according to a previous uniQure press release, had reversed course. They now wanted more robust, traditionally controlled data before considering approval.

This was a confusing and disappointing outcome for much of the community. This wasn’t about new safety concerns or efficacy problems, because the scientific data hadn’t changed. AMT-130 still appeared safe, well-tolerated, and potentially disease-modifying. But now the regulatory pathway in the US, which had seemed clear just weeks earlier, was blocked.

For a community that has endured generations with no way of stopping this disease, this felt especially cruel. The FDA seemingly provided guidance in multiple Type B meetings that the Phase 1/2 data with external controls would be sufficient. UniQure appeared to follow that guidance. And now, at the finish line, it seems the rules had changed.

The impact went beyond drug discovery. Many families from the US who had allowed themselves to see a potential future without HD, some of whom were making life decisions based on the possibility of treatment, were left reeling.

December: The Community Responds

But the HD community didn’t stay silent. The response that emerged was remarkable both in its scale and unity.

Over 45,000 people signed Change.org petitions urging the FDA to reconsider, to recognize the severe unmet medical need, and to allow uniQure to submit their BLA under the Accelerated Approval pathway using existing Phase 1/2 data. You can find those petitions HERE and HERE. 

Major US-based HD advocacy organizations issued a Statement of Unity, proposing to coordinate efforts with regulatory agencies. Many American organizations that often work independently came together with one voice: this community deserves better than regulatory whiplash.

On December 4, uniQure received the official FDA meeting minutes from the October 29 meeting. UniQure says they confirm what the community feared, stating that the Phase 1/2 data, as currently structured, were unlikely to support a BLA submission. But they also provided something concrete to work with, including specific feedback that uniQure could use to chart a path forward.

UniQure’s CEO Matt Kapusta emphasized the company’s commitment: “We are committed to collaborating with the FDA to advance AMT-130 to patients and their families as rapidly as possible. The support we have seen these last weeks from the Huntington’s disease community, including patients, families, caregivers, clinicians and advocates reinforces the urgency of the unmet need in Huntington’s disease.”

The company plans to urgently request a follow-up meeting with the FDA in Q1 2026 to determine the path forward. Meanwhile, they’re advancing regulatory discussions in the EU and UK as parallel pathways.

The AMT-130 story of 2025 isn’t over. It’s a difficult reminder that getting safe, effective therapies to patients involves navigating complex regulatory systems that sometimes shift unpredictably.

What This Means

It’s crucial to separate the science from the US regulatory strategy:

The scientific data remain unchanged and promising:

• Disease progression appears to slow by 75% compared to natural history controls
• Strong safety profile with no new drug-related serious adverse events since December 2022
• Levels of NfL seem to show improvement and encouraging functional capacity

The US regulatory challenge is real but not insurmountable:

• This represents a delay, not the end of AMT-130’s development
• Previous trial disappointments for the HD community involved safety or efficacy failures, and this is different
• Multiple pathways remain: possible US reconsideration, EU approval, UK approval, or approval in another jurisdiction
• Scientific progress and regulatory progress don’t always move at the same speed

The AMT-130 story of 2025 isn’t over. It’s a difficult reminder that getting safe, effective therapies to patients involves navigating complex regulatory systems that sometimes shift unpredictably.

But it’s also a testament to a community’s refusal to accept disappointment quietly. The 45,000 signatures represent 45,000 people saying, “we’re still here, we still believe in science, and we demand that regulatory processes serve patients, not bureaucracy.”

The HTT-Lowering Pipeline: Multiple Shots on Goal

The HTT-lowering pipeline continued to expand in 2025, with multiple companies pursuing different approaches to the same goal: reducing levels of the toxic HTT protein. This “multiple shots on goal” strategy means the HD community isn’t dependent on any single therapy succeeding, as several promising candidates are advancing through clinical trials simultaneously.

SKY-0515: An Oral Option Shows Promise

Skyhawk Therapeutics provided encouraging updates on SKY-0515, an oral HTT-lowering drug that works by splice modulation, essentially changing how cells process the HTT RNA message so that less protein gets made.

In September, Skyhawk reported Phase 1 results showing that SKY-0515:

• Appeared safe and well-tolerated
• Lowered HTT protein levels in a dose-dependent manner, meaning more drug meant more lowering
• Achieved greater HTT reduction than has been reported before with a pill

Intriguingly, SKY-0515 may also lower PMS1, a protein involved in CAG repeat expansion. This “two-for-one” approach that may target both the toxic protein and the DNA instability that drives progression makes SKY-0515 particularly interesting, although more data is needed to see if this would be meaningful.

The larger Phase 2/3 FALCON-HD trial launched in Australia and New Zealand, recruiting 120 participants to test SKY-0515 for up to one year, with global expansion planned.

Votoplam (PTC-518): Fast Track Designation and Positive Trends

PTC Therapeutics’ splice modulator votoplam (formerly PTC-518) also showed encouraging progress. In May, the company announced that their Phase 2 PIVOT-HD trial met its primary endpoint, showing that votoplam appears to lower HTT protein levels.

The FDA granted Fast Track designation to votoplam, accelerating the development and review process. Key findings included:

• The drug continued to appear safe with no serious adverse events caused by votoplam
• HTT levels were lowered through the 12-month mark
• Participants showed positive trends in cUHDRS scores
• NfL levels remained stable, suggesting potential brain health benefits

PTC and Novartis (who partnered on the program) are preparing for a Phase 3 trial. PTC will complete the ongoing PIVOT-HD trial, while Novartis will lead future studies.

The HTT-lowering pipeline continued to expand in 2025, with multiple companies pursuing different approaches to the same goal: reducing levels of the toxic HTT protein.

Roche: Three Trials

Roche provided updates on GENERATION HD2, their trial testing the antisense oligonucleotide (ASO) tominersen in people with early HD. In April, an independent data monitoring committee recommended that the trial continue with only the higher dose (100 mg every 16 weeks), dropping the lower 60 mg dose.

Importantly, the committee confirmed that tominersen continues to appear safe with no major safety concerns. The decision to continue with just the high dose suggests this dosing regimen shows more promise for potential benefit.

This represents a measured, data-driven approach to finding the right dose following the early termination of the GENERATION HD1 trial in 2021. The HD community watches these developments closely, as tominersen represents one of the most advanced ASO approaches for HD.

Roche also shared that they’ve begun dosing the first participants in POINT-HD, a Phase 1 trial testing RG6496, a selective HTT-lowering ASO that targets only the expanded, disease-causing HTT protein while preserving regular HTT. 

The drug works by targeting a specific genetic marker (SNP) found in about 40% of people with HD, delivered by spinal tap. The trial started in New Zealand and Australia and plans to enroll 40 adults with early HD symptoms, with the main goals being safety, tolerability, and measuring expanded HTT reduction in spinal fluid.

A third trial in which Roche is involved, in partnership with Spark Therapeutics, is testing  a one-time gene therapy delivered via brain surgery that uses a harmless virus to lower HTT levels. 

The first participant was dosed in June 2025, marking the culmination of years of preclinical work in mice and primates showing the therapy could spread throughout the brain and lower HTT for up to a year. The multi-phase trial will start with 8 participants receiving the treatment in a careful dose-escalation approach, with later phases including a placebo and long-term follow-up to assess both safety and effectiveness. 

