"This breakthrough gene therapy for Huntington’s disease represents a historic advance in neurodegenerative medicine. The data revealing a 75% slowing of clinical progression over three years is unprecedented and genuinely transformative, as it targets the disease’s root cause. Current therapies mainly manage symptoms like movement difficulties and mood changes but do not alter disease progression. These symptom-relief drugs will remain vital, especially as patients live longer, making improved and safer symptomatic treatments an urgent research priority. Monitoring and mitigating gene therapy side effects, such as inflammation and neurological issues, is also crucial.

A bold next step is prevention trials in gene-positive people before symptoms appear, involving young individuals undergoing 12–18 hours of delicate brain surgery. Ethical and safety challenges are significant, requiring careful patient selection and close monitoring. Nevertheless if successful, this could shift treatment from symptom management to stopping Huntington’s before it starts, revolutionising patient care. This comprehensive approach: combining gene therapy, better symptom management, and prevention research, heralds a new era of hope for those affected by Huntington’s disease."

"This promising treatment for people with or at risk of Huntington’s is the result of a phase 1/2 clinical trial for the AMT-130 drug developed by UniQure, a Dutch gene therapy company. Although the study has not been published in a peer-reviewed journal, I understand the results have been submitted to the FDA for regulatory approval.

AMT-130 is in essence an RNA-based gene silencing technology. Unlike mRNA vaccines, AMT-130 delivers DNA inside neurons using a virus-based delivery system, microinjected into the brain’s basal ganglia. The virus is modified by swapping-out its normal DNA with a circular DNA vector that contains the RNA sequence. The patient’s brain cells then produce a "synthetic microRNA precursor" from the circular DNA vector, and this is where the magic happens: the resulting RNA gets processed by the cell to act like a heat-seeking missile, which targets specific sequences in the mRNA from the Huntingtin gene that gets transcribed into the pathogenic protein that causes the neurodegenerative disease.

Not all neurodegenerative diseases have aetiologies as 'simple' as Huntington's, which is a very well understood monogenic disease. Most other neurodegenerative diseases aren't as well understood or have complex predisposing and compounding factors (pleiotropy).

ALS, for example, also involves a gene with a repeat expansion, but the cause and effect is less clear cut.

I think the greatest hope lies in the digital nature of these therapies, where we can design a sequence that targets a specific gene or mRNA to modulate pathogenicity. The applications are almost boundless, in my opinion.

Another example is Spinraza, a drug that targets mRNA splicing associated with motor neuron disease. One of the first examples of a targeted RNA therapy.

The delivery of these drugs is the hardest part. It often needs to be tissue or cell-type specific. Hence the need for 12 hours of surgery to inject a virus into the core of the brain. Lots of research being done in this space (shout-out to the RNA institute)."

To detect such a large effect in such a small patient group is incredibly promising. If this is reflected in a large patient group, this could be a major breakthrough in the search for effective treatment for such a devastating disease.

This was only a small trial, with data from only 12 patients who received the high-dose of AMT-130 available for analysis, but the results were impressive. These patients were in the early diagnosed stage of the disease, and compared to a larger group of people with HD who were at a similar stage of progression, the treatment group showed significant slowing of disease progress measured across multiple gold-standard measures of severity, including their clinical symptoms (cUHDRS), their everyday function (TDF), and their cognitive function, specifically, their speed of information processing.

Motor symptoms were not significantly slowed in this analysis, however, keep in mind these are very small samples. Although preliminary, these positive findings across multiple measures after three years indicate that this really could be a promising, long-lasting treatment for this devastating disease. Further, although AMT-130 is invasive, as it involves brain surgery, it is potentially a permanent treatment, which would be a huge bonus for patients who commonly need regular visits to specialists, and regular adjustments to medications, as the disease progresses. It will be very exciting to see where this leads as it progresses to Phase III, where it would be testing in a much larger group of patients.

