Four Years In, uniQure's Huntington's Gene Therapy Still Slows Decline as It Heads to the FDA
On September 29, 2026, uniQure released four-year results for AMT-130, its one-time gene therapy for Huntington's disease. Patients who received the high dose were still declining more slowly than a matched comparison group, 48 months after a single surgery.
The update arrives just weeks after uniQure asked the FDA to approve the treatment. It also showed a smaller effect on one key measure than the three-year data did, and uniQure's stock fell about 40% the next day. Here is what the numbers say and why they are being read in two very different ways.
Why Huntington's is hard to treat
Huntington's disease is caused by an expanded CAG repeat in the HTT gene. The mutation produces a toxic form of the huntingtin protein that slowly damages neurons, especially in the striatum, a deep brain region made up of the caudate and putamen. Symptoms usually begin in mid-adulthood and include involuntary movements, loss of thinking skills, and psychiatric changes. Each child of an affected parent has a 50% chance of inheriting the gene.
There is no approved treatment that slows the disease. Current medicines only manage symptoms such as chorea. Because the striatum sits deep in the brain, getting any therapy there in a lasting way has been a major obstacle.
How AMT-130 works
AMT-130 (ifezuntirgene inilparvovec) uses an AAV5 vector to deliver a gene that encodes a microRNA targeting HTT messenger RNA. Once inside neurons, the microRNA binds the HTT message and triggers its breakdown, so cells make less huntingtin protein. It lowers both the mutant and the normal forms.
The vector is given once, through MRI-guided neurosurgery that infuses it directly into the caudate and putamen. Because the DNA stays in the treated neurons, the goal is lasting huntingtin lowering from a single procedure. If you are new to how AAV vectors deliver genes, my book The Life-Changing Power of Gene Therapy walks through the basics.
What the four-year data showed
The analysis covered 12 patients on the high dose and 12 on the low dose, followed for 48 months. With no placebo group, uniQure compared them with an external control: matched patients from Enroll-HD, a large natural-history study of people living with Huntington's.
Composite UHDRS (cUHDRS), which combines movement, thinking, and daily-function scores: high-dose patients declined 44% more slowly than the updated control group. This difference was not statistically significant (p = 0.144). Against the control group used in earlier analyses, slowing was 53.5% (p = 0.041).
Total Functional Capacity (TFC), which measures everyday abilities such as working, managing money, and self-care: high-dose patients declined 61% more slowly (p = 0.008). Against the earlier control, slowing was 68.3% (p = 0.001).
Neurofilament light chain (NfL) in spinal fluid, a marker released when neurons are damaged, was only 4% above baseline after four years in the 11 patients measured. In untreated Huntington's, NfL usually rises steadily.
The TFC result is the strongest signal. The NfL result matters because it is a biological measure that does not depend on how a patient is scored on a given day.
Why the comparison group matters
The headline cUHDRS number changed partly because uniQure updated its external control. Different rules for picking matched patients from Enroll-HD give different estimates of how fast untreated people decline, and that changes the size of the treatment effect.
This is the central weakness of single-arm trials. Patients in natural-history studies drop out over time, and the ones who stay may not represent everyone. Researchers in the Huntington's community have pointed out that missing data in these registries can tilt comparisons in either direction. Analysts also noted that the cUHDRS effect at four years looked weaker than at three years, which drove the sharp drop in uniQure's share price, a loss of roughly $1 billion in market value.
None of this means the drug stopped working. It does mean the size of the benefit is uncertain, and that the FDA will have to judge an effect measured against a moving reference point.
Safety
The surgery and the vector carry real risks.
Five high-dose participants (17%) had serious inflammation in the central nervous system that was judged related to treatment. All cases resolved.
Headaches and inflammation after surgery were the most common side effects.
One patient in the low-dose group died about five years after treatment. Investigators assessed the death as unrelated to AMT-130.
What happens next
The regulatory path has not been smooth. In March 2026 the FDA questioned whether external-control data could support approval. In June, the agency reversed course and agreed that the three-year results could serve as the main evidence.
On September 2, 2026, uniQure submitted a Biologics License Application to the FDA seeking accelerated approval, along with a marketing application to the UK's MHRA. The filing rests on the three-year data. The four-year results will be part of the review, but they are not the basis of the application. A public decision date has not been confirmed.
If approved, AMT-130 would be the first therapy shown to slow Huntington's disease, not just treat its symptoms.
The bottom line
Four years after one surgery, high-dose AMT-130 patients are still losing everyday function more slowly than comparable untreated patients, and a nerve-damage marker has barely moved. The weaker composite score and the reliance on an external control give regulators real questions to answer. For families living with Huntington's, the next few months at the FDA will decide whether this becomes the first disease-slowing option.
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