The Bigger Picture: Multiple Mechanisms, Multiple Chances

There are also other companies working on HTT lowering approaches who didn’t share major updates in 2025, such as Alnylam Pharmaceuticals, Wave Life Sciences, and Vico Therapeutics. What’s striking about 2025 is the diversity of approaches advancing through clinical development:

• Gene therapy (AMT-130): One-time administration via brain surgery
• Oral splice modulators (SKY-0515, votoplam): Daily pills that work systemically throughout the body
• ASOs (tominersen, RG6496): Spinal injections that target the CNS

Each approach has distinct advantages and challenges. This diversity maximizes the chances that effective therapies will reach patients, while also providing potential options for different disease stages, patient preferences, and clinical situations.

Cracking the Code: Understanding and Stopping CAG Expansion

One of 2025’s most exciting developments happened in understanding some of the fundamental biology now thought to drive HD pathology. Scientists made exciting progress in figuring out how CAG repeats seem to be expanding in brain cells over time, and more importantly, how we may be able to take advantage of that biology to develop possible medicines for HD.

The DNA Repair Paradox

The key insight: some proteins that normally protect our DNA from damage (MSH3, MSH2, MLH3, PMS1) may accidentally be making CAG repeats longer when trying to “fix” them. They recognize the repetitive CAG sequence as an error, but instead of removing it, they copy-paste more repeats. 

Meanwhile, another protein called FAN1 can do the opposite, in that it cuts out extra repeats. The balance between these opposing forces seems to contribute to whether CAG repeats grow or shrink in individual brain cells.

This year, researchers reconstructed this molecular tug-of-war in test tubes, providing the clearest picture yet of how this process may work at a molecular level.

From Biology to Therapeutics

This mechanistic understanding is translating into potential therapies:

MSH3 as a drug target: Multiple groups showed that lowering levels of MSH3 or reducing its function may be able to stop CAG expansion. The lab of Dr. Sarah Tabrizi at University College London published work showing that an antisense oligonucleotide (ASO) targeting MSH3 halted, and even reversed, expansion in brain cells generated from stem cells. Dr. X. William Yang’s group at UCLA knocked out Msh3 in HD mice and completely blocked expansion while improving brain cell changes and behavior. Latus Bio is successfully moving forward with their work, the next steps for which are to submit an Investigational New Drug application from the FDA for their MSH3-targeting gene therapy.

CAG interruptions: A stem cell study showed that inserting CAA “interruptions” into long CAG stretches may be a feasible therapeutic approach, as it seems to stop expansion and improve cellular problems. While this approach is in very early stages, this study suggests that the purity of the CAG DNA sequence, not just the expanded protein length, contributes to disease. Some people naturally carry these interruptions and have later symptom onset.

The Bottom Line

2025 transformed somatic instability from an interesting biological observation into a potentially druggable target. Multiple therapeutic strategies are now in development to stop, or even reverse, the CAG expansion that appears to contribute to disease progression. This represents an entirely new angle of attack on HD from what we currently have in the clinic, separate from HTT lowering but potentially complementary to it.

Actionable Health: What You Can Do Today

Heart Health is Brain Health

One of 2025’s most actionable findings for everyone within the HD community, both those with and without HD, came from a study linking cardiovascular health to neurofilament light (NfL) levels, a key biomarker of brain cell damage in HD.

The research examined the American Heart Association’s “Life’s Simple 7” factors (diet, physical activity, nicotine exposure, BMI, cholesterol, blood sugar, and blood pressure) and found striking connections to brain health. While it’s critical to note that this study wasn’t done on people with HD, it supports the fact that taking care of our bodies is good for our brains.

For every 1-point increase in cardiovascular health score, study participants had 3.5% lower NfL levels. Those with the highest heart health scores had nearly 19% lower NfL than those with the lowest scores.

In a 10-year follow-up, participants with low cardiovascular health scores saw NfL increase by 7.1% annually, while those with high scores had a slower increase of 5.2% per year.

The message for HD families is that heart-healthy habits like regular exercise, balanced diet, maintaining healthy weight and blood pressure may genuinely influence brain health and the rate of neuronal damage. While this study wasn’t specific to HD, NfL is used as a biomarker across neurodegenerative diseases, making these findings directly relevant.

While rigorously tested for people HD, studies in the general population link the following with better overall health:

• Aim for 150 minutes of moderate exercise weekly
• Eat a diet rich in vegetables, fruits, whole grains, and healthy fats
• Monitor and manage blood pressure, cholesterol, and blood sugar
• Maintain a healthy weight
• Avoid smoking and limit alcohol
• Get regular checkups

The message for HD families is that heart-healthy habits like regular exercise, balanced diet, maintaining healthy weight and blood pressure may genuinely influence brain health and the rate of neuronal damage.

The Importance of Sleep

Multiple studies published in 2025 revealed that sleep disturbances in HD start earlier than previously recognized and treating them might make a real difference.

A 12-year study following people with the HD gene but no obvious symptoms found:

• Sleep disturbances emerged 10-15 years before predicted symptom onset
• Two types of problems: “sleep stage instability” (disrupted sleep architecture) appeared earliest, while “sleep maintenance insomnia” (trouble staying asleep) emerged closer to symptom onset
• Sleep maintenance insomnia correlated with worse cognition and higher NfL levels
• Sleep stage instability could predict who would develop HD over the next decade with about 70% accuracy

The bidirectional relationship between sleep and neurodegeneration is crucial given that HD causes sleep problems, but poor sleep may accelerate brain decline. This creates a vicious cycle, but also a potential therapeutic opportunity.

While not proven to prevent or delay symptoms of HD, studies in the general population link the following with better sleep:

• Sleep hygiene basics: Regular sleep schedule, dark and cool bedroom, avoid screens before bed
• Limit stimulants: No caffeine after 2 PM, limit alcohol (disrupts sleep architecture)
• Physical activity: Regular exercise improves sleep quality, but not within 3 hours of bedtime
• Light exposure: Get bright light in the morning, dim lights in the evening to support circadian rhythms
• Consider CBT-I: Cognitive Behavioral Therapy for Insomnia is highly effective and available through apps like Sleepio (free through NHS in UK, covered by many US employers)
• Talk to your doctor: If sleep problems persist, discuss whether a sleep study or medication might help

Mental Health and Cognitive Changes

Mental health and cognitive symptoms received significant attention in 2025, with multiple articles exploring how HD affects thinking, emotion, and psychological well-being.

Psychosis: A study found that psychosis symptoms affect about 1 in 6 people with HD and may change how movement symptoms like chorea manifest. Understanding these symptoms helps break stigma and reminds us that each person’s HD journey is unique.

Irritability: Research explored how irritability in HD is a brain-based symptom that can escalate into severe storms of emotion. Understanding the neurobiology can help families respond with compassion rather than frustration.

Emotion recognition: HD can disrupt how people recognize and process emotions in others, affecting social interactions and relationships. This isn’t intentional, it’s a measurable brain change that family members benefit from understanding.

Childhood experiences: A powerful study examined how growing up in HD families affects adult mental health, revealing that early experiences and family dynamics have lasting impacts on psychological well-being.

Staying mentally active: Research suggested that cognitive engagement, like learning new skills, social connection, challenging activities, may help slow cognitive decline. While not a treatment, staying mentally active provides “cognitive reserve” that may maintain function longer.

