In an hours-long brain surgery, doctors delivered a new piece of genetic code directly into patients’ brains. Early data suggests this one-time procedure could treat Huntington’s disease. It may be up for FDA review as soon as 2026.
Doctors have tested, for the first time, a gene therapy that could treat Huntington’s disease with just a single brain surgery. The experimental treatment, called AMT-130, uses a virus to deliver a piece of genetic code that shuts down production of the toxic protein behind this incurable and fatal neurodegenerative disorder.
Huntington’s is caused by a mutation in the HTT gene, which leads to the production of the toxic form of the Huntingtin protein. Symptoms of the disease usually start when someone is in their 30s or 40s, affecting movement and coordination and eventually progressing to cognitive decline and psychiatric problems.
This new genetic treatment, developed by gene therapy company uniQure, could change that. In a three-year, 17-patient, Phase 1/2 trial, it appeared to slow down disease progression.
The therapy uses a small piece of genetic code, called microRNA, designed to prevent the mutated form of the Huntingtin protein from forming. It’s packed into a virus and delivered to the brain via a 12- to 18-hour brain surgery. This is a one-time procedure.
“These findings reinforce our conviction that AMT-130 has the potential to fundamentally transform the treatment landscape for Huntington’s disease,” Dr. Walid Abi-Saab, MD, chief medical officer of uniQure said in a press release. He hopes the findings will support broad efforts for developing “one-time, precision-delivered gene therapies for the treatment of neurological disorders.”
What the trial found
UniQure enrolled 29 people with Huntington’s disease into their study. Seventeen received a high dose of the gene therapy, while 12 received a low dose.
Since the study didn’t have a placebo group, the researchers compared the progression to historical data that followed patients progressing with the disease. The researchers used the 18-point composite Unified Huntington’s Disease Rating Scale, which combines movement and cognitive symptoms, as well as day-to-day function, to monitor changes in their condition. On this scale, higher scores indicate more decline.
On average, historical data showed that people with the disease decline by 1.52 points over three years. However, the study participants who received the gene therapy declined by 0.38 points, a difference of 1.14 points (or a slowing of the disease by 75 percent).
Some researchers suggest that a 1.2 point change on this scale is needed to be noticeable for patients and doctors. The benefits in this trial fall just short of this number.
Participants receiving the high dose of the drug also showed benefits on some, but not all, other scales of motor and cognitive ability. So far, AMT-130 appears to be safe: None of the participants experienced any serious drug-related side effects.
What do other experts think about the results?
Though the results of the trial haven’t been reviewed by outside scientific experts and published in a scientific journal, the press release generated cautious excitement.
Paresh Malhotra, a professor at Imperial College London, called the findings a “potential major step” in treating the disease, while David Rubinsztein of the Cambridge Institute for Medical Research described the results were “promising.”
Dr. Roger Baker, neurologist and professor at the University of Cambridge, was more cautious, writing that “the results are encouraging, but it is early days and we have been here before with other similar therapies for Huntington’s disease.”
Indeed, it is early for optimism: For example, in 2017, many outlets reported “excitement” and “enormously significant” results for a gene therapy called Ionis-HTTRx, also called tominersen, after drugmaker Ionis Pharmaceuticals shared early trial results — but the drug was discontinued during its Phase 3 trial in 2021 because of its lack of efficacy.
Neuroscientist Bryce Vissel at UNSW Sydney in Australia noted just how early on scientists are in determining whether this therapy works: “These findings are an early snapshot of results reported by the company, not yet peer-reviewed,” he wrote. “The study compared treated patients to an external matched control group, not people randomized to placebo at the same time. This design can introduce bias. The numbers are also small – only 12 patients at the three-year mark – so we can’t draw solid conclusions.”
What’s next for this Huntington’s disease stem cell treatment?
Uniqure is running two more combination Phase 1 and 2 trials of the drug in the U.S. and Europe to find out the ideal, safe dose for the treatment.
The U.S. study of 26 participants includes 10 who underwent surgery but did not receive gene therapy allowing researchers to control for this effect. If all goes well, UniQure hopes to file for approval with the Food and Drug Administration early next year.
What about other genetic therapies for the brain?
Meanwhile, several companies and researchers are trying out various forms of gene therapy to treat neurodegenerative diseases, including Alzheimer’s.
Biogen, one of the drug makers behind Leqembi and now retired Aduhelm, is testing their drug BIIB080 that stops the formation of tau proteins, which form toxic tangles in Alzheimer’s. Researchers at Ohio State are in the earliest stages of testing a gene therapy that boosts the levels of a neuroprotective protein to slow the course of the disease. Lexeo Therapeutics is testing whether inserting a copy of a protective gene called ApoE3 could slow the disease.
Though the jury is out on gene therapy for Alzheimer’s, the data from these trials will help researchers know if they’re on the right track.