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Every week neurologist Victor Sung sees people with Huntington\u2019s disease, a rare and devastating neurodegenerative disorder, at his clinic at the University of Alabama at Birmingham. But last Wednesday was a day unlike any other.<\/p>\n
\u201cI cried with every single patient,\u201d Sung says. \u201cIt just was this crazy feeling that, for the patients and families, almost can\u2019t feel real.\u201d That day the results of important phase 1\/2 clinical trials had finally been released: an experimental gene therapy drug was the first treatment shown to slow the progression of Huntington\u2019s disease.<\/p>\n
The treatment, known as AMT-130, is delivered deep into the brain during an eight- to 10-hour surgery. The trials were small; the three-year follow-up results were based on just 24 participants who received the treatment. These results showed a 75 percent slower progression of disease among treated patients than that of external control participants who were not given the treatment, according to the new therapy\u2019s developer uniQure, which posted the results ahead of their review by the Food and Drug Administration (FDA). The company hopes to receive accelerated approval from the FDA, which could allow the drug to be approved by the end of 2026 without the need for phase 3 trials, according to a uniQure spokesperson.<\/p>\n
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Because the therapy is still in clinical trials, it is not yet approved or available for wider use. The patients that Sung saw last Wednesday hadn\u2019t received it and likely won\u2019t be able to anytime soon. But this early success has given the Huntington\u2019s disease community measured hope after years of disappointments.<\/p>\n
\u201cWe\u2019ve had so many failures, and there\u2019s been a lot of heartbreak over many years in this community,\u201d Sung says. \u201cSo to have something that at least really appears to be having [an] impact is really significant.\u201d<\/p>\n
Other researchers also praised the development. \u201cThis is a community that has been waiting for so long for some kind of breakthrough,\u201d says Rachel Harding, a toxicologist at the University of Toronto, who helps develop therapies that target the cause of Huntington\u2019s disease and was not involved in the uniQure trials. \u201cThis news has really buoyed everyone\u2019s expectations of what might be possible.\u201d<\/p>\n
When someone is diagnosed with Huntington\u2019s disease, their treatment options are limited. Doctors can offer patients medications to treat their symptoms, such as reducing chorea (involuntary, unpredictable muscle movements) and depression. But until now, nothing could slow or halt the progression of the disease itself. People usually exhibit their first symptoms between the ages of 30 and 50 and can expect to live another 10 to 30 years after that. Because the gene that causes Huntington\u2019s runs in families, people affected by the disease have often watched many loved ones struggle and die from it, too.<\/p>\n
In some ways, Huntington\u2019s disease seems like it should be the easiest neurodegenerative condition to treat. Unlike Parkinson\u2019s and Alzheimer\u2019s, scientists know exactly what causes Huntington\u2019s: a mutation of the HTT gene in which a short, three-letter DNA sequence is repeated many times, causing it to produce a faulty version of the huntingtin protein. These faulty proteins accumulate in a deep brain structure called the striatum and cause symptoms such as uncontrollable movements, muscle spasms and cognitive decline that worsen over time.<\/p>\n
Although the cause of Huntington\u2019s is a simple genetic mutation, preventing that mutation from resulting in disease is a challenge. Researchers have traditionally focused on treatments that can lower the levels of abnormal huntingtin protein in the brain. For years, the most promising treatments were antisense oligonucleotides (ASOs), which are delivered by recurring injections into a patient\u2019s cerebrospinal fluid. These drugs contain small pieces of genetic material that bind to and “silence” the messenger RNA molecules that carry instructions for building the mutant huntingtin protein.<\/p>\n
But in 2021 clinical trials of three ASOs were abruptly halted. One phase 3 trial of a drug produced by Roche called tominersen was stopped because the condition of participants in the trial\u2019s treatment group was no better than that of those that received a placebo. In some cases, it appeared to actually worsen symptoms\u2014an outcome a neurologist called \u201cthe saddest possible result\u201d for a drug that so many in the Huntington\u2019s community had pegged their hopes on.<\/p>\n