Acceptance and Commitment Therapy (ACT): An HDBuzz Prize-winning article by Nicolo Zarotti explored how ACT improved psychological well-being for both a person with HD and their caregiver, demonstrating how mental health interventions can complement biomedical advances.

Mental health and cognitive symptoms received significant attention in 2025, with multiple articles exploring how HD affects thinking, emotion, and psychological well-being.

If you or a loved on is struggling with mental health issues or challenging cognitive changes, you could consider: 

• Working with a therapist who understands neurodegenerative disease; don’t wait for a crisis
• Explore evidence-based approaches like ACT, which helps people engage with their values despite difficult circumstances
• Join support groups (virtual or in-person) to connect with others facing similar challenges
• Recognize that symptoms like irritability and emotion recognition difficulties are brain-based, not character flaws
• Caregivers: prioritize your own mental health and remember that you can’t pour from an empty cup
• Stay socially connected and cognitively engaged through hobbies, learning, and meaningful activities

Biomarkers: Measuring What Matters

NfL: An Impressive 14-Year Study

A 14-year longitudinal study confirmed that neurofilament light (NfL) is a powerful tool for tracking HD progression. The study demonstrated that NfL can signal disease progression many years before symptoms start, making it an incredibly sensitive biomarker for both understanding disease and testing treatments.

NfL levels are increasingly used as a key measure in clinical trials (as seen in trials for AMT-130), and the FDA has accepted NfL alongside cUHDRS as evidence of therapeutic benefit. Being able to detect these subtle changes in NfL before symptoms of HD are overtly apparent means that we may soon be able to start clinical trials in people with HD when they are much younger, before disease onset. 

EEG and MRI: Windows into the Brain

HDBuzz Prize winners highlighted how:

• EEG recordings reveal brainwave differences in people who carry the HD gene even before symptoms appear
• MRI scans help explain anosognosia (reduced self-awareness) by linking brain structure changes with this symptom

These non-invasive imaging techniques complement fluid biomarkers, like NfL, providing multiple ways to track disease, which is critical for testing and advancing interventions.

Beyond HTT Lowering: Alternative Approaches

Stem Cells from Teeth

A small Phase II trial from Brazil tested an unusual approach: infusing people with HD with dental pulp stem cells obtained from human teeth. The therapy, called NestaCell, appeared safe with no serious side effects linked to treatment.

Both treated groups appeared to show better movement scores than placebo, and the higher-dose group may have improved in functional capacity. However, the study was small (26 participants total), and the mechanism by which dental stem cells might help HD is unclear.

This is early-stage research requiring larger, controlled trials before conclusions can be drawn, but it represents creative thinking about cell-based therapies.

SOM3355: Symptom Management

While many people are understandably focused on disease-modifying therapies, symptom management remains crucial for quality of life. SOM3355, a drug originally developed for other neurological conditions, received encouraging regulatory signals from both the European Medicines Agency and the US FDA following a Phase 2 trial. The hope is that the drug will help successfully treat HD chorea as well as mood-related symptoms, like anxiety.

A Phase 3 trial is in preparation. If successful, SOM3355 could become a new option for managing symptoms caused by HD.

Sertraline: Multiple Mechanisms?

Research suggested the common antidepressant sertraline (Zoloft) might have effects beyond mood. When scientists dug into the Enroll-HD database, they found the drug may improve function in people with HD. They also carried out studies in mice that model HD and found that sertraline may prevent motor problems and stabilize protein production. While more research is needed, this raises the intriguing possibility that some existing medications might impact HD through unexpected mechanisms.

Nurturing the Next Generation: Mentorship and Fresh Voices

The HDBuzz Prize for Young Science Writers

2025 marked the return of the HDBuzz Prize for Young Science Writers, this year sponsored by the Huntington’s Disease Foundation (HDF). The competition invited early-career researchers, PhD students, postdocs, early-stage investigators, and clinicians, to write about HD research in accessible language.

The prize serves multiple goals:

• Diversify voices: HD researchers come from varied backgrounds with different perspectives on data
• Train communicators: Science communication is a critical skill often neglected in training
• Engage the community: Fresh voices bring energy and new angles to explaining complex science

2025 Prize Winners

Prize winners published articles throughout the year, bringing attention to emerging topics:

Mustafa Mehkary wrote about how expanded HTT disrupts DNA repair processes, creating a vicious cycle where protective mechanisms become liabilities.

Eva Woods highlighted EEG recordings that reveal brainwave differences in people who carry the HD gene before symptoms appear, which could potentially act as an early biomarker for disease.

Jenna Hanrahan explained how MRI scans link brain structure changes with anosognosia (reduced self awareness), bridging neuroscience with the lived reality of HD.

Nicolo Zarotti explored Acceptance and Commitment Therapy (ACT) as a mental health intervention that improved well-being for both a person with HD and their caregiver.

Gravity Guignard examined why lowering “good” HTT might complicate safe drug development, reminding us that therapeutic strategies must carefully balance benefits and risks.

Chloe Langridge highlighted the protein SGTA as a potential therapeutic target, adding to the growing list of “support proteins” that may indirectly improve disease effects.

These mentorship programs, both the HDBuzz Prize and HD-CAG partnership, represent an investment in the future of HD research. They recognize that scientific progress requires not just brilliant experiments, but clear communication, diverse perspectives, and a pipeline of talented investigators committed to the field for the long haul.

Mentoring HD-CAG Award Recipients

Beyond the HDBuzz Prize, 2025 saw HDBuzz partner with the Huntington’s Disease Foundation’s HD-CAG (Huntington’s Disease Career Advancement Grant) program. This inaugural program supports senior postdoctoral researchers bridging the difficult transition to independent investigators.

The 2025 HD-CAG recipients are:

• Sonia Vasquez-Sanchez, PhD (UC San Diego, mentored by Don Cleveland)
• Chris Kay, PhD (University of British Columbia, mentored by Michael Hayden)
• Shota Shibata, PhD (Harvard Medical School, mentored by Ricardo Mouro Pinto)
• Devon Pendlebury, PhD (UC Irvine, mentored by Leslie M. Thompson)
• Piere Rodriguez-Aliaga, PhD (Stanford University, mentored by Judith Frydman)

HDBuzz has been working with these HD-CAG awardees, mentoring them in science communication and featuring their articles on the website. This partnership ensures that the next generation of HD researchers not only conducts excellent science but can also communicate it effectively to the community that needs it most.

The Bigger Picture

These mentorship programs, both the HDBuzz Prize and HD-CAG partnership, represent an investment in the future of HD research. They recognize that scientific progress requires not just brilliant experiments, but clear communication, diverse perspectives, and a pipeline of talented investigators committed to the field for the long haul. The articles published in 2025 from these young researchers prove that the future of HD science is in capable, creative hands.

Conferences: Where the Community Gathers

CHDI HD Therapeutics Conference (February 2025, Palm Springs)

The 20th annual CHDI meeting showcased significant advances across therapeutics development, with over 400 scientific experts convening to discuss:

• Clinical trial updates on HTT-lowering approaches
• Advances in genetic modifiers and DNA repair targeting
• Biomarker development and validation
• Innovative technologies like CRISPR delivery systems

HD Clinical Research Congress 2025 (October 2025, Nashville)

The Huntington Study Group (HSG) meeting emphasized big-picture alignment and data sharing:

• New trial designs and endpoint refinement
• Current challenges in clinical trials
• Community-researcher interactions
• Early-phase results from multiple therapeutic programs

These gatherings serve as idea greenhouses, nurturing collaborative relationships and refining research priorities. The value lies not just in results presented, but in connections built and directions set.

