November 2025: This Month in Huntington’s Disease Research

Welcome back to the HDBuzz monthly research roundup! November was a busy month, with new developments in everything from gene therapy and stem cells to DNA repair, genetic modifiers, and protein folding. Here’s a friendly guide to what scientists learned this month, why it matters, and what it might mean for the future of Huntington’s disease (HD) research and treatment.

uniQure and FDA No Longer in Alignment on Approval Pathway for AMT-130

The most closely watched HD gene therapy program, uniQure’s AMT-130, hit a significant regulatory road bump as uniQure shared a press release stating they are no longer in alignment with the U.S. Food and Drug Administration (FDA). While the company had hoped to use an “external control group” (data from registries such as Enroll-HD) to support their application for approval, the FDA says it won’t accept this approach.

This doesn’t mean the data from the AMT-130 clinical trial shared last month don’t hold true. But it does mean the FDA wants uniQure to use more traditional comparison data before moving forward with a possible approval. Regulatory strategy can change a timeline even when the science looks promising.

This is a reminder that scientific progress and regulatory progress don’t always move at the same speed. Gene therapies for HD, like AMT-130, are still promising, but the path to approval might take longer or require new types of evidence.

SOM3355 moves toward a Phase 3 trial

In more positive news, SOM3355, a drug originally developed for other neurological conditions, received encouraging regulatory signals from both the European Medicines Agency and the U.S. FDA. A Phase 3 clinical trial is now in preparation. SOM3355 is not a disease-modifying therapy; instead, it targets symptoms, potentially addressing movement difficulties, behaviour, or mood.

While the hunt for disease-modifying treatments continues, symptom-focused drugs can make an immediate difference in quality of life for people with HD. If Phase 3 results are positive, SOM3355 could become a valuable new option for treating HD symptoms.

A “tooth fairy” stem-cell therapy enters early clinical testing

A small clinical trial tested a novel approach: infusing people with HD with dental pulp stem cells obtained from human teeth. The treatment was safe, and some participants showed small improvements on clinical measurements. But the study was small, only ran for a relatively short time, and the underlying of the biology of the rationale for how this approach might be working remains uncertain.

It’s an encouraging sign that researchers are exploring bold and diverse ideas, but the HD community should remain cautious. Larger, controlled trials are needed before drawing conclusions about whether this therapy can truly help.

Intermediate CAG repeats behave more like HD than once thought

Scientists took a deep look at “intermediate” CAG repeats; CAG numbers that fall below the traditional disease threshold but above typical “normal” ranges. Using ultra-sensitive methods, they found that even these intermediate alleles can undergo somatic expansion, the same DNA-instability process that drives HD onset and progression.

Surprisingly, this expansion didn’t neatly predict symptoms or disease. People with similar repeat instability differed widely in clinical outcomes. This supports the idea that HD risk exists on a spectrum. CAG length is important, but it’s not destiny, and DNA repair, genetic modifiers, and other biological factors might shift that risk substantially.

Cracking the structure of DNA repair: MutSβ in the spotlight

Repeat expansion in HD is strongly influenced by DNA mismatch repair, the system cells use to fix errors in DNA copying. Researchers have revealed new high-resolution structures of MutSβ, one of the key repair complexes involved in CAG repeat instability.

These structures show how MutSβ recognizes and binds DNA loops (including those formed by repeated CAG sequences), and they hint at why its activity sometimes makes things worse rather than better. Understanding these molecular machines could help scientists design therapies that slow or prevent somatic expansion, potentially delaying onset or slowing progression for people with HD.

A tiny genetic tweak that boosts the cell’s cleanup crew

A newly identified genetic variant may help delay HD onset by ramping up the cell’s recycling and cleanup pathways, especially autophagy, the system cells use to remove damaged proteins and waste. This is part of a growing wave of research showing that genetic modifiers (genes other than HTT) can accelerate or delay symptoms.

Modifiers are rewriting the story of HD. Even people with the same CAG repeat length can show dramatically different ages of onset. Understanding these modifiers might someday help researchers design treatments that mimic their protective effects.

Untangling protein folding in HD

Expanded huntingtin protein can misfold and forms harmful aggregates, but the details of this process have been notoriously hard to nail down. New structural biology tools are giving researchers a clearer look at how the expanded protein folds incorrectly, and how that misfolding leads to toxicity.

The metaphor in the article’s title captures it well: imagine trying to fold a shirt that suddenly has sleeves three times longer than expected. Better understanding of misfolding opens the door to new strategies, molecules that stabilize huntingtin, prevent aggregation, or help cells clear misfolded proteins more efficiently.

What we learned this month

Across November’s articles, several themes emerge:

1. Risk and progression are nuanced

Intermediate CAG alleles and genetic modifiers show that HD is perhaps more complex than a single genetic change.

2. DNA repair remains a key driver of HD biology

Multiple studies point to somatic repeat expansion as a central player, a target for future therapies.

3. Discovery science is thriving

From high-resolution protein structures of genetic variants, basic research continues to uncover the molecular foundations of HD.

4. Clinical innovation is broadening

Gene therapy, small molecules, and even stem-cell approaches are all being explored, each with its own challenges and opportunities.

5. Regulator–industry alignment matters

The AMT-130 story shows that even promising science can hit speed bumps. Patience and persistence are part of progress.

Looking ahead

As 2025 winds down, HD research is more active, more interdisciplinary, and more globally connected than ever. Whether it’s genetic modifiers, new drug targets, or next-generation clinical trials, momentum is building on many fronts simultaneously.

Stay tuned for the HDBuzz end-of-year review, where we’ll recap the most important HD research stories of 2025, and look forward to what’s coming next.