Hunting for a Cure

"You have Huntington's."

Few diagnoses carry such profound psychological weight as that of Huntington's disease (HD), an incurable inherited disorder that causes the gradual destruction and eventual death of neurons in certain deep structures of the brain.

The reason a Huntington’s diagnosis carries such weight is that the brain regions affected are responsible for such a large percentage of what makes us human and makes life liveable, from mental functions like learning, memory, motivation, emotions, and executive and inhibitory control, to bodily functions like motor control, speech articulation and language.

In fact, such is the psychological impact of the diagnosis and the disease itself, that the suicide rate in HD patients is estimated to be above 10%, 7 to 12 times higher than that of the general population and significantly above that of any other neurodegenerative disease.

But the clinical trial results of a novel gene therapy are providing a glimmer of hope to sufferers, representing the first time that a therapy has been able to slow the progression of the disease to such an extent that patients may be able to life full lives well into old age. 

What is Huntington's Disease?

Huntington's disease (HD) is caused by a mutation in the HTT gene responsible for producing a protein called Huntingtin. The HTT gene is dominant, which means that only one parent needs to carry the gene for a child to inherit it, and the child of a HTT gene carrier therefore has a 50% chance of getting the disease.

The mutation involves too many repetitions of a certain sequence of DNA building blocks, specifically the cytosine, adenine and guanine (CAG) sequence. A CAG repeat count of 26 or below is considered normal, while a count of 40 or more means the person will almost certainly develop HD. Those with intermediate counts may escape the symptoms themselves, but could pass on the disease to future generations.

Huntington’s is a stark reminder of just how powerful our genes are, as those few tiny extra CAG sequences and the mutant protein they create, have a profound effect on both body and mind. The onset of symptoms is usually in middle age, typically when a person is in their 30s or 40s, and average survival from that point on is 20 years.

The first thing to be affected is voluntary movement, with patients progressively developing uncontrollable movements (known as chorea) or abnormal fixed body postures (known as dystonia). Conversely, some people may instead become more rigid (known as akinesia), but either way the patient is likely to become wheelchair bound in the long run. Other motor functions that may be affected include speech, swallowing, eating and speaking.

Worse perhaps are the cognitive and behavioural changes. The disease impairs higher brain functions like attention, judgement, decision making and problem solving, while the patient may also experience personality changes, including irritability, aggression, apathy and a lack of inhibition, or even (in extreme cases) psychosis.

All in all, the effects are devastating to both the patient and their loved ones, so the question then becomes, what can be done about it?

Current Treatment Options

There are currently no treatments available that can stop or reverse HD. The best that can be done is to treat the most common symptoms. Chorea, for example, can be treated with tetrabenazine and deuterabenazine, while antipsychotics may be prescribed for extreme behavioural symptoms like hallucinations, delusions and violent outbursts.

Unfortunately, some antipsychotics could potentially worsen the physical symptoms, while the anti-chorea drugs, which affect the levels of neurotransitters like dopamine and serotonin in the brain, may actually trigger psychological symptoms like depression and apathy. In short, current solutions are far from ideal.

Given that HD affects approximately 75,000 people in the US, Europe and the UK alone, the lack of effective treatments makes HD one of the largest clinical unmet needs in the rare disease space.

Hope on the Horizon

Cue uniQure's investigational AVV gene therapy candidate AMT-130, the first drug with the potential to slow the course of the disease and provide sufferers with real hope. But what is it and how does it work?

Adeno-associated viruses (AAVs) are single-stranded DNA viruses capable of infecting human tissues. What makes them so useful in medical biotechnology is that they do not cause disease and cannot replicate on their own, making them ideal delivery vehicles for gene therapies.

AVV gene therapies use modified versions of these viruses, in which the genetic material of the virus is removed from its shell (called the capsid), and replaced with the therapeutic gene. This is then used as a delivery vehicle to safely get the functional gene where it needs to go (inside the target human cells).

In the case of AMT-130, the AVV platform is used not to deliver a new gene, but to silence an existing one. The AVV5 vector carries an artificial micro-RNA specifically tailored to suppress expression of the Huntingtin gene, making use of uniQure’s proprietary miQURE™ gene-silencing technology to do so.

