September 2025: This Month in Huntington’s Disease Research

This month brought landmark therapeutic news, advances in biomarkers, deeper insights into what drives Huntington’s disease (HD), and fresh perspectives on mental health in HD. In particular among the developments, we learned from uniQure that the AMT-130 gene therapy appears to be slowing disease progression in their trial. Across the board, all of these updates speak to how far the field has come, and how many exciting directions remain.

A Big Milestone: AMT-130 Gene Therapy Offers Hope, but Caveats Remain

The headline story of the month was a press release from uniQure about their gene therapy, called AMT-130, which is designed to lower huntingtin protein levels in the brain. In this release we learnt that the trial met its primary endpoint as the data indicate approximately 75% slowing of disease progression based on cUHDRS, a clinical metric based on measures of lots of different signs and symptoms of HD. This is the first time a gene therapy for HD has shown the potential to modify disease progression in humans. 

Despite this hopeful news, key questions remain: what is the durability of effect? How about the long-term safety? What stage of disease might, or might not, benefit from this treatment? The underlying data for the conclusions made by the company in the release have not yet been shared or gone through the peer review proceed. There are sure to be more updates, and lots of discussion, on uniQure’s approach in the coming months. 

Huntingtin-Lowering and Other Therapeutic Strategies

SKY-0515 Trial Update: 

This small molecule therapy, a pill taken by mouth, showed dose-dependent lowering of huntingtin in people with HD and was reported to have a possible secondary effect on the DNA repair protein PMS1. It is early, but the results from Skyhawk Therapeutics add momentum to other approaches which aim to lower huntingtin levels, like AMT-130.

PROOF-HD Revisited: 

The results of the PROOF-HD trial were published in a peer reviewed journal. PROOF-HD set out to test pridopidine, to see if this drug might improve signs and symptoms of HD but did not meet its endpoints. In this publication, the data were dissected, highlighting some possible subgroup effects, potential variables which could have confounded the effect of pridopidine, and lessons for future trial design.

Together, these studies show that multiple therapeutic strategies, with very different approaches, are progressing, with some showing promise. 

Biomarkers, Brain Imaging, and Drivers of Disease

DNA Repair and Expanded Huntingtin:

September featured several articles from the HDBuzz Prize for young science writers, sponsored this year by the Huntington’s Disease Foundation (HDF). In a winning article by Mustafa Mehkary, we learned how expanded huntingtin may disrupt some aspects of the DNA repair process. What should be a protective cellular process instead becomes a liability, leaving nerve cells vulnerable to accumulating damage.

Electrophysiology: Early Clues in Brainwaves

Another prize winning article from Eva Woods focused on brain activity, showing how EEG recordings reveal differences in people who carry the HD gene before symptoms appear. These subtle brainwave changes could become useful biomarkers for identifying early disease features and testing new treatments.

MRI and Awareness (Anosognosia)

A third prize article from Jenna Hanrahan highlighted how MRI scans may help explain anosognosia, the reduced self-awareness some people with HD experience. Linking brain structure changes with this symptom bridges neuroscience with the lived reality of HD, opening the door to better support and interventions.

These mechanistic and biomarker advances will be essential both for understanding disease and for powering future clinical trials.

Mental Health, Care, and Lived Experience

Another winning HDBuzz prize article from Nicolo Zarotti explored a case study of Acceptance and Commitment Therapy (ACT). In this instance, ACT improved psychological well-being for both a person with HD and their caregiver. It underscores how mental health strategies can complement biomedical advances, helping families navigate the challenges of HD with resilience and support.

Themes That Unified the Month

1. Therapies have the potential to change the course of HD reality

With the cautious optimism we have for AMT-130’s success and encouraging data from SKY-0515, HD is no longer just a target for future therapies but now entering a new era of interventions that might tangibly move the needle.

2. Biomarkers and mechanisms setting the stage

Development of biomarkers such as EEG, MRI, and molecular marker measurements, as well as mechanistic insights into the drivers of HD, like DNA repair disruption, are paving a clearer path for how we design, test and understand new treatments.

3. Holistic care matters

Therapeutics are vital, but mental health, caregiver support, and quality of life perspectives continue to be crucial complements to scientific advances.

4. Transparency and trust

Open publication of trial results, such as the PROOF-HD study, allows the HD community to scrutinize findings and learn from them. We hope to see the same level of openness for AMT-130.

Falling Into Hope

HDBuzz has launched “Falling Into Hope”, an 8-week campaign to raise $30,000 by October 28, 2025. This pivotal year in HD research brings us closer than ever to disease-modifying treatments, and independent, unbiased reporting has never been more important.

Unlike many organizations in the HD landscape, we make a deliberate choice not to accept funding from pharmaceutical companies. That independence means you can trust us to remain unbiased, especially as we get closer to having disease-modifying drugs.

Your gift makes the difference between simply reporting on progress and ensuring every HD family, everywhere, has the knowledge they need to face the future with the knowledge they’ll need as we advance toward disease-modifying therapies. Please consider donating if you’re able.