Huntington’s disease (HD) is a rare, genetic neurodegenerative disorder associated with devastating impacts on motor, cognitive and behavioural function for those affected. It is normally fatal within two decades of diagnosis. Further, given its autosomal dominant inheritance pattern, 50% of the children of those affected go on to develop HD. While it is known that HD is caused by a mutation in a specific gene, leading to the production of abnormally misfolded and aggregated huntingtin protein, there are no treatments currently available to delay onset or slow disease progression. An earlier highly-anticipated trial of the antisense oligonucleotide, tominersen, which aimed to block production of the mutant huntingtin protein, was halted by Roche in 2021 due to an adverse benefit/risk profile.

This makes the announcement by uniQure of the positive topline results from the Phase I/II trial of the gene therapy AMT-130 very exciting. In a study of 29 individuals with HD, those receiving a high dose of AMT-130 showed a 75% slowing in disease progression over a 36-month period. These individuals also showed less decline on the Total Functional Capacity scale, and favourable trends for performance on cognitive and motor measures. Encouragingly, beyond clinical measures, individuals treated with high-dose AMT-130 also showed reductions from baseline in levels of neurofilament light protein (NfL) within their cerebrospinal fluid. This is significant, as NfL is a biomarker of neurodegeneration known to be associated with greater severity of symptoms in HD. This suggests that AMT-130 may help to prevent the death of brain cells.

This therapy has the potential to transform how we think about HD and its treatment. It is important to acknowledge, however, that it is still early days, and key questions remain, such as the long-term effects of the treatment and its potential cost. At this stage, results have also not yet been peer-reviewed. The 12–18-hour complex brain surgery required to deliver the treatment may also limit its availability. Despite these caveats, however, the preliminary results offer real hope for those affected by HD and their families.

Today’s report that a single, gene-targeted treatment slowed measured progression of Huntington’s disease in a clinical study marks a genuine step forward. It is early, based on an externally matched comparison rather than a traditional randomised control, and it must be confirmed, but it shows what careful science can deliver.

The gene that causes Huntington’s disease was identified in 1993, thirty-two years ago! Seminal mouse studies showed that turning off the mutant huntingtin protein after symptoms had begun could reverse signs and improve behaviour, suggesting that lowering the toxic protein might modify disease. Multiple efforts at therapies for humans have not shown clear clinical slowing to date, including trials of huntingtin-lowering drugs and other approaches. However all that experience has lead to where we are today. Today’s report is, to my knowledge, the first public claim of statistically significant slowing on both the composite clinical scale and the functional scale over three years in a clinical Huntington’s study, albeit using an externally matched comparison rather than a concurrent randomised control. It requires independent scrutiny and, ideally, confirmation.

For families who carry this gene, the future has too often felt pre-written. The data reported today do not prove success, but they make a credible case for hope grounded in biology and careful clinical measurement. This is very exciting."

What the new trial shows

"The treatment tested, called AMT-130, is a one-time gene therapy delivered by a neurosurgeon directly into deep brain regions. It carries a genetic “microRNA” sequence designed to switch down production of the mutant huntingtin gene. At three years, people given the higher dose had significantly less decline in movement, thinking and daily function compared to a matched group from a global registry. Decline on key scales was slowed by about two-thirds, and a marker of brain injury in spinal fluid fell below baseline. Side effects were mainly linked to the surgical procedure."

What this study means and what the limits are

"These results, if upheld, represent the first convincing signs that gene-targeted treatment might slow the disease in people. They build on decades of failed attempts and offer a new path where none has existed. At the same time, caution is essential. Only a small number of patients have been followed, the comparison is with an external group not a randomised placebo, and the findings come from company announcements rather than peer-reviewed data. Larger and longer studies will be needed to confirm whether this treatment truly changes the lives of people with Huntington’s disease.”

What Huntington’s disease is

"Huntington’s disease is a rare inherited disorder of the brain. It causes uncontrolled movements, personality changes, depression, and a steady decline in thinking and memory. Symptoms usually begin in mid-life and worsen over ten to twenty years, leading to loss of independence and premature death. The disease is caused by an expanded stretch of DNA repeats in the huntingtin gene, which leads to a toxic protein building up in brain cells. The longer the repeat, the earlier the disease tends to begin.