Overview of the Breakthrough

On September 24, 2025, uniQure, a Dutch biotechnology company, announced preliminary results from a phase 1/2 clinical trial of their experimental gene therapy, AMT-130, marking the first evidence of a treatment that meaningfully slows the progression of Huntington’s disease (HD). HD is a rare, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene, leading to the production of toxic mutant huntingtin protein that damages brain cells, particularly in the striatum region responsible for movement and cognition. Symptoms typically emerge in a person’s 30s or 40s, progressing over 10-20 years to severe motor impairment, cognitive decline, and loss of independence. Currently, no therapies exist to slow or halt its course—only symptomatic treatments are available. This trial’s results show a 75% reduction in disease progression over three years in treated patients compared to a matched untreated group, offering hope for extending “good quality life” by years or even decades.

Trial Design and Participants

The trial, known as UHT-130-101 and coordinated by University College London (UCL), enrolled 29 early-stage HD patients across sites in the US and UK. Participants received either a low or high dose of AMT-130 via a one-time stereotactic neurosurgical procedure, which involves drilling small holes in the skull to inject the therapy directly into the brain’s striatum over 12-18 hours. Seventeen patients received the high dose, and 12 received the low dose. The primary endpoint was change in the composite Unified Huntington’s Disease Rating Scale (cUHDRS), a comprehensive score assessing motor function, cognition, and daily living abilities. Outcomes were compared to a propensity score-matched external control group from the Enroll-HD natural history study, which tracks untreated HD patients.

Follow-up data cutoff was June 30, 2025, with the 36-month analysis focusing on the 12 high-dose patients who completed three years of observation. Full results will be presented at the HD Clinical Research Congress in Nashville in October 2025.

Key Results

High-dose recipients showed a statistically significant 75% slower disease progression (p=0.003) on the cUHDRS, with a mean score decline of 0.38 points versus 1.52 points in the control group. This translates to the typical one-year decline taking about four years post-treatment. Benefits extended to:

• Total Functional Capacity (TFC): A 60% slowing (p=0.01), measuring independence in daily activities like work and self-care.
• Biomarkers: Cerebrospinal fluid neurofilament light chain (NfL), a marker of neuronal damage, remained stable or decreased by 8.2% from baseline, contrasting with rises in untreated patients.

Low-dose results were less pronounced but still positive, suggesting a dose-response effect. One patient, previously medically retired due to HD, returned to work—a rare outcome in the disease’s natural course. No new drug-related serious adverse events were reported since December 2022, with the therapy deemed “generally well-tolerated” and manageable.

How the Therapy Works

AMT-130 uses an adeno-associated virus (AAV5) vector to deliver a microRNA payload directly to neurons. Once inside, it instructs cells to produce microRNA that binds to and silences the mutant HTT messenger RNA, preventing production of the toxic protein (and its highly damaging exon-1 fragment). This turns affected neurons into “factories” for ongoing therapy, potentially providing lifelong effects since brain cells don’t regenerate like other tissues. Unlike earlier antisense oligonucleotides (which failed in 2021 trials due to dilution or degradation), this approach targets the source with precision, minimizing off-target effects.

Safety, Limitations, and Accessibility

The procedure’s invasiveness—requiring general anesthesia and hospital stays—poses risks like infection or bleeding, though none were severe in this trial. Long-term monitoring continues for durability and rare events like immune responses to the virus. Limitations include the small sample size (phase 1/2 trials prioritize safety over large-scale efficacy) and lack of randomization, relying on historical controls. Larger phase 3 trials are needed for confirmation.

Cost estimates hover around $2 million per treatment, driven by the surgery and custom viral production, limiting initial access to wealthier patients or those in trials. uniQure aims to streamline manufacturing and seek broader reimbursement. If given earlier (e.g., pre-symptomatically), it could potentially prevent onset, as suggested by lead investigator Prof. Sarah Tabrizi.

Next Steps and Broader Implications

uniQure plans a Biologics License Application (BLA) submission to the FDA in early 2026, leveraging the cUHDRS as a surrogate endpoint with NfL as supportive evidence for accelerated approval. Similar filings are eyed for Europe. This could inspire therapies for other triplet-repeat disorders like ALS or spinocerebellar ataxias, and even broader neurodegenerative conditions by validating brain-targeted gene silencing. As Prof. Ed Wild noted, it’s “the dawn of a new age” for HD families, with about 75,000 affected in the US, UK, and Europe, plus hundreds of thousands of at-risk carriers.

The HD community reacted with joy and cautious optimism on platforms like X, with posts highlighting patient bravery and the therapy’s potential to restore independence. This isn’t a cure, but it’s the closest yet to rewriting HD’s devastating timeline.