Community Talks

In 2025, HDBuzz delivered research updates directly to the HD community through live presentations and interactive sessions. 

Our team delivered talks at three major conferences across the globe: the HDSA National Convention in Indianapolis, US; the Huntington Society of Canada National Conference in Niagara Falls, Canada; and the HDYO International Young Adult Congress in Prague, Czech Republic, where we translated the latest clinical trial developments and research breakthroughs into accessible science for diverse audiences. 

We also engaged directly with community questions through a live social media takeover for the Huntington’s Disease Foundation and an ask-me-anything style webinar for HDSA, creating opportunities for real-time dialogue about the science that matters most to HD families.

HDBuzz in 2025: Independence, Growth, and Community Support

HDBuzz generated a record 100 articles in 2025!

A Year of Transformation

2025 marked HDBuzz’s most ambitious year yet. One year into new leadership under Dr. Sarah Hernandez and Dr. Rachel Harding, the organization underwent dramatic growth and transformation:

Doubled article output: From roughly 2 articles per month to a consistent twice-weekly publication schedule (Mondays and Thursdays), matching the accelerating pace of HD research. HDBuzz generated a record 100 articles in 2025!

Expanded the writing team: Brought in new writers from top research institutions, diversifying perspectives and expertise across the HD field.

Launched new platforms: Expanded our reach with a new social media manager to Instagram, Bluesky, and LinkedIn, meeting readers where they are and reaching broader audiences across multiple social media channels. 

Established independent governance: Formed an advisory board and completed transition to standalone 501(c)(3) nonprofit status, ensuring long-term sustainability and independence.

Revitalized mentorship programs: Launched the HDBuzz Prize for Young Science Writers (sponsored by HDF) and partnered with HDF HD-CAG awardees to mentor the next generation of HD researchers in science communication.

Two Fundraising Campaigns

HDBuzz ran two major fundraising campaigns in 2025, both emphasizing the organization’s commitment to independence from pharmaceutical funding. 

Our Spring fundraising campaign, “Hope in Full Bloom”, launched in anticipation of major clinical trial results expected in Q2 2025, raising funds to ensure HDBuzz could provide comprehensive, real-time coverage of pivotal updates from various clinical trials. 

Our Fall campaign, “Falling Into Hope”, following the September AMT-130 announcement and subsequent November regulatory setback, emphasizing HDBuzz’s crucial role as an unbiased source during moments of both hope and disappointment. Funds raised helped support continued independence, website updates, social media expansion, and our mentorship programs.

Why Independence Matters

HDBuzz has never accepted funding from pharmaceutical companies. This policy ensures the unbiased reporting that is especially critical as we approach the era of disease-modifying therapies. When regulatory decisions shift unexpectedly (as happened with AMT-130), or when trial results disappoint, families need a trusted source that reports facts without conflicts of interest.

Reader donations support:

• Website maintenance and updates
• Translation into 11 languages
• Presence at conferences for real-time reporting
• Time for writers and editors to read, research, and create content
• Mentorship programs for young researchers
• Social media outreach to expand global reach

The Model Going Forward

If just 5% of HDBuzz readers gave $20/month, the organization would achieve independent sustainability. Every article will always remain free and accessible – no paywalls, no ads, no pharmaceutical funding. Just clear, accurate, accessible HD research news supported by the community it serves.

Our transition to independence in 2025 positioned HDBuzz not just to survive, but to thrive as HD research enters its most exciting and complex phase yet.

HDBuzz has never accepted funding from pharmaceutical companies. This policy ensures the unbiased reporting that is especially critical as we approach the era of disease-modifying therapies.

Looking Forward: What 2026 May Hold

The AMT-130 Question

The regulatory pathway for AMT-130 remains the biggest unknown. UniQure plans to meet urgently with the FDA in Q1 2026 to determine what’s needed, whether that’s additional data from existing trials, a new trial design, or some middle ground. Simultaneously, they’re advancing discussions with European and UK regulators, which may move faster than the US pathway.

The outcome will have implications beyond just AMT-130. It will shape how other HD therapies, particularly gene therapies, navigate regulatory approval. The community is watching closely and won’t hesitate to make their voices heard again.

Phase 3 Trials Launching

Multiple therapies are preparing to enter or are already in Phase 3:

• Votoplam’s large-scale trial (PTC/Novartis partnership)
• SKY-0515’s FALCON-HD expansion into Phase 2/3 
• SOM3355 for symptom management
• Continued follow-up on tominersen

These advanced phase trials represent diversification of the pipeline, giving us multiple shots on goal with different mechanisms and delivery methods.

DNA Repair Targeting Moves Forward

The explosion of mechanistic understanding around somatic instability in 2025 sets the stage for therapies specifically targeting CAG repeat expansion. Latus Bio’s IND submission for their MSH3-targeting gene therapy is just the beginning. We expect more companies to enter this space in 2026, joining those already working here, like Rgenta Therapeutics, LoQus23 Therapeutics, and Harness Therapeutics.

If just 5% of HDBuzz readers gave $20/month, the organization would achieve independent sustainability.

What We’ve Learned

Looking back at 2025, perhaps the most important lesson is this: scientific progress is real but insufficient on its own. Getting therapies to patients requires navigating regulatory systems, manufacturing scale-up, insurance coverage, surgical capacity, and countless other challenges that exist outside the laboratory.

The HD community has proven it can unite when necessary, that it won’t accept disappointments quietly, and that it understands both the science and the bureaucracy well enough to fight effectively. This year has highlighted that those qualities matter as much as any clinical trial result.

The Bottom Line

2025 will be remembered as a year of extremes. September 24, the day uniQure announced AMT-130’s positive results, gave the HD community something it desperately needed: evidence that slowing HD progression is scientifically possible. Six weeks later, November 3 delivered a crushing blow when the FDA reversed course on the regulatory pathway. And in December, the community’s extraordinary response with 45,000+ petition signatures and unified advocacy from major organizations showed the resilience and determination that has always defined HD families.

The AMT-130 saga taught us painful lessons about the gap between scientific achievement and regulatory approval. But it also demonstrated something powerful: this community will not accept setbacks silently. Families are demanding that regulatory processes serve patients, not bureaucracy.

Our transition to independence in 2025 positioned HDBuzz not just to survive, but to thrive as HD research enters its most exciting and complex phase yet.

Beyond AMT-130, 2025 was about so much more:

• Multiple therapies advancing through the pipeline, each with distinct mechanisms and potential
• Deepened understanding of how CAG repeats expand and how we may be able to stop that process
• Actionable insights into heart health, sleep, and mental wellness
• Young researchers bringing fresh perspectives to HD science
• A community pulling together to support independent science communication

The snowflakes of individual studies continue compacting into a glacier of progress. No single discovery will solve HD, and the path forward isn’t as smooth as we’d hoped for in September. But the accumulating progress is real, and it’s transforming what we know is possible.

