Scientists report a significant step toward combatting two degenerative brain diseases that chip away at an individual’s ability to move, and think. A targeted therapy developed by scientists at University of Utah Health slows the progression of a condition in mice that mimics a rare disease called ataxia. In a parallel collaborative study, led by researchers at Stanford University, a nearly identical treatment improves the health of mice that model amyotrophic lateral sclerosis (ALS).

The findings benchmark a new approach toward alleviating these previously untreatable conditions. In addition, they suggest that the therapy’s target, the ataxin–2 gene, may be important for maintaining the health of brain cells. Additional work needs to be done to determine whether the regimen is safe and effective in humans and forestalls the death of brain cells over the long–term.

“This is a proof of concept that these new compounds could become the basis for new therapies for neurodegenerative disease, which so far have been largely impenetrable,” says Stefan Pulst, MD, Dr Med, chair of neurology at U of U Health, also senior author on the first study and a collaborator on the second.

Both reports were published online in the journal Nature on April 12, 2017.

At first glance, patients with a type of ataxia, called spinocerebellar ataxia type 2, appear drunk. They stumble, slur their speech and have trouble keeping balance. Patients are often puzzled by the odd collection of symptoms when they first appear, usually after they reach adulthood. But for Pulst, a neurologist, the signs raise alarm bells. They flag a genetic mutation that causes brain cells to die and symptoms to worsen over time.

“It is frustrating when I have to tell patients that there is no magic bullet,” says Pulst. In the most severe cases, ataxia resembles ALS, making it difficult to swallow and eventually to breathe. “At this point there’s nothing we can do to slow the pace of their disease.”

In order to test experimental treatments, Pulst’s team engineered mice that carry the human disease gene. Like their human counterparts, the rodents have many of the same signs of disease, including an overactive ataxin–2 gene that is toxic to brain cells. The scientists injected the rodents with small snippets of manufactured, modified DNA, called antisense oligonucleotides. Like a homing beacon, these compounds found instructions the mutated gene and targeted them for destruction by natural processes.

In less than two months following treatment, mice performed significantly better on a balance and coordination test, an improvement that the scientists showed was more than skin deep. The brain’s cerebellum, a region that coordinates movement, showed signs of restoration, too.

The activity of cells in the cerebellum, which had slowed considerably, returned to firing at normal rates after treatment. Further, expression of a handful of genes that had diminished during disease reverted back to normal.

“The antisense oligonucleotides are directly targeting the root cause of disease inside the cell, explaining why the mice recover some of their motor behavior,” says lead author Daniel Scoles, PhD, associate professor of neurology at U of U health.