Even hearing the phrase “Huntington’s disease” will make a room suddenly somber. So the joy that accompanied a recent announcement of results of an experimental gene therapy for the deadly diseases signaled an unfamiliar sense of hope.
In a small clinical trial, brain injections of a virus that codes for a tiny segment of RNA may have prevented the formation of the rogue proteins that make Huntington’s so devastating. The early results, announced September 24 in a news release, show that over three years, the treatment slowed Huntington’s progression by up to 75 percent. While not a cure, the treatment could potentially give people living with Huntington’s disease, who might otherwise face early disability and death, the gift of many more years of life.
“We’re doing science because it’s interesting and important, but we’re also in this game to save our friends and family from a horrible fate,” says Ed Wild, a neurologist at University College London. “That’s the most meaningful thing, looking my friends in the eye and [saying], ‘We did it.’”
Huntington’s disease currently has no effective treatments or cures. It is relatively rare, affecting about 7 out of every 100,000 people, and is the result of mutation in a single gene, appropriately called huntingtin. In the disease, that gene is mutated in only one way, making the front end of the resulting protein grow, says Russell Snell, a geneticist at the University of Auckland in New Zealand who was not involved in the study.
This expanded huntingtin is a protein gone toxic. It aggregates in the brain and kills cells largely in brain areas crucial for voluntary movements. Patients end up with increasing involuntary movements, stiffness, difficulties speaking and swallowing and cognitive decline. Huntington’s is genetically dominant — it takes only one copy of the defective gene to cause it — so a patient’s offspring have a 50 percent chance of inheriting the disease.
Wild and his colleagues, working with the Dutch pharmaceutical company uniQure, used microRNA — tiny segments of RNA that can trigger machinery to break down huntingtin RNA before it gets made into protein. Some other trials have tried simply injecting some of these RNAs, but have not succeeded, possibly because they were injected into the cerebrospinal fluid and couldn’t infiltrate the right areas of the brain.
This time, the scientists injected them directly into the brain, packaged inside a well-studied viral vector. The virus would “infect” neurons in the brain with the RNA, and “it basically reprograms the neuron to become a factory for a molecule that tells it not to make huntingtin protein,” Wild says.
In a surgery lasting 12 to 18 hours, 17 patients with early symptoms of Huntington’s disease received injections of viral payload into three spots on each side of the relevant brain areas. The research team then assessed 12 of those patients for 36 months, testing their motor scores, attention, working memory and how well they could go about their daily lives. “It was heroic, really, on behalf of the patients and on behalf of the doctors,” Snell says.
The treatment didn’t arrest disease progression. But compared with patients who did not receive the treatment, those receiving the highest dose of the treatment saw an average of 75 percent less decline in their cognitive and motor symptoms over 36 months.
One patient is a former information technology professional who had to stop work due to his symptoms. “About a year after being given the gene therapy, he was able to go back to work,” Wild says. In his 20 years of research, Wild says, this is the only patient he’s seen who could do that. But others who expected to be in a wheelchair by now “are still walking.”
Their symptoms almost appear to stabilize, says David Rubinsztein, a neuroscientist at the University of Cambridge who was not involved in the study. While it’s a small number of patients, “at face value, I think that’s quite promising.”
Wild and his colleagues also tracked a measure of nerve cell damage in the patients’ cerebrospinal fluid, levels of a protein called neurofilament light chain. The numbers went up immediately after treatment, he says — expected after an invasive brain surgery — but then dropped. While people’s ratings of their symptoms could be subject to a placebo effect, Wild says, the neurofilaments are not. “And by year three, that drop from baseline has been maintained, which is great.”
The next step is ongoing: recruiting more patients for multicenter trials, and working to reduce the neurofilament spike right after surgery.
Those larger trials are necessary, Rubinsztein says, and while the data will be sent to the U.S. Food and Drug Administration in hope of approval, the current results haven’t been published or peer reviewed. If it is approved, the treatment will be expensive, with every dose having to be made in the lab. “One’s got to steer a middle line,” he says, between enthusiasm and caution. But “if this was my experiment, I’d be over the moon.”
The therapy won’t be available unless and until the results are peer reviewed and the treatment is approved by government bodies like the U.S. Food and Drug Administration, agrees Anne Rosser, a neurologist at Cardiff University in Wales who helped to conduct the trial. Another important challenge is the extensive surgery required to deliver the treatment. “It will be necessary to work on the best ways to make this surgery faster,” she says. “We are already working on this challenge.”
Continued positive results are important beyond Huntington’s disease, Rubinsztein says. “MicroRNA is easy to deliver because it’s small. So this does give you many possibilities” for potential treatments for other neurodegenerative diseases, including Parkinson’s. Other therapies using viral vectors have already been approved for rare diseases such as aromatic L amino acid decarboxylase (AADC) deficiency.
Snell expressed delight that the company released results even in preliminary form. “It’s not about us science geeks,” says Snell, who teared up as he shared his reaction to the results. “It’s about the families, the brave people who joined this trial.”
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