As we enter 2026, families facing HD carry both hope and hard-earned wisdom. We’ve learned that promising data doesn’t guarantee approval, that regulatory systems can shift unpredictably, and that patience is demanded even when time is the one thing many families don’t have. But we’ve also learned that the science is advancing, the tools are sharper, and this community’s voice is louder and more unified than ever before.

The HD community has proven it can unite when necessary, that it won’t accept disappointments quietly, and that it understands both the science and the bureaucracy well enough to fight effectively.

Disease-modifying therapies for HD are no longer theoretical. They’re in trials, showing real effects in real people, and working through (admittedly complex) regulatory processes. The path isn’t straight, and there could be more challenges to navigate ahead. But with continued community advocacy, scientific rigor, and collective determination, meaningful treatments are coming.

2025 showed us that changing the course of Huntington’s disease is possible. It also showed us that possible doesn’t mean easy. But this community has never had the luxury of easy. We know we have to keep fighting, keep hoping, and keep demanding better. And that matters more now than ever before.

Huntington’s disease (HD) is caused by a repeated stretch of the genetic letters C-A-G within the huntingtin (HTT) gene above a critical number. If the repeats exceed 40, then signs and symptoms of HD will begin at some point in that person’s life, if they live long enough. The disease-causing CAG stretch expands throughout life, particularly in vulnerable brain cells, which scientists think eventually triggers cell death. 

New research used cutting-edge gene editing to create human stem cells with different CAG repeat lengths and genetic spellings. They then tracked how these repeats changed over time using advanced sequencing technology. The team discovered that inserting multiple genetic “interruptions” into the CAG repeat, breaking up the pure stretch of CAGs, had major benefits. What exactly did they find and what does this mean for future therapeutics? Let’s find out!

A Cellular Time Machine

Imagine watching a disease unfold in slow motion so you could track the exact moment when things start to go wrong. That’s essentially what researchers at the University of Milan have created – a platform to watch HD develop at the cellular level, repeat by repeat, day by day.

The team, led by Dr. Elena Cattaneo, engineered human stem cells carrying different versions of the HTT gene. Using CRISPR gene editing, they swapped in HTT sequences with various CAG repeat lengths, ranging from 21 repeats (below the disease threshold) up to 107 repeats (well into the disease range).

They called this collection of cell lines the “CAGinSTEM platform,” and it could become a powerful tool for understanding how CAG repeats behave over time.

Watching Repeats Grow

One of the trickiest aspects of studying CAG repeat instability has been measuring the expansion accurately. Traditional sequencing methods can struggle with repetitive DNA. Imagine trying to accurately count 42 of the same letters in a row. It’s likely at some point you may question if you were on 31 or 32 and have to start over. The same process happens in an experiment when molecular machines try to read the number of CAG repeats.

The researchers solved this problem using a specialized type of sequencing that can read very long stretches of DNA in a single pass, maintaining information about the exact sequence composition.

Over 120 days of growing cells in dishes, the team observed that cells that start with 81 and 107 CAG repeats showed steady, linear expansion of their repeats. In contrast, cells with 45 or fewer repeats remained stable, with no major changes to their CAG number. When they turned these stem cells into striatal neurons, the brain cells most affected in HD, they saw similar patterns, with the 107 CAG line showing expansion even in neurons.

Looking at cells before and after they became neurons allowed the researchers to determine if cell division was influencing CAG expansion. While stem cells divide again and again to create more cells, most neurons don’t – they’re what scientists called “post-mitotic,” meaning “after mitosis” or “after cell division”. Because CAG expansion remained at very high repeat numbers both before and after the cells became neurons, it suggests cell division isn’t the contributing factor.

The Power of Interruption

Here’s where the study gets really interesting. Most people (over 95%) have a natural interruption in their CAG repeat: it reads CAG over and over until the end of the repetitive section, where it reads CAG-CAA-CAG, with that single CAA near the end. Previous studies in people have shown that losing this CAA interruption leads to earlier disease onset, while having an extra CAA delays onset. 

Here’s where the study gets really interesting. Most people (over 95%) have a natural interruption in their CAG repeat: it reads CAG over and over until the end of the repetitive section, where it reads CAG-CAA-CAG, with that single CAA near the end.

The researchers tested this directly in their cell platform. They created lines with 107 pure CAGs (no interruption), lines with the typical single interruption, lines with 2 CAA interruptions, and (most dramatically) lines with 4 CAA interruptions strategically placed throughout the repeat.

The results were striking. The double CAA interruption reduced instability compared to the standard single interruption. But the 4 internal CAA interruptions appeared to completely abolish repeat expansion over 120 days. The repeats simply stopped growing, both in dividing cells and in neurons. Quite intriguing!

More Than Just Stability

Stopping repeat expansion would be valuable on its own, but the researchers also discovered that the multiple CAA interruptions had other benefits, as they appeared to prevent several HD-related problems in the cells.

Neurons with the 107 CAG repeat with the regular 1-CAA interruption showed difficulty developing into the right type of neuron. They had fewer markers defining them as striatal neurons and more markers from a different brain region, suggesting their development into this specific type of neuron was a bit confused. These findings are in line with work from other labs using brain samples from people, which have shown an erosion of cellular identity of this type of neuron with expanding CAG repeats.

However, the 4-CAA-interrupted line seemed to maintain normal striatal neuron development. This suggests that 4 CAA interruptions preserve the genetic identity of the striatal neurons!

The team also examined how the DNA and other molecules were organised in a region called the nucleus of the cells, an area of growing interest in HD research. Cells with 1 CAA interruption in 107 repeats had a smaller nucleus on average, more compact DNA that isn’t turned into protein, and disrupted structures important for regulating which genes stay turned off during development. The 4-CAA interruptions normalized all of these features, restoring nuclear size, DNA organization, and features used to control levels of different genes.

Interestingly, some cellular disease aspects weren’t improved by the CAA interruptions. Neurons with interrupted repeats still showed abnormal cell shape similar to the cell line with 1 CAA interruption in 107 repeats, with shorter neuron branches (dendrites) and smaller cell bodies. This suggests that these particular features may depend on the protein encoded by the HTT gene and its repeats, rather than on DNA instability or repeat purity.

The DNA Matters, Not Just the Protein

For many years, HD research focused almost exclusively on the toxic protein. But this study reinforces a paradigm shift happening in the field: the DNA sequence itself, including its purity and tendency to expand, seems to also play a direct role in disease.

And here’s where it gets a little bit wild – CAA and CAG both code for the protein building block glutamine. So inserting CAA interruptions doesn’t actually change the protein! Yet these interruptions seem to prevent repeat expansion and prevent cellular problems. We told you it was wild…

This seems to support the “two-stage” model of HD as it relates to the CAG expansion: you inherit a CAG repeat that isn’t overtly toxic initially, typically allowing for decades of healthy life, but it expands over your lifetime in certain brain cells until it crosses a threshold and triggers cell death.

While some researchers have theories about what exact length triggers toxicity related to CAG expansion and how exactly this happens, no one knows for sure. One theory is that the pure CAG repeat forms stable DNA structures that promote slippage and expansion when the gene is copied. CAA interruptions could disrupt these structures, preventing the expansion process.

A Therapeutic Possibility?

