Gene therapy appears to slow Huntington’s disease progression

The researchers found that patients receiving the treatment experienced 75% less progression of the disease overall, compared to a matched cohort of people with Huntington’s who were not receiving the treatment.

This is the first time a drug trial has reported continuing, statistically significant slowing of Huntington’s progression.

uniQure plans to submit an application to the US Food and Drug Administration early next year requesting accelerated approval to market the drug, with applications in the UK and Europe to follow.

Huntington’s disease is a fatal neurodegenerative disease caused by a single genetic mutation. 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. About 8,000 people in the UK are currently living with Huntington’s disease.

The gene that causes Huntington’s disease was discovered in 1993 but until now, there were no effective treatments to prevent or slow the progression of the disease.

The new gene therapy, AMT-130, is the first gene therapy to be tested in people with Huntington’s, and was developed by uniQure, a gene therapy company based in the Netherlands and USA.

uniQure is announcing results now that 29 patients have completed up to 36 months of the 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 are reporting that people who were given a high dosage of AMT-130 have 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. The scientists 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. They say this suggests the course of the disease has been modified and neuronal damage slowed.

The team also found that AMT-130 is generally well-tolerated by study participants and has a manageable safety profile.

Professor Sarah Tabrizi (UCL Huntington’s Disease Research Centre, UCL Queen Square Institute of Neurology, and UK Dementia Research Institute at UCL), lead scientific advisor on the trial, said: “l am thrilled that this study of AMT-130 showed statistically significant effects on disease progression at 36 months. 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. 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 at UCL and UCLH, said: “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.

“Trial results come through in numbers and graphs, but behind each datapoint is an incredible patient who volunteered to undergo major neurosurgery to be treated with the first gene therapy we’ve ever tested in Huntington’s disease. That is an extraordinary act of bravery for the benefit of humanity.

“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.”

More about Huntington’s disease

Huntington’s disease is caused by the HTT gene, which tells our cells to make a protein called huntingtin. In its harmful form in people with the disease, this is called mutant huntingtin, and causes mounting damage to the brain over years.

The disease typically lasts around 20 years from the onset of neurological problems to death. Disability and loss of function happen fairly early on, leading to the need for intensive multidisciplinary care for decades.

About the treatment

AMT-130 is a gene therapy that permanently introduces new functional DNA into a person’s cells. It consists of particles of a harmless, empty virus, plus a set of instructions encoded in custom-made DNA. The virus is injected directly into a part of the brain called the striatum which is particularly vulnerable in Huntington’s disease. This is done using a highly complex neurosurgical technique called stereotactic surgery, in which tiny tubes called catheters are guided to the right part of the brain, supported by live MRI images. Once in the brain, the virus particles enter the neurons and release the DNA cargo.

The AMT-130 DNA becomes a permanent addition to the neuron. It contains a set of instructions for making a molecule of RNA which has been designed to bind to the RNA that is produced when a cell is making the huntingtin protein. When AMT-130 RNA binds to the cell’s own huntingtin RNA, it summons an enzyme to destroy it. As a result, the huntingtin message is deleted and less of the protein is made – permanently.

It is expected that a single dose of AMT-130 would last for a person’s whole life.

The neurosurgeries for the UK arm of the trial were conducted in Cardiff at the University Hospital Wales, by a team led by Professor Liam Gray at the Advanced NeuroTherapies Centre with Cardiff University, and funded by Health and Care Research Wales.

The trial results will be presented formally at the HD Clinical Research Congress next month in Nashville, USA.

Source: https://www.ucl.ac.uk/news/2025/sep/gene-therapy-appears-slow-huntingtons-disease-progression 

Source: Gene therapy appears to slow Huntington’s disease progression – Scents of Science