Just mentioning “Huntington’s disease” can cast a veil of sorrow over any gathering. However, the recent announcement concerning a groundbreaking experimental gene therapy offers a novel source of optimism amidst the stark realities of this devastating condition.
In a small-scale clinical trial, injections to the brain using a virus that encodes a small segment of RNA demonstrated the potential to halt the creation of harmful proteins associated with Huntington’s disease. Announced on September 24, the initial findings reveal that the treatment could slow the progression of Huntington’s by up to 75% over a span of three years. Though it is not a cure, this avenue of treatment may grant individuals living with Huntington’s disease the promise of significantly extended years free from debilitating symptoms.
“Our pursuit of science isn’t just for the sake of discovery; we are driven by the desire to save our loved ones from a tragic fate,” remarks Ed Wild, a neurologist at University College London. “Nothing is more meaningful than being able to look my friends in the eye and say, ‘We did it.’”
At present, Huntington’s disease lacks effective treatment options or cures, affecting approximately 7 out of every 100,000 individuals. This neurological disorder results from a specific mutation in the huntingtin gene. In cases of Huntington’s, the mutated gene results in an elongated protein that becomes toxic. According to Russell Snell, a geneticist at the University of Auckland who was not involved in the current study, “The elongated huntingtin protein aggregates in the brain, leading to the degeneration of cells in critical regions responsible for voluntary movement.”
Consequently, patients can experience a host of symptoms including involuntary movements, stiffness, difficulties with speech and swallowing, and cognitive decline. Notably, since Huntington’s is genetically dominant, an individual with the disease has a 50% chance of passing the mutated gene to their offspring.
In the study, Wild and his team, in collaboration with the Dutch pharmaceutical company uniQure, implemented a strategy involving microRNA—tiny RNA segments capable of initiating the breakdown of huntingtin RNA before it culminates in protein formation. Prior trials had attempted to deliver these RNAs directly, but they failed due to improper administration methods, such as injecting them into the cerebrospinal fluid which hindered their required penetration into specific brain regions.
This particular study, however, utilized direct brain injections, with the viral vectors “infecting” brain neurons with the RNA. “The virus effectively transforms the neuron into a factory that produces a molecule instructing it not to synthesize the huntingtin protein,” explains Wild.
During meticulous surgeries lasting between 12 to 18 hours, 17 patients showing early symptoms of Huntington’s received viral injections at three targeted locations on both sides of the brain. Over a period of 36 months, the research team monitored 12 of these patients, assessing their motor function, attention span, working memory, and daily living capabilities. “It was a heroic effort, both by the participating patients and the medical professionals,” commends Snell.
While the treatment did not halt disease progression entirely, those who received the highest dosage exhibited an impressive average of 75% less cognitive and motor decline when compared to untreated patients over the same period.
One notable success story involves a patient who had previously left his job due to symptoms. “About a year post-treatment, he returned to work,” says Wild, a remarkable instance in his two-decade research career. Several other individuals who anticipated they would be reliant on wheelchairs are still, remarkably, able to walk.
According to David Rubinsztein, a neuroscientist at the University of Cambridge who did not participate in the study, the observed symptom stabilization in many patients is noteworthy. “While the participant numbers are limited, these results appear promising at first glance,” he notes.
Furthermore, the team monitored the levels of neurofilament light chain—a marker of nerve cell damage—found in the patients’ cerebrospinal fluid. Initially, these levels surged post-treatment, which is expected following an invasive procedure, but subsequently, the numbers reduced. “While subjective symptom ratings can sometimes be influenced by a placebo effect, the neurofilament data is objective. By the third year, we observed a sustained decline from baseline levels, which is a positive indication,” asserts Wild.
Ongoing efforts are focused on recruiting a larger participant group for multicenter trials while also seeking to mitigate the neurofilament spike that occurs immediately post-surgery.
As Rubinsztein underscores, larger trials are essential, and although data will soon be submitted to the U.S. Food and Drug Administration for potential approval, the current findings remain unpublished and unpeer-reviewed. Should it receive approval, the treatment is likely to come with a hefty price tag due to the need for lab-prepared doses. “We must strike a balance between excitement and caution,” he advises, “but if it were my experiment, I would certainly be ecstatic.”
Rosser, a neurologist at Cardiff University involved in the trial, concurs on the importance of peer review and governmental approval before the therapy can become widely available. She also highlights the need for advancements aimed at making the surgical process more efficient. “We are already addressing this issue,” she adds.
The significance of sustained positive outcomes extends beyond Huntington’s disease, according to Rubinsztein. “MicroRNA’s small size allows for straightforward delivery, suggesting multiple avenues for novel treatments for other neurodegenerative disorders, including Parkinson’s disease. Other gene therapies using viral vectors have already found success for rare conditions like aromatic L-amino acid decarboxylase (AADC) deficiency,” he affirms.
As Snell reflects on the preliminary divulgence of these findings, he expresses gratitude. “This is for the families, for the courageous individuals willing to participate in this trial,” he states, his emotions evident.
