A brain scan of a person with Huntington’s disease, which causes a loss of brain volume as neurons are killed off by the accumulation of a mutant protein.Credit: Zephyr/Science Photo Library
A one-time gene therapy can markedly slow the progression of Huntington’s disease, potentially paving the way for the first ever treatment to alter the course of this rare, inherited brain disorder.
In a small trial of 29 people who were in the early stages of Huntington’s-related decline, participants who received a high dose of the therapy directly into their brains saw the disease slow by 75% over three years, compared with those in a control group.
Genetic therapies offer new hope against incurable brain diseases
The benefit was statistically significant across several clinical measures, according to data released this week by uniQure, a gene-therapy company based in Amsterdam. Trial investigators also observed a reduction in the level of a toxic protein linked to neurodegeneration in the spinal fluid of people who received the therapy. On the strength of these findings, uniQure executives said they plan to seek regulatory approval for the treatment next year.
“This gene therapy is obviously a big step forward,” says Sandra Kostyk, a neurologist at the Ohio State University Wexner Medical Center in Columbus, who was involved in the trial. “The data look quite good.”
Slowing the disease’s advance could translate into many extra years of independence for people with Huntington’s, Kostyk says, but it is not a cure. And, with so few participants, the trial’s results — still unpublished — should be viewed as preliminary, she adds. “I think we need more time and more data.”
A deadly repeat
People living with Huntington’s disease typically see their symptoms progress year by year, usually starting between the ages of 35 and 55. What often begins as a subtle loss of coordination or forgetfulness then often progresses to involuntary movements, sharp mood swings and a gradual unravelling of memory and thought.
The disease is caused by excessive DNA repeats in a gene called huntingtin, which leads to the production of a faulty protein that slowly poisons the brain. There are currently no therapies that address this root cause, so those who inherit the mutation are left only with drugs that ease symptoms.
Some of the first attempts to develop a treatment focused on antisense therapy, a gene-targeted strategy that uses short strands of DNA or RNA to dial down production of the defective huntingtin protein. The approach showed promise in early clinical development1. But hopes dimmed in 2021 after a leading candidate failed in late-stage testing, with those receiving the therapy seeming to fare worse than those who were given a placebo2.
This clinical setback redirected attention towards a different strategy: gene therapy, which aims to provide a one-time intervention that permanently silences or modifies the deficient gene at its source.
Molecular muzzle
In the case of uniQure’s gene therapy, the treatment uses a harmless virus to deliver the recipe for making a short RNA sequence known as a microRNA directly into cells in the affected parts of the brain. The microRNA is designed to ‘muzzle’ the defective huntingtin gene — and stop the cells producing the faulty protein — by blocking the molecular instructions encoded by the gene, known as mRNA. Once delivered, the virus-encoded instructions stay inside the cells, which continue to produce the therapeutic microRNA. The discovery of microRNAs was feted with a Nobel Prize last year, although the technology has yet to yield any approved medicines.
Administering the treatment requires a lengthy surgery in which clinicians use magnetic resonance imaging to precisely place a cannula through small holes in the skull. The therapy is then infused slowly into the striatum, a part of the brain that is among the first and hardest hit by Huntington’s disease.
