AMT-130 Trial for Huntington’s Treatment Slows Progression

In a significant development for the field of neurodegenerative medicine, updated data released in late 2025 regarding the investigational gene therapy AMT-130 indicates a potential breakthrough in Huntington’s treatment.

According to reports covering the ongoing Phase I/II clinical trials by biotechnology firm uniQure, the therapy has demonstrated the ability to slow disease progression by approximately 80% in patients receiving high-dose interventions. This data, gathered over a 36-month follow-up period, suggests that AMT-130 may be the first therapeutic agent capable of fundamentally altering the biological course of this fatal condition, moving the field beyond mere symptom management.

The Pathology of Huntington’s Disease

To understand the significance of this trial, one must first look at the mechanism of the disease. Huntington’s is an autosomal dominant genetic disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. This mutation leads to the production of a toxic, mutant protein (mHTT) that aggregates within neurons, specifically targeting the striatum—the brain region responsible for motor control, habit formation, and reward systems.

As these neurons degrade, patients experience the hallmark triad of HD symptoms: chorea (involuntary movements), cognitive decline, and psychiatric disturbances. Until now, pharmacological interventions have been limited to managing these downstream behaviors without addressing the upstream production of the toxic protein.

The Mechanism of AMT-130

AMT-130 represents a shift toward etiological treatment—treating the root cause. It is not a small-molecule drug, but a gene therapy utilizing an AAV5 viral vector (adeno-associated virus serotype 5).

The mechanism of action is RNA interference. The viral vector is engineered to carry a microRNA (miRNA) payload. Once delivered into the nucleus of the patient’s neurons, this miRNA binds specifically to the messenger RNA (mRNA) produced by the huntingtin gene. By binding to the mRNA, it triggers the cell’s natural degradation machinery to destroy the blueprint before the toxic protein can be manufactured.

This process, known as “gene silencing,” effectively lowers the total burden of mutant huntingtin protein in the brain, theoretically preserving neuronal integrity.

Analysis of the Clinical Data

The data reported in New Scientist and supported by uniQure’s clinical updates highlights a dose-dependent response. The trial compared patients receiving the gene therapy against a natural history cohort (a database of how the disease typically progresses in untreated patients).

• Composite UHDRS Scores: The primary metric used was the Composite Unified Huntington’s Disease Rating Scale (cUHDRS), which combines measures of motor function, cognitive capacity, and functional independence. At the 36-month mark, patients in the high-dose cohort showed an 80% slowing of clinical decline compared to the natural history baseline.

• Biomarker Evidence (NfL): Crucially, the study monitored levels of Neurofilament Light Chain (NfL) in the cerebrospinal fluid (CSF). NfL is a structural protein released when neurons are damaged or die. In typical HD progression, NfL levels rise as brain atrophy accelerates. In the AMT-130 trial, treated patients showed NfL levels that remained below baseline, providing biological corroboration that neurodegeneration was being physically halted, not just masked.

Neurosurgical Delivery

Unlike systemic drugs that struggle to cross the Blood-Brain Barrier (BBB), AMT-130 requires direct neurosurgical administration. The therapy is delivered via convection-enhanced delivery (CED) directly into the caudate and putamen (the striatum).

This localized delivery is strategic. By saturating the striatum—the epicenter of HD pathology—neurosurgeons aim to protect the most vulnerable circuits while minimizing off-target effects in other parts of the body. The 2025 data suggests that this one-time surgical intervention provides durable gene expression, meaning patients may not require repeated doses.

Future Implications and Regulatory Status

The success of AMT-130 has garnered it the RMAT (Regenerative Medicine Advanced Therapy) designation from the US FDA, a status reserved for therapies that show potential to address unmet medical needs for serious conditions.

While the sample size of the Phase I/II trial remains relatively small, the magnitude of the effect—an 80% preservation of function—is statistically robust enough to warrant accelerated movement toward Phase III pivotal trials.

For the neurology community, this offers a proof-of-concept for intracranial gene therapy. If AMT-130 can successfully silence the huntingtin gene, similar AAV-vector approaches could theoretically be adapted for other protein-aggregation disorders, such as certain forms of Alzheimer’s (targeting tau or amyloid) and SOD1-ALS.

Conclusion

The 2025 data on AMT-130 marks a transition point for Huntington’s research. We are moving from an era of palliative psychiatric care to an era of molecular neurosurgery. By targeting the genetic architecture of the disease, science is finally catching up to the biological reality of the condition. Source