The way it works is that the introduced micro-RNAs latch on to the natural mRNA that creates the mutant HTT protein (mHTT), effectively intercepting the message (the mRNA) from the boss (the gene) to the body’s protein producing factory. This inhibits the production of the harmful protein responsible for all the debilitating symptoms.

For the neuroscientists out there, the brain region they target is the striatum region, which includes the caudate nucleus and the putamen. For us mere mortals, what matters is that these are deep brain structures responsible for executive and cognitive brain functions (the caudate nucleaus), and motor control and learning (the putamen), as well as being the first to be affected by the disease.

How do they get the drug that deep into the brain? Well, AMT-130 is administered via a microcatheter in three infusions to different areas of the caudate and putamen, and delivery of the drug is monitored using MRI. From its original infusion sites, AM-130 diffuses throughout the caudate nucleus and putamen, before spreading to the rest of the brain, including the cortex. 

And although the operation is delicate and can take upwards of 10 hours to perform, the good news is that it is a once-off procedure that is expected to have long-term effects.

Promising clinical results

That's the theory, but how are they doing in practice? Well, the results from a phase I/II clinical trial in progress have exceeded even the expectations of the researchers themselves, meeting both the primary and secondary endpoints.

The clinical trial consisted of 29 patients, who received either a high dose or a low dose of AMT-130. The patients were evaluated 36 months after receiving the treatment and the results compared to an external control group from Enroll-HD, a worldwide observational study that collects data from individuals with HD.

The Unified Huntington's Disease Rating Scale (UHDRS), which assesses four crucial aspect of HD (motor function, cognitive function, behavioural abnormalities and functional capacity), was used to make the comparison and determine the primary endpoint.

The results? Patients treated with high-dose AMT-130 had UHDRS scores of -0.38 from baseline, compared to -1.52 in the control group, representing a 75% slower progression of the disease. With another indicator (the secondary endpoint), Total Functional Capacity (TFC), the results were slightly lower, with a 60% slowdown (-0.36 vs. -0.88 in the control group), but equally statistically significant.

In practical terms this means that the disease progresses three to four times slower in treated patients that in untreated patients, potentially adding decades to the expected lifespan and healthspan of HD patients.

A further impressive result was that the levels of cerebrospinal neurofilament light protein, a known biomarker of neurodegeneration, were 8.2% lower in treated patients than at the start of the trial, compared to an expected increase of one third in the same time frame.

A Regulatory Star

Of course, a treatment cannot be brought to the market without jumping through a bunch of regulatory hoops along the way, and AMT-130 has accumulated an impressive collection of hoops along its developmental path.

• It was granted Orphan Drug Designation by the FDA in October 2017 as a therapy for a rare disease, providing potential market exclusivity for up to seven years post-approval.
• It received Orphan Medicinal Product Designation (OMPD) from the EMA in January 2018, the first AAV gene therapy in Huntington’s disease to receive this designation.
• Fast Track Designation from the FDA followed in April 2019, due to the high unmet medical need it addresses, which supported expedited review and development.
• The FDA granted it Regenerative Medicine Advanced Therapy (RMAT) Designation in June 2024,  based on the potential of AMT-130 to address the major unmet medical need in Huntington’s disease, facilitating accelerated development.
• Finally, in April 2025, it received Breakthrough Therapy Designation from the FDA due to its potential to substantially improve patient outcomes in Huntington's disease.

With this impressive list of regulatory achievements already under their belt, uniQure plan to go for the final hurdle early next year: a biologics license application (BLA) that will allow them to bring the drug onto the market.

Final Thoughts

Despite the promising results and the favourable regulatory environment, they are not quite out of the woods yet. There have been many unsuccessful attempts to bring a new therapy for Huntington’s onto the market, with big names like Bayer, Novartis and Roche dropping out of the game, some at very late stages.

Will uniQure succeed where others have failed? This remains to be seen. And there are other promising approaches in development, including AtmosR, a company in our own portfolio. But for the individuals and families whose lives have been changed forever by this debilitating disease, I certainly hope they do!