The findings from this recent work raise an intriguing question: could introducing CAA interruptions be therapeutic? Recent proof-of-principle studies have used CRISPR base editing to convert some CAGs to CAAs in cells and mice, with encouraging results. However, translating gene editing to post-mitotic human neurons in living brains faces enormous technical challenges – delivery efficiency, precision, and safety all remain major hurdles.

Perhaps more immediately, the CAGinSTEM platform itself offers value for drug discovery. Researchers can now screen for potential medicines that either reduce repeat instability or mitigate its downstream cellular effects, using these well-characterized, quality-controlled cell lines that seem to faithfully recapitulate some aspects of HD pathology.

And here’s where it gets a little bit wild – CAA and CAG both code for the protein building block glutamine. So inserting CAA interruptions doesn’t actually change the protein! Yet these interruptions seem to prevent repeat expansion and prevent cellular problems.

Natural Protection?

The study also hints at an intriguing possibility that some people might carry naturally occurring internal CAA interruptions that protect them from disease despite having pathogenic-range CAG repeats.

While never observed in the existing databases with information on people who have HD, such protective variants could exist in presymptomatic individuals who never develop symptoms.

The Bottom Line

It’s important to note that studies like this, that grow a specific type of cell alonel in a dish, don’t recapitulate what’s happening inside the brain, which is made up of many different cell types all connecting and communicating with each other. These types of studies are good at getting an idea of what certain types of cells are doing on their own, and how those disease-related changes could contribute to and impact the entire system.

This study adds evidence to other work that suggests CAG repeat purity directly affects both repeat instability and cellular dysfunction in HD, while developing a tool researchers can use to ask questions around this finding.

By preventing the formation of long, pure CAG stretches through strategic interruptions, researchers may be able to block repeat expansion and prevent multiple HD-related effects in neurons, all without actually changing the glutamine protein length. Wild!

The work continues to shift our understanding of what drives HD pathology, emphasizing that it’s not just about the protein you make, but about the DNA sequence you inherit and how it changes over time. While therapeutic applications for these findings remain speculative, the CAGinSTEM platform offers researchers a powerful new tool for understanding HD mechanisms and testing potential interventions.

Summary

• The platform: Researchers created quality-controlled human stem cell lines with different CAG repeat lengths and compositions in the huntingtin (HTT) gene
• Advanced tracking: Using long-read DNA sequencing, they measured CAG repeat changes over time in both dividing cells and neurons
• Length matters: Cell lines with 81-107 CAG repeats showed linear expansion over time, while shorter repeats remained stable
• Pure vs. interrupted: Standard repeats with one CAA interruption near the end still expanded; adding a second CAA interruption reduced expansion
• Complete blockade: Inserting 4 CAA interruptions throughout the repeat seemed to stopp expansion in both dividing cells and post-mitotic neurons
• Cellular rescue: The 4-CAA interruptions prevented multiple HD cellular effects, including impaired striatal neuron development, disrupted nuclear organization, and altered gene levels, all without changing the glutamine protein length
• DNA-driven disease: The findings contribute to the theory that repeat purity and instability, not just polyglutamine protein length, directly drive HD pathology
• A research tool: The CAGinSTEM platform offers a robust system for studying HD mechanisms and screening potential therapies

A new Huntington’s disease (HD) clinical trial has reached an important milestone: the first participants have now been dosed in POINT-HD, a Phase 1 study testing a new, selective huntingtin-lowering drug. RG6496 is designed to only lower levels of the expanded form of huntingtin (HTT), preserving levels of regular HTT. This exciting new milestone is only possible because of the courage and generosity of participants and their families, who are helping to move HD research forward for everyone. Let’s get into this new trial and what drug they are testing. 

HD Biology 101 

Before we dive into the details of this clinical trial, a quick recap on some HD biology fundamentals. Every person has two copies of the HTT gene, one from their mum and one from their dad. 

In people with HD, one of these copies contains an expanded stretch of DNA that leads to production of a faulty, “expanded” HTT protein, while the other copy makes the healthy, or regular unexpanded, HTT protein. Both copies of the gene are active, so people with HD typically produce both regular and expanded HTT throughout their lives. 

Because HD is inherited in a dominant way, having just one expanded copy is enough to cause the disease, and each child of an affected parent has a 50% chance of inheriting the expanded gene.

What is POINT-HD?

POINT-HD is a Phase 1 clinical trial sponsored by the company Roche. The study is testing an investigational drug called RG6496, which they developed in partnership with Ionis Pharmaceuticals. This drug is designed to only lower levels of the faulty, expanded HTT protein that causes HD, while leaving the regular protein intact.

Phase 1 trials are primarily focussed on safety. This is the first time RG6496 is being tested in people, so the main goals are to understand how safe it is, how it behaves in the body, and how people tolerate it. Researchers will also measure levels of expanded HTT protein in spinal fluid, which can help guide future studies.

POINT-HD is separate from Roche’s other HD trials, including the ongoing Phase 2 GENERATION-HD2 study of tominersen and a Phase 1 gene therapy study they are working on with Spark Therapeutics. Both of these other trials seek to lower total HTT levels – both the regular and expanded proteins. 

A selective approach to lowering HTT

RG6496 belongs to a class of drugs called antisense oligonucleotides, or ASOs. This ASO targets the HTT message molecules, which are the copies made of the HTT gene by the cells’ machinery that encode the instructions to make the HTT protein. Like other ASOs in HD research, it is given by lumbar puncture, also known as spinal tap, into the fluid that bathes the brain and spinal cord.

What makes RG6496 different from tominersen, the other ASO the company has developed, is that it is designed to be selective. Rather than lowering HTT protein levels from both copies of the gene, sometimes referred to as total HTT, it aims to reduce only the expanded version, while sparing the healthy HTT protein.

The drug does this by targeting a tiny genetic difference, called a single nucleotide polymorphism (known as a SNP, pronounced “snip”), that sits on the expanded HTT gene in some people with HD. This “genetic signpost” allows the drug to distinguish between the faulty and healthy gene copies.

Based on large genetic datasets, including Roche’s global HD epidemiology work, around 40% of people with HD are thought to carry this particular SNP on their expanded HTT gene. Only people who carry this genetic marker are eligible to potentially receive RG6496.

While having a limiter on this clinical trial might seem discouraging, this study aims to test the proof-of-concept for this approach. If it works, Roche could then work to identify other SNPs that can be targeted for the remaining 60% of the population with HD. If successful, the end goal will be to treat as many people with HD as possible!

Who can take part in this trial?

POINT-HD plans to enroll 40 adults aged 25 to 65 who have early or mild HD symptoms and meet additional study criteria. Before becoming enrolled participants, volunteers are screened to see whether they carry the target SNP required for the drug to work.

The study has two parts and will last around two years in total:

Part 1 will last about seven months and is placebo-controlled. Participants are randomly assigned to receive either a single dose of RG6496 or a placebo, with three out of four participants receiving the study drug.

Part 2 is an open-label extension lasting about 13 months, in which all participants receive RG6496.

Participants will attend regular clinic visits and complete some digital tasks on a study-provided smartphone. 

Where is the study running?

POINT-HD has kicked off with study sites in New Zealand and Australia, where the first participants have now been dosed. These countries are attractive places for many companies to start early-stage clinical trials as they have fast regulatory and ethics approvals, as well as strong clinical infrastructure with lots of tax incentives for companies to work there. Together with high participant engagement and efficient trial systems, this allows studies to start quickly, and hopefully generate high-quality data, all to help accelerate drug development.

