Drug trial shows promise for deadly neurological disorder

Results of a small clinical trial show promise for treating a rare neurodegenerative condition that typically kills those afflicted before they reach age 20. The disease, called Niemann-Pick type C (NPC), causes cholesterol to build up in neurons, leading to a gradual loss of brain function. In the drug trial, researchers have shown that treatment with a type of sugar molecule called cyclodextrin slows progression of the disease.
The study, led by researchers at Washington University School of Medicine in St. Louis and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH).
“We were surprised to see evidence that this therapy could slow progression of the disease and, in some cases, get back some function — speech in particular,” said first author Daniel S. Ory, MD, the Alan A. and Edith L. Wolff Professor of Cardiology at Washington University School of Medicine in St. Louis. “In a neurodegenerative disease, therapies can’t recover neurons that have died. But if some brain cells are dysfunctional rather than dead, it seems this drug can recover some of that function.”
The findings are a result of efforts by the National Center for Advancing Translational Sciences of the NIH to find new treatments for rare and neglected diseases. NPC affects about one in 100,000 births, though Ory noted the disease is under-diagnosed and genetic studies suggest a true incidence of closer to one in 40,000 births.
The cholesterol buildup characteristic of NPC can affect organs other than the brain, such as the liver and spleen, but neurological symptoms often first suggest something is amiss. Age of onset varies considerably, but learning delays and clumsiness may emerge in early childhood, followed by progressive loss of brain function, including loss of motor control, hearing, speech and cognition. Most patients with the condition die 10 to 15 years after the onset of symptoms.
In the combined phase one/two clinical trial, 14 NPC patients who were ages 4 to 23 years and showing neurological symptoms were given cyclodextrin, administered into the spinal column once per month for 12 to 18 months. Another three patients were given cyclodextrin in the spinal column every two weeks for 18 months. Since cyclodextrin does not cross into the brain from the bloodstream, the drug must be injected into the spinal column by lumbar puncture, an outpatient procedure often referred to as a spinal tap. The study did not have a control group that received a placebo, so researchers compared the patients’ progression with historical data collected from past NPC patients.
Doctors used a specialized scoring system to measure disease progression. Called the NPC Neurological Severity Score, it helps assess eye movement, gait, speech, swallowing, fine motor skills, cognition, hearing, memory, and presence and severity of seizures. In each category, patients can score zero to five points, with zero indicating normal function and five indicating severe disability or loss of that category of function.
The historical data from past NPC patients showed that patients’ scores increased — meaning the disease worsened — an average of 2.9 points per year. In contrast, the scores of patients in the trial increased an average of 1.2 points per year, a difference that is statistically significant. The improvements compared with the historical data were seen most in gait, cognition and speech.
“Some of the patients began this trial without the ability to speak, and now they speak,” Ory said. “There is a slowing of the decline, but we were surprised to see trends toward improvement in a few categories. Compared with the historical data, half of the patients in this study saw an improvement or no worsening in the neurological severity score.”
However, hearing loss, a symptom of NPC, was also a major adverse effect of the drug.

Washington University School of Medicine