Gene therapy slows Huntington's disease progression in trial

A global clinical trial of a new Huntington’s disease treatment has posted positive results, with patients receiving the treatment found to experience 75% less progression of the disease overall. This is understood to be the first gene therapy to be tested in people with Huntington’s, and the first time a drug trial has reported continuing, statistically significant slowing of Huntington’s progression.

Huntington’s disease is a fatal neurodegenerative disease caused by a single mutation in the HTT gene, leading to the production of an abnormally misfolded and aggregated protein called huntingtin. People with an affected parent have a 50% chance of inheriting the mutation, meaning they will develop disease symptoms — typically in mid-adulthood — affecting their movement, thinking and behaviour. The problem gene was discovered in 1993, but current therapies can only manage symptoms like movement difficulties and mood changes — they do not alter disease progression.

The new treatment, known as AMT-130 and developed by gene therapy company uniQure, consists of a vector and a gene encoding a microRNA (miRNA). The vector is based on a harmless, empty virus that has been changed to carry and deliver a gene encoding a miRNA that will recognise, bind and lower the human huntingtin protein. It is expected that a single dose of AMT-130 — which is delivered into the brain using a highly complex neurosurgical technique called stereotactic surgery — would last for a person’s whole life.

uniQure has now announced that 29 patients have completed up to 36 months of a phase I/II clinical trial, 12 of whom were given a high dose and have a full 36 months of data. The participants’ progression is being compared to an external cohort of people with Huntington’s disease, who are part of a long-running natural history study called Enroll-HD, to predict the extent of disease progression that would have been expected if the patients were only receiving standard care.

The study team reported that people who were given a high dosage of AMT-130 experienced 75% less disease progression after 36 months as measured by the composite Unified Huntington’s Disease Rating Scale, which incorporates motor, cognitive and functional measures, compared to a matched cohort of Enroll-HD participants. There was also a statistically significant benefit as measured by another key scale of disease progression, Total Functional Capacity, and in three other measures of motor and cognitive function.

The researchers were also measuring participants’ levels of neurofilament light protein (NfL), a protein that is released into the spinal fluid when neurons are injured, as it is a useful marker of neuronal damage and is elevated in people with Huntington’s disease. They found that NfL levels in the spinal fluid were lower in people treated with the drug than they had been at the start of the trial, even though NfL levels would be expected to increase by 20–30% over three years. This suggests the course of the disease has been modified and neuronal damage slowed.

“These groundbreaking data are the most convincing evidence in the field to date and underscore the disease-modifying effect in Huntington’s disease, where an urgent need persists,” said Professor Sarah Tabrizi, lead scientific advisor on the trial, from University College London (UCL). “For patients, AMT-130 has the potential to preserve daily function, keep them in work longer, and meaningfully slow disease progression.”

Professor Ed Wild, principal investigator of the UCL Huntington’s Disease Centre trial site, added, “This result changes everything. On the basis of these results it seems likely AMT-130 will be the first licensed treatment to slow Huntington’s disease, which is truly world-changing stuff. If that happens, we need to work hard to make it available to everyone who needs it, while working no less diligently to add more effective treatments to the list.

“My patients in the trial are stable over time in a way I’m not used to seeing in Huntington’s disease — and one of them is my only medically retired Huntington’s disease patient who has been able to go back to work.”

Dr Walid Abi-Saab, Chief Medical Officer at uniQure, concluded, “These findings reinforce our conviction that AMT-130 has the potential to fundamentally transform the treatment landscape for Huntington’s disease, while also providing important evidence supporting one-time, precision-delivered gene therapies for the treatment of neurological disorders.

“We are eager to discuss the data with the FDA at our pre-Biologics License Application meeting expected later this year, with the goal of submitting a BLA in the first quarter of 2026.”

The trial results will be formally presented at the 2025 HD Clinical Research Congress in Nashville, USA, in the coming days.

Image credit: iStock.com/Dr_Microbe