The study is also expected to open soon in Argentina, with additional countries and sites to follow once regulatory and ethics approvals are in place. Details about participating sites will be posted on public trial registries such as ClinicalTrials.gov and on Roche’s ForPatients website as the study expands.

A thank you to participants

Every clinical trial begins with people who are willing to be first. Phase 1 participants, in particular, step into the unknown so that researchers can learn whether a new idea is safe enough to pursue further.

The start of dosing in POINT-HD is a moment to recognise those individuals and families, as well as the HD patient organisations and advisors who helped shape the study. Their involvement ensures that trials are not only scientifically sound, but also as respectful and practical as possible for the people taking part.

POINT-HD is still at a very early stage, and much more research will be needed before anyone knows whether RG6496 could one day become a treatment. But each new study adds another piece to the puzzle, and another reason for cautious optimism as HD research continues to move forward.

Summary

• A new Phase 1 Huntington’s disease trial has begun dosing, testing RG6496, a first-in-human, selective HTT-lowering drug.
• RG6496 is designed to lower only the disease-causing, expanded HTT protein, while preserving the regular protein that is important for healthy cells.
• The drug targets a specific genetic marker found in about 40% of people with HD.
• POINT-HD is primarily focused on safety, tolerability, and how the drug behaves in the body, while also measuring levels of expanded HTT in spinal fluid to guide future research.

Learn more

One mystery that many scientists think holds the key to curing HD is its mysterious age of onset. Although people with HD carry the expanded gene from birth, they generally don’t develop symptoms until later in life, suggesting something bad is brewing beneath the surface! One explanation, which has gained significant traction in recent years, is a process called somatic instability, where the expansion worsens over a person’s life. Recent work from the lab of Dr. Jeff Carroll at the University of Washington investigated several genetic techniques to understand what causes somatic instability and whether huntingtin-lowering therapeutics might slow it down. 

An Unstable Repeat

To understand somatic instability, let’s briefly revisit how genes work. Normally, genes like huntingtin, or HTT, are copied to make messenger molecules, called mRNA, through a process known as transcription. These genetic messages can then be used as a template to make proteins through another process called translation. 

However, in HD, the HTT gene contains extra genetic letters (C-A-Gs) that repeat too many times, causing its mRNA message to create an abnormal protein. In some cells, these repeating CAGs can grow even longer over someone’s life, leading to mRNA that is increasingly repetitive. By the time symptoms appear, these CAG repeats may have grown into the hundreds in certain cells. The continuously expanding CAG repeat in HTT, called somatic instability, is a leading theory for why the onset of HD is typically delayed into adulthood. 

Many ongoing clinical trials are focused on reducing the amount of HTT produced from the faulty gene. However, it’s unclear if lowering HTT levels will slow down the growth of the CAG repeat in the HTT gene. Although somatic instability is a prime suspect for causing HD’s delayed onset, it’s still only a correlation. Regardless, it’s certainly worth investigating what causes it and whether HTT-lowering therapies, which are already in clinical trials, can affect it. 

Dialling Down Huntingtin 

In a new study, a team at the University of Washington tested whether HTT lowering affects somatic instability. From previous work, they had used a type of therapy called Antisense Oligonucleotides (ASOs), which bind mRNA and send it to the cell’s trash can, to lower HTT levels in mice. They followed up on these experiments and discovered that ASOs also reduced CAG repeat growth by about 50%. This is good news because several ongoing clinical trials are already investigating ASOs.

Although the ability of ASOs to reduce target mRNA levels is well understood, the researchers were surprised that it stunted the growth of CAGs in the HTT gene. They suspected the ASOs might also disrupt mRNA at its source – a process called transcription. Recent work by other groups has linked rates of transcription with the growth of CAGs, such that the more the HTT gene is used to make mRNA, the quicker the CAGs build up. This hypothesis led the team to investigate exactly how ASOs were slowing CAG growth. 

The researchers considered two possible ways ASOs might be slowing somatic instability. 

1. The HTT protein itself was responsible for somatic instability, and by reducing the production of HTT, ASOs reduced somatic instability. 
2. The process of switching on the HTT gene was causing somatic instability, and by reducing transcription, ASOs reduced somatic instability. 

To find out how ASOs might affect somatic instability, the researchers injected a similar molecule into mice, called siRNA, which reduces HTT protein but does not affect transcription. When HTT protein levels were lowered using siRNA, they did not see any effect on somatic instability. This doesn’t mean siRNA wasn’t exerting a beneficial effect, just that siRNA wasn’t reducing somatic instability in the cells the team looked at. However, it does indicate that ASOs are slowing CAG growth by disrupting transcription, and not by lowering protein levels. 

Fewer Deliveries, Less Potholes?

To visualize the difference between siRNA and ASOs, imagine the HTT gene as an old road traveled by semi-trucks making deliveries, and the packages represent mRNA messages. With each year that the road is driven on, its potholes and cracks worsen, just as HTT’s CAG repeat worsens the more it’s used to make protein. Reducing HTT levels with siRNA is like reducing the number of packages, but the same number of trucks are still on the road – they are just emptier! ASOs, however, reduce the number of trucks, and fewer trucks mean less wear and tear on the road, and thus slower CAG growth. 

The researchers tried a more direct approach to test the connection between somatic instability and transcription. They turned to a genetically modified mouse model of HD where HTT transcription can be switched on or off, like a switch, by adding a special chemical to their drinking water. In mice where HTT transcription was switched off, they observed somatic instability slowing down. In addition, the longer HTT transcription was turned off, the less the CAG repeats grew. These results, in addition to their ASO experiments, provided good evidence that transcription was partially responsible for somatic instability. 

Zinc Finger Roadblocks

Although switching HTT on or off by adding a chemical to drinking water sounds fantastic, it only works in this specific type of genetically modified mice, which we sadly are not! So the researchers turned to a more practical approach using Zinc Finger Proteins (ZFPs), which are genetically modified proteins that attach directly onto CAG repeats and block transcription. From our analogy, ZFPs are like giant roadblocks cutting off traffic. If the delivery trucks driving over the road (representing transcription) are causing the potholes to worsen (CAG growth), then halting the traffic should slow somatic instability. 

To test ZFPs, they used a virus to deliver their DNA instructions into mouse brains. One side of the mouse’s brain got a version of the ZFP that latches onto the CAG repeat and shuts down transcription, and the other side got a version of the ZFP that binds HTT but does not shut down transcription. The ZFPs that block transcription showed an impressive 70% reduction in somatic instability. Surprisingly, ZFPs that bind to HTT but don’t block transcription still had a modest 42% reduction in somatic instability. This is good news because completely shutting down HTT transcription might be unsafe because HTT still performs important functions inside brain cells. So keeping HTT partially on while slowing somatic instability might represent a safer therapeutic approach. 

Therapeutic Directions

Collectively, these results show that dialing down HTT’s transcription not only reduces the amount of toxic HTT protein in the cell but might also slow its CAG growth. Although slowing CAG growth sounds like a home run, it’s important to reiterate that we still don’t know for sure if somatic instability is causing disease onset – it’s just a promising lead! In addition, reducing HTT transcription, which was linked to slowed somatic instability, might cause entirely unrelated problems in the cell. In our analogy, blocking package deliveries would stop the potholes from forming, but this would also surely create an angry bunch of customers waiting for their packages! 

