Hope for People with Huntington’s Disease

Huntington’s disease (HD) is a rare, inherited neurological disorder that attacks people in the prime of their lives, gradually affecting their movement, balance, cognitive function and emotional stability. There is no known cure.

Symptoms typically emerge in patients in their late 30s and early 40s, when “they’re at their peak of productivity, when they have their kids and are establishing careers,” says Henry Paul Moore, M.D., a neurologist with the University of Miami Health System. “It’s devastating for families.”

Now, a new treatment, tested in a small study, is providing a ray of hope for those affected by the fatal disease — even as it faces inevitable regulatory setbacks. Patients who received a high dose of the therapy during the trial showed a 75% slower rate of disease progression over 3 years compared to those who didn’t receive it.

Some have hailed the results as a breakthrough, for good reason.

Until now, treatments have only managed symptoms, while this is the first to show promise in changing the course of the disease. About 100 clinical studies testing other therapies have failed to halt the deterioration in Huntington’s patients.

“I look at this with cautious optimism,” says Dr. Moore, a specialist in movement disorders. “But there are a lot of things still up in the air. We have to be careful how we extrapolate from this study.”

About 41,000 people are living with Huntington’s in the U.S., according to the Huntington’s Disease Society of America. The prevalence of the disease is higher in North America – 8.87 per 100,000 people – than around the world. (4.88 per 100,000). This may be due to a combination of genetic, historical, and diagnostic factors. The U.S. has more widespread genetic testing, and the gene that triggers HD is more common among people of European ancestry than among those of Asian or African descent.

HD is an autosomal dominant disease, which means that it takes only one parent with the mutation to pass it on to their offspring.

In other words, each child of an affected parent has a 50% chance of inheriting the disease.

To appreciate how the therapy, a one-time brain infusion, slowed the disease in some study participants, it is essential to understand the biology of this progressive disease. HD is caused by a genetic mutation in the Huntington’s disease gene (HTT), located on chromosome 4. The mutation means that a DNA sequence called CAG – cytosine, adenine, and guanine — is repeated, but the number of repetitions can vary. A normal HTT gene will have 26 or fewer repeats. But when the CAG sequence is repeated 40 or more times, it results in Huntington’s disease.

The extra repeats produce a protein that can be potentially toxic. And though this protein is found in every cell of an affected individual’s body, it only damages brain cells, particularly those in the basal ganglia deep in the brain (which controls movement) and in the cortex (which governs thinking and decision making).

Hence, over time, a patient will experience stiffness and involuntary jerking, difficulty with focus, memory and planning as well as mood swings, anxiety, and depression.

What’s more, “the higher the number of repeats, the more severe the symptoms and the earlier their onset,” says Dr. Moore. For example, people with 27-35 repeats on the DNA sequence do not have symptoms. (Their children who inherit the gene, however, can have increased repetition.) Those with 36 to 39 may or may not develop symptoms, but usually later in life. And those with more than 60 repeats can develop juvenile onset, before age 20. Most Huntington’s patients die within 10 to 20 years of symptom manifestation.

In a clinical trial announced in a press release, the Amsterdam-based company uniQure used a one-time therapy called AMT-130, which contains an engineered, harmless virus that delivers genetic instructions to the HTT gene. That virus prevents the gene from making the protein.

The gene-therapy drug is infused through catheters inserted deep into the brain regions heavily affected in Huntington’s.

This infusion, guided by MRI, involves 12 to 18 hours of brain surgery.

Of the 29 patients who received and completed treatment, 12 were in the low-dose group and 12 in the high-dose group. They were followed for 3 years, with researchers comparing their movement, cognitive, and daily functions to a global Huntington’s disease registry. The higher-dose cohort declined at a considerably slower pace, a 75% slowing, according to UniQure. The company also reported a 60% slowing of the decline in the higher-dose group on a functional scale that measures independence. In addition, Neurofilament light protein (NFL), a marker of nerve-cell damage in spinal fluid, was lower in study participants than in untreated patients.

The results of this gene therapy received broad news coverage.

This prompted patients and family members to phone Dr. Moore and his colleagues at UHealth, one of only four Huntington’s Disease Centers of Excellence in Florida. “There’s a lot of hope,” he explains, “We got calls asking, ‘Is this a cure? Where do I get it?’ But this is only a [first] step.”

The study, he explains, is small and has not been peer-reviewed. It compared patients to an external control group, not others who received a placebo at the same time of the trial, a method that can introduce bias. Also, the delivery of the gene-therapy infusion involves delicate brain surgery and is likely to be very expensive. (Other companies are conducting gene-therapy trials, and some involve oral medications.)

That said, “the therapy appears to be well tolerated,” Dr. Moore said.

He hopes the company expands the next phase of the study to new sites.

It is not clear if and when this will happen. Initially, uniQure said it would seek accelerated approval from the U.S. Food and Drug Administration, but the agency advised the Dutch company that the data were likely not enough for a Biologics License Application under the accelerated approval pathway. UniQure officials said the news was “unexpected” and vowed to continue working with the FDA “to determine the best path forward to rapidly bring AMT-130 to patients and their families in the U.S.”

Though the delay is sure to disappoint people living with HD, Dr. Moore agrees with the FDA’s caution: “I agree with this regulatory setback. Science has to prevail when approving a medication, even if the disease being managed is as terrible as HD. If there are not enough elements to consider therapy efficacious and safe, the FDA cannot allow the medication to be on the market and be used on our patients.”

But for a disease that causes severe symptoms and is always fatal, any bit of progress — even if slow and circuitous — could be considered good news, particularly if the study on the gene therapy moves to the next phase.

Written by Ana Veciana-Suárez, a regular contributor to the University of Miami Health System. She is an acclaimed author and journalist who has worked for The Miami Herald, The Miami News, and The Palm Beach Post.

Tags: Dr. Henry Moore, Genetic mutation effects, Huntington's disease research, movement disorders, Patient advocacy for HD