'Groundbreaking' gene therapy is first treatment for Huntington's disease to slow the condition

In a groundbreaking first, a gene therapy in clinical trials has slowed the progression of Huntington's disease, a rare genetic disorder in which toxic bits of protein cause brain cells to malfunction and die.

To date, approved treatments for Huntington's disease aim to manage its symptoms, which most often emerge in a person's 30s or 40s. The progressive condition injures and kills key neurons involved in controlling mood, cognition and motor control. Various drugs can help to offset the depression, hallucinations and poorly coordinated movements that arise from that destruction.

However, no available treatments have been shown to slow the underlying drivers of Huntington's, and patients typically die within 10 to 25 years of their symptoms starting.

Now, in trial results shared Wednesday (Sept. 24), scientists announced that a new gene therapy called AMT-130 appears to slow the disease's progression — marking a first for the field.

"These groundbreaking data are the most convincing evidence in the field to date and underscore the disease-modifying effect in Huntington's disease, where an urgent need persists," Dr. Sarah Tabrizi, the lead scientific advisor on the trial and the director of the University College London (UCL) Huntington's Disease Centre, said in a statement. "For patients, AMT-130 has the potential to preserve daily function, keep them in work longer, and meaningfully slow disease progression."

Huntington's disease, estimated to affect about 1 in every 20,000 to 10,000 people in the U.S., is caused by mutations in a gene called HTT, which carries instructions for a protein known as huntingtin. The protein is found in many tissues across the body, but its quantities are highest in the brain. The role of the protein in cells isn't fully understood, though its proposed jobs include repairing damage to DNA and transporting materials within cells.

There's a portion of the HTT gene in which three letters — CAG — in its DNA code repeat about 10 to 35 times, depending on the person. However, in people with Huntington's disease the repetition becomes extreme, with CAG appearing 36 to over 120 times. People with 40 or more repeats nearly always develop the disease, while those with 36 to 39 have a lower risk. The repeats result in cells making a too-long version of the huntingtin protein, which then gets broken apart into smaller, toxic fragments that accumulate inside brain cells.

The gene therapy AMT-130, developed by the trial's sponsor uniQure, works by silencing the HTT gene — both healthy and mutant versions. Notably, gene therapies aren't typically 100% efficient, meaning the treatment wouldn't affect every single copy of HTT in the targeted tissue; so rather than eliminating the gene's activity, it turns it down significantly.

To do so, the therapy introduces a new gene into cells in two parts of the brain hit hard by Huntington's: the putamen and caudate nucleus. The gene itself carries instructions for a microRNA, a type of molecule that controls gene activity. In this case, the microRNA derails the process by which the HTT gene's code gets translated into proteins. It latches onto messenger RNA (mRNA) in cells, which would normally relay the HTT's blueprints out to protein-building factories in the cell.

The AMT-130 therapy is delivered into the body inside a harmless virus, which serves as a delivery truck for the microRNA. (These types of viruses are commonly used in gene therapy.) Getting the treatment into the brain requires a complex surgery, during which doctors use MRI to guide tiny catheters into the correct spots in the organ. The treatment is given in one dose, so only one surgery is needed to administer it.

In the trial, 29 patients received this new therapy, with 17 getting a high dose and 12 getting a low dose. Twelve patients from each group then had three years of follow-ups that were included in this new analysis.

The treated patients were compared against a cohort of people with Huntington's who received only standard care and are being followed in a long-term study called Enroll-HD. The trial runners used a standard rating scale for Huntington's disease progression to track patients and compare them to one another. They also measured patients' levels of neurofilament light protein (NfL), which appears in the fluid surrounding the spinal cord when neurons are injured.

The trial results showed that, at the three-year mark, patients given the high dose of AMT-130 had 75% less disease progression compared to the cohort given standard treatment. The high-dose group also showed a decline in average NfL levels over that timeframe, suggesting a decline in the degree of neuronal damage being wrought. Normally, the protein's levels would spike by about 20% to 30% over three years.

"AMT-130 was generally well-tolerated, with a manageable safety profile at both doses," the statement notes. "The most common adverse events [side effects] in the treatment groups were related to the administration procedure, which all resolved."

"My patients in the trial are stable over time in a way I'm not used to seeing in Huntington’s disease," Dr. Ed Wild, principal investigator of the trial site at the UCL Huntington's Disease Centre, said in the statement. "One of them is my only medically-retired Huntington's disease patient who has been able to go back to work."

He added that "trial results come through in numbers and graphs, but behind each datapoint is an incredible patient who volunteered to undergo major neurosurgery to be treated with the first gene therapy we've ever tested in Huntington's disease. That is an extraordinary act of bravery for the benefit of humanity."

According to the statements released by uniQure and UCL, the company plans to submit an approval application to the U.S. Food and Drug Administration (FDA) early next year, with applications in Europe to follow. AMT-130 has already been granted Breakthrough Therapy designation and Regenerative Medicine Advanced Therapy designation by the U.S. FDA, which both signal that regulators feel the therapy holds great promise to treat patients with an unmet medical need.