For some people who get genetic testing, the results can be life changing. That’s the case for people who learn that they have Huntington’s disease, a devastating neurodegenerative disease that leads to cognitive and physical symptoms starting in middle age. These symptoms worsen and can become incapacitating over time.
This brain breakdown is caused by a genetic mutation that some people carry with them from birth. But even if people find out that they have the mutation before symptoms emerge, there is still no treatment that can stop or reverse the process. A new Phase 1/2 clinical trial hopes to change that by striking right at the genetic source of the disease.
The trial, conducted by biotech company uniQure, is the first for a one-time gene therapy for Huntington’s disease. “This is one of the diseases where we absolutely understand the cause,” said Ricardo Dolmetsch, president and chief scientific officer of uniQure. “We thought that this is a place where there was a nice mix between what our technology can do and the really giant unmet medical need.”
Interim clinical trial data released in June suggests that clinical metrics and biomarkers are moving in the right direction, but there’s a long road ahead to see if the drug has a lasting benefit. If it works, the drug may be the first treatment for Huntington’s disease and a new hope for thousands of patients and their families.
New genetic technology to defend neurons
The culprit in Huntington’s disease is the huntingtin protein, which is found almost everywhere in the body and serves an unknown but seemingly important function in nerve cells. People with Huntington’s disease have a mutation in the gene that encodes huntingtin that makes the protein longer and more susceptible to degradation. When the mutant protein gets broken down into small pieces in the brain, these pieces clump together in neurons and keep them from functioning normally, ultimately killing the neurons.
Scientists have tried to target mutant huntingtin to treat Huntington’s disease, but attempts have fallen short. Protein drug candidates intended to keep mutant huntingtin from aggregating in neurons didn’t improve Huntington’s disease symptoms (1). In 2021, two promising gene therapy candidates using multiple infusions of antisense oligonucleotides (ASO) to reduce mutant huntingtin gene expression failed in clinical trials (2).
uniQure’s drug, referred to as AMT-130, takes a different approach. AMT-130 is a one-time gene therapy. It contains a microRNA (or miRNA) that targets the mutant huntingtin gene. When infused into the patient’s brain, the miRNA can direct cellular machinery to cut up RNA encoding mutant huntingtin, with the goal of making the RNA unusable and reducing the amount of mutant protein accumulating in the neurons. miRNA is similar to previously tested ASO because they are both small pieces of genetic material that can be designed to target and reduce mutant huntingtin, although they act through different cellular mechanisms.
AMT-130 may have a leg up. While many ASO-based gene therapies require monthly infusions into the spinal cord, AMT-130 is a one-time infusion into the brain. “Once you have it, you have it for the rest of your life,” Dolmetsch said. This is because the miRNA is packaged into an adeno-associated virus (AAV) vector for delivery into cells. AAV vectors can ferry genetic material into cell nuclei, where the cells can express a new gene indefinitely.
While uniQure’s goal for AMT-130 is to minimize the production of disruptive mutant huntingtin, Dolmetsch knows its limits. “We don’t really think we can bring back dead brain,” he said. That’s why the uniQure team is testing AMT-130 in early Huntington’s disease where patients may just be starting to experience physical or cognitive symptoms. By striking early in this disease course, the researchers hope to stop the brain from deteriorating and preserve cognitive and motor function.
This could lay the groundwork for a treatment for later Huntington’s disease in the future, said Edward Wild, a neurologist at the University College London who consults for uniQure. “If we find a therapeutic that engages with core pathogenic mechanisms in the disease, we will then be able to test them throughout the disease and find out to what extent meaningful deflection of the trajectory or even reversal is possible,” he said.
Early signs of improvement
After testing the drug in mice, pigs, and monkeys, the uniQure team moved to their current human clinical trial (3-5). They began the randomized, double-blinded Phase 1/2 clinical trial four years ago to test AMT-130’s safety and efficacy.
The trial is still relatively small compared to most clinical trials. The researchers divided twenty-six individuals into two groups: a low-dose cohort and a high-dose cohort. With the low-dose cohort, the researchers administered the drug at a dose that would remain near the injection site and not enter far into the brain. For some scientists, including Wild, the real test is the high-dose cohort, which received ten times more of the drug with the goal of reaching more of the brain at therapeutic levels. “The low dose is something that we can default to if the high dose isn't safe, but if the high dose is safe, then that's the one to go for,” Wild said.
Delivering the drug to a patient’s brain only requires one procedure, but it is no small task. A surgeon drills two to six holes in the patient’s skull and inserts a small catheter to infuse the drug into part of the striatum. It is a long surgery — around one whole day — and is as invasive as surgeries for deep brain stimulation. It’s also more complex than more common brain surgeries such as brain biopsies and fixing aneurysms. To imitate the surgery in people serving as controls, doctors drilled superficial holes in their skulls without infusing any drugs.
