Gene therapy is becoming a powerful way to treat challenging diseases that don’t respond to traditional treatments, and researchers now report the first success in modifying genes to slow Huntington’s disease.
In a study reported by Uniqure, which developed the experimental gene therapy, scientists found that it slowed progression of Huntington’s disease by 75% over three years. The study has not yet been published in a scientific journal.
“I went into the trial cautiously optimistic but very anxious, as one does when starting a gene-therapy trial,” says Dr. Sarah Tabrizi, director of the University College London Huntington’s Disease Center and a lead investigator on the study. “I was blown away when I saw all of the data and it was very, very clear that the gene therapy worked.”
The study involved 29 patients with Huntington’s disease who were given one of two doses of gene therapy that targeted the huntingtin gene, which is mutated in the disease. The aberrant gene makes a form of the huntingtin protein that clumps into toxic aggregates, which prevent nerves from functioning normally. Eventually, nerve cells—particularly those in the part of the brain that regulates movement and cognitive skills like motivation, habit formation, and decision-making—degrade, leading to physical and cognitive symptoms.
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Everyone in the trial was monitored for a number of biological and behavioral measures, including markers for degraded nerve proteins in spinal fluid and their ability to perform normal daily activities, manage their finances, and keep working. The gene therapy involved a 12- to 15-hour brain operation in which surgeons drill through the skill to access a deep part of the brain called the striatum, where nerve cells are most affected by the damaged huntingtin protein. The surgeons injected the gene therapy, which included DNA delivered by an inactivated virus vector, coding for instructions to turn off production of the huntingtin protein.
The 17 people who received the high dose showed a 75% slowing in the progression of their symptoms overall. The 12 people who got the lower dose—which was 10 times less concentrated—showed similar progression as placebo, although some of their symptoms improved.
Because the brain surgery was invasive and risky, the researchers had to find a reliable way to evaluate what effect the gene therapy was having without subjecting some patients to a sham surgery, says Dr. Walid Abi-Saab, Uniqure’s chief medical officer. The participants who received the gene therapy were monitored for several years and compared to a group of about 2,000 untreated Huntington’s patients—because there are currently no treatments for the disease—who were matched to the study patients getting the gene therapy by factors like age and stage of disease.
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The 75% slowing in the progression of the disease among those receiving the gene therapy is “huge,” says Tabrizi, who has been studying potential therapies for Huntington’s for two decades. “I have never seen anything that shows that [benefit],” she says. In Huntington’s patients, levels of neurofilament, which is produced by damaged nerve cells, in the spinal fluid increase by 30% to 45% in the early years of the disease, Tabrizi says. People receiving the gene therapy in the study actually showed drops in their levels—below their baseline levels, in some cases. “That tells you that neurons are being saved,” she says.
She says that the encouraging results are inspiring her to think about extending the benefits to people even earlier in their disease, with the hope that they might be able to prevent many of the disease’s worst symptoms from ever appearing. The patients in the trial were at Stage II or III, but, “when people who carry the Huntington’s gene are completely well, we might be able to prevent the disease from ever occurring and prevent the symptoms from ever occurring,” she says. “I personally want to start thinking about how we can get this therapy to people at Stage 0 or I to prevent this disease.”
Matt Kapusta, CEO of Uniqure, says the therapy is “transformational” and that giving patients more time with loved ones, with milder or fewer symptoms, is “priceless.” Uniqure plans to submit a request for the U.S. Food and Drug Administration to grant accelerated approval of the gene therapy to treat Huntington’s in the first part of next year, and, if approved, is prepared to provide it to patients later in 2026.
