A New Approach Could Transform Huntington’s Disease Treatment

Huntington’s disease is extremely cruel. Symptoms start with random, uncontrollable twitches of the hand. Over time the disease eats aways at memory, thought, and reason. Mood swings and personality changes strip away your identity. Eventually, it leads to an early death.

Worse, unlike other diseases that gradually destroy brain function, such as Alzheimer’s disease, Huntington’s can be diagnosed with a simple genetic test. The disease is inherited through a mutated gene. People with a family history often struggle to decide if they want to get tested. If the results are positive, there are no treatments, and their fates are set.

A new therapy may now kneecap Huntington’s before symptoms take over. Preliminary results from a small group of patients found a single injection of microRNA, a type of gene therapy, into affected brain regions slowed the disease’s progression by 75 percent over three years. The patients had far better motor control, attention span, and processing speed compared to an untreated control group who had similar baseline symptoms.

The drug is being developed by the Dutch gene therapy company uniQure, which summarized the findings in a press release this month. The data hasn’t been published in a preprint article or a scientific journal nor scrutinized by other experts. With only 29 patients involved, it’s hard to generalize the benefits and safety profile for the roughly 75,000 people with Huntington’s in the US, Europe, and UK.

But the findings offer a beacon of hope. Previous attempts at a cure “have shown some small signals if you squint…but there has not been anything close to this,” Steven Finkbeiner at the Gladstone Institutes in California, who was not involved in the study, told the New York Times. And because Huntington’s can be caught early on, the treatment—if further proven effective in a larger population—could begin to ward off symptoms at an earlier age.

Genetic Coin Toss

All of us have the Huntington’s gene, or HTT. While its exact role in cells is debatable, the gene acts as a central communicator across multiple cellular “phone lines.” It coordinates a large assembly of molecules to turn genes in brain cells on or off and is critical for early development, neuron survival, and maintaining the brain’s overall health.

In Huntington’s disease, however, HTT goes awry. Our genes are made of four molecules represented by the letters A, T, C, and G. Triplets of these letters often dictate the sequence, structure, and function of proteins, the workhorses of our cells. In the disease, one triplet, CAG, repeats like a broken record, resulting in mutated huntingtin proteins that increasingly build up inside the brain throughout a person’s life and gradually wreak havoc.

Although in the beginning brain cells can adapt, their defenses eventually stumble, and symptoms appear. In the US, this usually happens between 30 and 55 years of age.

Families with Huntington’s face a terrible dilemma. If one parent has the disease, each of their children has a 50 percent chance of inheriting it. If they don’t, their offspring are safe. Knowing the diagnosis can help with family and life planning—but it comes at a hefty emotional cost.

Micro But Mighty

How the mutated huntingtin protein destroys brain cells isn’t yet clear, but most scientists agree that clearing it—or preventing it from forming in the first place—could protect the brain.

The protein is massive and made up of multiple fragments. One treatment idea uses small protein “jammers” to prevent an especially toxic form of huntingtin from weaving into large, dangerous aggregates. Another directly targets the CAG repeats with a classic but powerful form of gene therapy. But after initially promising results, a trial was halted due to a high risk of side effects and low chance symptoms would improve. Gene editing strategies, such as CRISPR, that cut out the mutated sequences are gaining steam, but they’re very early stage.

The new therapy developed by uniQUre taps into microRNA. These molecules don’t code for proteins, but they can stop a gene from making one. Like DNA, RNA can also form a double strand if its sequences match. Cells identify double-stranded RNA as alien and destroy it—potentially stopping a toxic protein from forming. The company’s new drug contains two components: A benign viral carrier and a custom genetic sequence that, once inside the cell, produces microRNA tailored to inhibit mutant protein production.

The drug, called AMT-130, doesn’t integrate into or directly edit a patient’s genome, which lowers the risk of disrupting healthy genes or triggering cancer. Although the viral carrier is eventually wiped away by the immune system, the genetic code could last for years, making the drug a potential long-term treatment.

The team injected either a low or high dose of AMT-130 into the brains of volunteers with Huntington’s using an established and highly precise surgical technique. They targeted the striatum, a nub tucked deep inside the brain that’s critical for movement and decision-making and one of the first regions ravaged by the disease. As a control group, they found hundreds of patients of similar age and disease severity, according to an investor presentation (PDF) from the company.

The results were promising. When given the highest dose, 12 people with early stages of the disease experienced, on average, a 75 percent slower decline than those without treatment, as measured using multiple standard Huntington’s assessments.

Roughly 88 percent of treated patients showed marked improvement in their attention, memory, and information processing speed based on one test. Their control over random muscle movements got better, and they were able to perform daily activities with less struggle. A brain protein often associated with symptom severity dropped to levels seen before the trial began. In contrast, those treated with a low dose of the drug had more modest and mixed results.

Multiple people experienced side effects related to the brain surgery. Headaches were the most common complaint. Some experienced brain swelling a few days after the surgery. But overall, the treatment seemed safe.

“The majority of drug-related serious adverse events occurred within the first weeks post treatment and fully resolved with steroids or palliative case,” the company noted in their presentation.

There’s reason to be skeptical. Huntington’s is a life-long disease, and it’s unknown how long the benefits of the single shot last beyond three years. It’s likely multiple shots would be needed throughout a patient’s lifespan, and future studies would have to test the additive effects. The drug slashes levels of both the mutated and normal versions of the huntingtin protein—drugs in the past have as well—which could potentially produce side effects.

New patients are now being enrolled for the trial, and the company hopes to submit an application for FDA approval by late 2026.

“This result changes everything,” Ed Wild, a leader of the project at the UCL Huntington’s Disease Center trial site, said in the press release. “On the basis of these results it seems likely AMT-130 will be the first licensed treatment to slow Huntington’s disease, which is truly world-changing stuff.”