Clinical trials using ASOs are already underway, and therapies based on ZFP are being worked on. Although there’s plenty of room for optimism, there are some important caveats. First of all, the mice used in these experiments are genetically engineered with an extreme CAG repeat mutation, because they otherwise wouldn’t show symptoms due to their short lifespan. And whether these therapies will translate effectively or safely into humans is another big question mark. For example, although ASOs and ZFPs might be tolerated within the very short lifespan of a mouse, we don’t know the long-term safety or effectiveness in humans. Regardless, we’ll be following every development closely and sharing updates as soon as they are released! 

Summary

• CAG repeats in the HTT gene keep expanding over life, and this somatic instability may contribute to HD’s delayed onset.
• ASO treatments slow repeat expansion by reducing HTT transcription, not just HTT protein levels.
• Multiple experiments, including siRNA, switchable transcription, and Zinc Finger Proteins, confirm that less HTT transcription means less CAG growth.
• Therapies targeting transcription look promising, but it’s still unclear whether slowing somatic instability will change HD onset in humans.

Learn more

Suppression of Huntington’s Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding

Ever since large genetic studies in Huntington’s disease (HD) revealed that the longer the CAG expansion, the earlier symptoms appear, we’ve known that repeat length matters. Recent work has highlighted just how that repeat length increases within vulnerable brain cells — from about 50 CAGs to over a thousand. 

Understanding how these expansions happen, and how they influence the disease, is crucial for developing the right therapeutic strategies. Can we correct the expanded DNA in affected cells? Well… maybe the cells can do it themselves!

The players in a molecular tug-of-war

DNA-repair genes can strongly influence when HD symptoms begin. For years, researchers have been asking: what do these genes actually do to the faulty stretch of DNA that causes HD? And can we harness this knowledge to delay symptom onset — perhaps long enough that the disease never develops?

A new study in Nature Communications from Petr Cejka’s group reconstructs, molecule by molecule, how two opposing DNA-repair teams compete inside our cells. One team mistakenly lengthens the CAG repeat when trying to fix it, while another trims it back. This elegant biochemical dissection finally shows why players such as MSH3, MLH3, and FAN1 have such a strong impact on disease onset — and opens new routes to slow or even prevent HD.

Why DNA repair matters in HD

DNA is stored in the nucleus forming a double helix, the letters on each strand pair precisely, like the matching teeth of a zipper.

But when the CAG sequence in the huntingtin (HTT) gene becomes too long, the strands no longer line up perfectly. One side can end up with extra “teeth,” creating a mismatch that bulges out from the helix — what scientists call an extrusion loop (imagine a zipper with a kink on one side!).

Everyone inherits some CAG repeats in their HTT gene, but in general, people with 40 or more eventually develop the disease. When these repeats get longer, the DNA can’t zip up neatly anymore, and the cell’s repair machinery rushes in to fix it. And here is where the tug-of-war game starts. Repair can go two ways: some machinery complexes smooth things out and stabilize the DNA, while others accidentally make the repeat longer and longer.

The “expansion crew”: MutSβ and MutLγ

DNA repair usually acts like a spell-checker, scanning for errors, mismatches, or small loops that appear when our DNA is copied. In HD, however, part of the repair team creates the problem.

It’s a literal tug-of-war between two DNA-repair pathways acting on the same repeat. Which side wins likely determines whether CAGs grow or shrink in a given cell.

Two complexes — MutSβ (made of MSH2 + MSH3) and MutLγ (MLH1 + MLH3) — recognize the extrusion loop that forms when there are lots of CAG repeats. Instead of removing the loop, the expansion crew uses the loop as a template and fills in extra CAGs.The result? The repeat grows even longer. MutSβ and MutLγ turn a normal repair job into a “copy-and-paste” mistake that expands the CAG number.

The “contraction crew”: FAN1 to the rescue

Enter FAN1, a nuclease — essentially a pair of molecular scissors — that can do the opposite. FAN1 recognizes these DNA loops and cuts them directly at the site of the problem. Working with helper proteins, the FAN1 crew removes extra repeats instead of adding new ones.

FAN1 also has a clever second trick: it physically blocks MutLγ from partnering with MutSβ, stopping the expansion machinery before it even starts.

A molecular tug-of-war

By setting up both reactions side by side in a test tube, the team revealed a literal tug-of-war between two DNA-repair pathways acting on the same HTT repeat. Which side wins likely determines whether CAGs grow or shrink in a given cell.

Connecting biochemistry to human genetics

The discovery that DNA repair genes affect when symptoms appear didn’t come out of the blue — it started with genome-wide association studies (GWAS) enabled by donated DNA samples from thousands of people with HD. These large-scale studies searched the entire genome for genetic variations that modify the age of onset. The clear message was that genes involved in DNA repair — like MSH3, MLH3, and FAN1 — are major players.

This new biochemical model beautifully explains why those GWAS signals point to repair genes. Variants that boost MutSβ or MutLγ activity (in MSH3 or MLH3) speed up CAG expansion and lead to earlier symptoms, while variants that enhance FAN1 activity can slow expansion and delay onset.

Scientists had long seen these correlations — now, thanks to the Cejka team’s molecular reconstruction, we can finally connect the dots between human genetics and the actual DNA chemistry that could be driving Huntington’s disease.

Why this matters

Understanding these precise mechanisms isn’t just fascinating biology — it’s a roadmap for how we could develop therapies. If we can tilt the balance toward contraction or stabilization, we might slow or even halt the disease process itself.

Some companies are already pursuing this idea:

• ASOs targeting MSH3 or inhibitors of MutSβ aim to reduce expansion activity are being developed by Ionis Pharmaceutical, LoQus23 Therapeutics and Pfizer
• Harness Therapeutics is trying to boost FAN1 function, or mimicking its blocking effect on MutLγ, could offer another route to protect HTT from runaway expansion

What’s next?

Although strong evidence suggests that somatic repeat expansion drives when symptoms begin, this remains a working model. Researchers are now trying to map how these repair processes differ across brain cell types and how they interact within living tissue.

Learning how cells naturally correct their own DNA errors could inspire treatments that let them fix Huntington’s disease from within.

The key challenge is balance: the same DNA-repair systems that sometimes lengthen the HTT repeat also protect the rest of our genome. The ultimate goal will be to fine-tune these pathways to suppress CAG expansion without compromising DNA integrity elsewhere.

If this model holds true, it could open an entirely new therapeutic avenue — targeting DNA repair itself to delay or even prevent Huntington’s disease.

Summary

• HD onset is strongly influenced by genes involved in DNA repair.
• MutSβ (MSH2–MSH3) and MutLγ (MLH1–MLH3) cooperate to nick CAG DNA, adding extra repeats.
• FAN1 and its crew cut the CAG loop instead, removing excess repeats. FAN1 also blocks the MutSβ–MutLγ partnership, preventing expansions.
• These opposing reactions explain why enhancing FAN1 or reducing MLH3/MSH3 activity could delay HD onset.

Learn more

Mechanism of trinucleotide repeat expansion by MutSβ–MutLγ and contraction by FAN1.