It would be really nice to see everything going in the same direction. But if the clinical benefit is there, the biomarker doesn't matter.
- Edward Wild, University College London
After the surgery, the team followed up with the patients for one to two years and measured side effects, various movement and cognitive function scores, and molecular markers of brain function. Last year, uniQure reported a few cases of patients in the high-dose group who suffered side effects such as swelling, headache, and cognitive symptoms. The researchers suspected that these were immune responses to the procedure, and the patients recovered after treatment. The interim data released in June reported that no participants had serious side effects that required leaving the trial.
uniQure also reported that many people who received the drug were at least maintaining their current levels of brain function, and some even improved. On the other hand, people who received the control procedure reported worsening motor symptoms.
“The most important thing you're looking for is the clinical outcome,” Dolmetsch said. “Do people feel better?”
The researchers also measured decreasing levels of neurofilament light chain, a molecule in the cerebrospinal fluid that reflects brain damage. But not all biomarkers were as encouraging. Even though the drug targets mutant huntingtin, the lab tests showed that mutant huntingtin levels were not substantially decreased. This might be partly because the tests that measure mutant huntingtin are not very sensitive, Dolmetsch said. Wild agreed, adding that with so few patients in the trial, it’s hard to draw a conclusion about the trend.
Meeting patients’ needs
For Leora Fox, the assistant director of research and patient engagement at the Huntington's Disease Society of America, the small size of this trial is a key piece of information to communicate to patients and their families. “There's definitely excitement that there's positive signals, but it's also variable and it's a very small set of data,” she said. “It’s really a waiting game.”
This waiting will continue as uniQure investigates AMT-130 in their current cohorts and in new cohorts. So far, 43 patients have enrolled in the trial. Dolmetsch hopes to continue enrolling batches of patients and releasing data every six months to show how patients fare over time. By doing this for the next year, he hopes to have compelling enough evidence on whether the drug is safe and effective to proceed to FDA approval without having to embark on a resource- and time-intensive Phase 3 trial.
“Once we get to enough people and enough time, there is a point at which you can no longer say this is just pure chance,” he said.
As soon as there’s something that moves the needle on progression in a way that’s meaningful, I think that there will be a lot more people who are willing to come out and talk about Huntington’s disease and test for Huntington’s disease. People are really desperate and really excited about anything in any direction that could work.
- Leora Fox, Huntington's Disease Society of America
Wild agreed that following the current trial participants will offer powerful insights into the long-term effectiveness of the drug. He is also interested in how to avoid some of the adverse immune responses observed in patients in the high-dose cohort early in the trial. Immunosuppressive drugs seemed to help those people, so later this year, uniQure will recruit 10 more patients to study a combination of AMT-130 and immunosuppression.
Fox noted that there are still other considerations such as limited global access to gene therapy and the permanent, invasive nature of the treatment. uniQure is working on reducing the length of the surgery from one day to half a day, but some Huntington’s disease patients are hesitant. “There are those who say I would never undergo brain surgery,” Fox said. “There are very different perspectives depending on what the people have going on in their lives.”
AMT-130 isn’t the only drug with promising clinical trial results: an oral drug called PTC518 recently also showed positive preliminary effects on brain markers. Fox thinks that having multiple effective options is the best way to cater to the diversity of people with Huntington’s disease. A viable drug could also have broader effects on diagnosis and care. “As soon as there’s something that moves the needle on progression in a way that’s meaningful, I think that there will be a lot more people who are willing to come out and talk about Huntington’s disease and test for Huntington’s disease,” she said. “People are really desperate and really excited about anything in any direction that could work.”
- Landwehrmeyer, G. B. et al. Riluzole in Huntington’s disease: a 3-year, randomized controlled study. Ann Neurol 62, 262-72 (2007).
- Kwon, D. Failure of genetic therapies for Huntington’s devastates community. Nature (2021).
- Caron, N. S. et al. Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease.Nucleic Acids Res 48, 36-54 (2020).
- Evers, M. M. et al. AAV5-miHTT Gene Therapy Demonstrates Broad Distribution and Strong Human Mutant Huntingtin Lowering in a Huntington’s Disease Minipig Model. Mol Ther 26, 2163-77 (2018).
- Thomson, S. B. et al. AAV5-miHTT AAV5-miHTT-mediated huntingtin lowering improves brain health in a Huntington’s disease mouse model. Brain 146, 2298-315 (2023).