Finally, a One-Time Treatment that May Slow the Course of Huntington’s Disease

It’s rare that clinical trial findings are as exciting as what biotech company UniQure has just announced. The company is based in Amsterdam and Lexington, Mass.

Early results, after three years of a clinical trial conducted in the US, UK, and Europe, suggest that the treatment, for now called AMT-130, significantly slows the progression of Huntington’s Disease (HD). And it could be approved in the US as early as 2026, according to a Uniqure news release.

A Variation on the Gene Therapy Theme: MicroRNAs
The strategy uses microRNA technology to stamp tiny pieces of RNA onto the mRNA molecules that carry the information in the overextended gene behind HD, which encodes a protein called huntingtin. The oversized protein gums up parts of the brain that are critical for movement.

The new treatment slows the decline so that what typically happens by a year takes four. That’s a change that would be life-altering for the families of the 75,000 or so people with HD in the US, UK, and Europe, and many others around the world and their families.

I’ve written about HD for decades, and this, I think, is the first real ray of hope for families with this devastating disease. Back in 2021 I covered the UniQure research that led to the clinical trial here at DNA Science, and two weeks ago wrote about a father honoring his remarkable daughter, who died of HD.

AMT-130 is a type of gene therapy that is injected, one time, into the brain.

The Biology of HD
HD is one of more than forty “expanding repeat” disorders, in which a gene actually grows with each generation. Beyond a certain number of repeats in the DNA sequence, the encoded protein clogs brain parts that control movement, and more.

The gene that causes HD when expanded is called Htt, and it encodes the protein huntingtin. The gene normally includes, at the start of its sequence, up to 35 copies of a DNA triplet (GTC, which encodes an mRNA that is CAG), which tells the cell to insert the amino acid glutamine into the growing protein chain. (Most articles say CAG repeats in the DNA, but that is an oversimplification, it’s really in the mRNA that the DNA encodes.)

The extra glutamines in huntingtin protein trigger a cascade of destruction, gradually destroying the “medium spiny neurons” in the movement centers of the brain. The expanded protein can’t fold properly, sticking to itself and to other proteins. It blocks axons in neurons of the brain’s striatum, preventing distribution of essential growth factors. The brain’s white matter shrinks.

The result is the unfurling, uncontrollable movements of Huntington’s, subtle at first, eventually more expansive and dancelike, and finally, ebbing into an eerie stillness. Psychological symptoms arise too, like anger, agitation, frustration, and confusion.

People can live with HD for many years. It devastates the extended family, for autosomal dominant mutations affect females and males, need be inherited from only one parent, and transmission halts only when, by chance, the functional gene and not the mutant one is passed on. I described a family with the “cruel mutation” of the juvenile form of HD here – it struck a father and three young daughters.

Harnessing and Directing a MicroRNA
The new treatment is a variation on the gene therapy theme. It is many copies of a short sequence of RNA, called a microRNA, that is introduced into the brain aboard viruses in a 12-to-14-hour surgery. The microRNAs then bind to the messenger RNA (mRNA) molecules that are transcribed from the huntingtin gene. It’s a little like molecular velcro.

Preclinical studies first tested the treatment in mice and pigs. Also vitally important in drug development are natural history studies. These gather information on the course of the illness in many people for decades, using such tools as biomarkers, scans, and rating scales.

For HD, since 1993, family members have been able to take a “premanifest” test to find out whether they’ve inherited the mutation, before symptoms begin. It is a tough decision. But these selfless and brave people are critical for planning and executing clinical trials.

The clinical trial for AMT130 evaluated a low dose, a high dose, and sham procedures, in patients with early disease.

In the US arm, 6 participants received a low dose, 10 a high dose, and 10 a sham procedure (a brief injection to mimic having had the treatment). In the European arm, 7 patients got the high dose and 6 the low dose. More people are enrolling. Nor surprisingly, the value of UniQure stock shot up.

Signs of Success
Patients who received the new treatment experienced a slowing of their disease over the course of the three years. Lead researcher Sarah Tabrizi, professor of clinical neurology and director of the University College London Huntington’s Disease Center, calls the findings “spectacular,” exceeding all expectations.

Participants in the higher dose group showed a 75 percent slowing of disease progression by the end of the 3 years, according to a rating scale of function called the cUHDRS. That was the study’s primary endpoint; even a lesser slowing would have been great news for this condition that has eluded efforts to vanquish it for many decades.

Another measure, the total functioning capacity (TFC) scale, indicated a 60% slowing of disease progression. The TFC score, from 0 (complete incapacitation) to 13 (normal), considers abilities in the areas of job or occupation, handling of financial affairs, carrying out domestic chores, activities of daily living, and level of care required.

Yet another assessment tool is a biomarker of neurodegeneration in spinal fluid, called neurofilament light protein. The more severe the disease, the higher the NfL measurement. Levels fell on average 8.2 percent.

Plus, the treatment was safe and tolerable. It is the first light in a long, dark tunnel.

Said Dr. Tabrizi, “I believe these groundbreaking data are the most convincing in the field to date and underscore potential disease-modifying effects in Huntington’s disease, where an urgent need persists. AMT-130 has the potential to meaningfully slow disease progression – offering long-awaited hope to individuals and families impacted by this devastating disease.”

Of course, the price will be steep, but the ability to slow, perhaps one day stop, this neurological assault that combines effects of Parkinson’s, ALS, and Alzheimer’s, is priceless.

If all goes well, a year from now, families with HD may at least be able to slow the course of this most terrible condition.