Gene therapy is emerging as a powerful way to treat complex diseases that are resistant to traditional treatments, and now researchers are reporting the first success in modifying genes to slow Huntington's disease.
In a study published by Uniqure, which developed the experimental gene therapy, scientists found that it slowed the progression of Huntington's disease by 75% over three years. The study has not yet been published in a scientific journal.
“I approached the study with cautious optimism but a lot of trepidation, as is the case when starting a gene therapy trial,” said Dr. Sarah Tabrizi, director of the Huntington's Disease Center at University College London and the study's lead investigator. “I was shocked when I saw all the data and it became very, very clear that gene therapy works.”
The study involved 29 patients with Huntington's disease who were given one of two doses of gene therapy targeting the huntingtin gene, which is mutated in the disease. The aberrant gene creates a form of the huntingtin protein that clumps together into toxic aggregates that interfere with normal nerve function. Eventually, nerve cells, especially in the part of the brain that regulates movement and cognitive skills such as motivation, habit formation and decision-making, degrade, leading to physical and cognitive symptoms.
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All study participants were monitored on a range of biological and behavioral measures, including markers of neural protein degradation in the cerebrospinal fluid, and their ability to perform normal daily activities, manage their finances and continue to work. The gene therapy involved a 12- to 15-hour brain operation in which surgeons honed their skills in accessing a deep part of the brain called the striatum, where nerve cells are most affected by damaged huntingtin protein. The surgeons administered gene therapy that included DNA delivered by an inactivated viral vector encoding instructions to turn off the production of the huntingtin protein.
The 17 people who received the high dose experienced a 75% slowdown in symptom progression overall. The 12 people who received the lower dose (which was 10 times less concentrated) experienced the same progress as the placebo, although some of their symptoms improved.
Because brain surgery was invasive and risky, researchers had to find a reliable way to evaluate the effect of gene therapy without subjecting some patients to sham surgery, says Dr. Walid Abi-Saab, Uniqure's chief medical officer. Participants who received gene therapy were followed for several years and compared with a group of about 2,000 untreated patients with Huntington's disease (as there are currently no treatments for the disease), who were matched with study patients who received gene therapy on factors such as age and stage of the disease.
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A 75% slowing of disease progression among those receiving gene therapy is “huge,” says Tabrizi, who has been studying potential treatments for Huntington's disease for two decades. “I've never seen anything to indicate that. [benefit]”In Huntington's patients, the levels of neurofilaments, which are produced by damaged nerve cells, increase in the cerebrospinal fluid by 30 to 45% in the early years of the disease,” Tabrizi says. The people who received the gene therapy in the study actually saw their levels decrease—in some cases below their baseline levels. “This suggests that the neurons are being preserved,” she says.
She says the encouraging results are encouraging her to consider extending the benefits to people even in the early stages of the disease, in the hope that they could prevent many of the disease's worst symptoms from occurring. The patients in the study were in stage II or III, but “when people who carry the Huntington's gene are completely healthy, we can prevent the disease from occurring and prevent symptoms from occurring,” she says. “Personally, I want to start thinking about how we can provide this therapy to people at stage 0, or to me, 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 “invaluable.” Uniqure plans to submit a request to the US Food and Drug Administration for accelerated approval of the gene therapy for Huntington's disease in the first half of next year and, if approved, is poised to make it available to patients later in 2026.