While this development was devastating at the time, Sung sees it as an inevitable part of the scientific process. \u201cIf a technology is completely brand-new, we still need to test it. And with each failure, we learn something,\u201d he says. Developers of new therapies targeting genes often try to tackle Huntington\u2019s disease first because of its straightforward genetic cause\u2014meaning it\u2019s the site of both failure and innovation. \u201cSometimes the first generation of the thing doesn\u2019t work out, and we move to the next,\u201d he says.<\/p>\n
Unlike ASOs, the new gene therapy drug AMT-130 is a one-time treatment, but it also involves lengthy and invasive brain surgery. Physicians insert catheters into deep parts of the brain where they can deliver the AMT-130 drug right to the neurons in the striatum that produce the abnormal huntingtin protein. The medication is transported through \u201cshuttles\u201d called adeno-associated viruses\u2014noninfectious viral shells that can be packaged with genetic material. This genetic payload enters neurons, where it continuously produces tiny pieces of genetic code called microRNA. These microRNA specifically target and degrade messenger RNA carrying the instructions to build more huntingtin protein, therefore lowering the amount of huntingtin protein in the cell.<\/p>\n
Three years after participants received the treatment, their disease had progressed 75 percent more slowly compared with that the of people in the control group. Disease progression was measured by the participants\u2019 combined results on many tests measuring their motor and cognitive functioning. \u201c75 percent disease-slowing\u2014that\u2019s better than we would have hoped for,\u201d Sung says.<\/p>\n
The treatment was tested in patients who were administered either a high dose or low dose of the drug. Their results were compared with the progression of the disease among a database of matched control participants that has been built through the hard work of the Huntington\u2019s disease community, Harding explains. (Because of the invasive nature of the surgery, it was not considered ethical to give a placebo version of the drug, but three years is generally thought to be an implausibly long time for a placebo effect to persist, Sung says.)<\/p>\n
Three of the participants who received high doses of AMT-130 experienced serious neurological side effects, such as swelling and severe headache. The trial was paused in August 2022, but was resumed after the participants recovered and the data were reviewed. Since then, no serious adverse events have been reported. Most adverse events were related to the initial surgery, uniQure said, and those all eventually resolved.<\/p>\n
Next, the FDA will review results from the phase 1\/2 study, and uniQure plans to apply for accelerated approval, an expedited FDA-approval process for treatments that address serious conditions or meet an unmet medical need. If this is granted, the company expects that approval could come by the end of 2026, a spokesperson said. This would forego the need for a larger phase 3 study, though other trials may be done to confirm the treatment\u2019s efficacy.<\/p>\n
It is not clear at this stage how much the treatment would cost or how it would be paid for, although it will almost certainly be very expensive, experts say. This, in addition to the invasive nature of the treatment, means it likely won\u2019t be available to most people around the world who have Huntington\u2019s or carry the faulty HTT gene. Even if the drug wins FDA approval, \u201cthis is not a therapy that will be available for everyone\u201d with this disease, says Harding, who is also an editor in chief of HDBuzz, a Huntington\u2019s disease news site that tracks research developments for the community. But \u201cwhat it does is give us hope that perhaps Huntington-lowering is a really viable therapeutic strategy.\u201d<\/p>\n
Other huntingtin-lowering therapies are currently in development, and some are in clinical trials. SKY-0515 from Skyhawk Therapeutics is currently in phase 2\/3 clinical trials, and Novartis is planning to develop phase 3 trials of PTC-518, now called votoplam. Both are taken by pill. Roche\u2019s tominersen is back in trials with a more restricted group of people who may benefit most from the therapy, and another ASO called WVE-003 from Wave Life Sciences may soon be entering phase 2\/3 trials. Both drugs are delivered through a spinal tap.<\/p>\n
Along with the AMT-130 results, this competitive field brings Harding hope. \u201cI don\u2019t think it\u2019s that the others haven\u2019t succeeded. It\u2019s just they haven\u2019t succeeded yet,\u201dshe says\u2014and if they do, they could allow even more people to access treatment.<\/p>\n","protected":false},"excerpt":{"rendered":"
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