Early-stage study gives hope for rare and fatal neurodegenerative condition

NPC is known to affect around one in 100,000 people, though it is thought to be underdiagnosed, with genetic data indicated that that figure could actually be closer to one in 40,000. Its onset can first be observed in early childhood through clumsiness and learning difficulties; this is followed by progressive loss of brain function which deteriorates motor function, hearing, speech and cognition. The disease also causes a cholesterol build-up which can interfere with the functions of organs beyond the brain, including the liver and spleen.

The team took 14 participants aged between four and 23 and administered cyclodextrin into their spinal columns once a month for 18 months. Cyclodextrin is a sugar molecule that has traditionally been used as a minor ingredient to help drug compounds dissolve in water, but in the treatment of NPC it is able to release cholesterol trapped in cells caused by the disease.

As the trial did not utilise a placebo control group, the team used historical data of past NPC patients, and compared them against the NPC Neurological Severity Score, which evaluates  symtoms of the disease such as eye movement, fine motor skills, memory and severity of seizures. Using this system, historical patient data indicated that the disease worsened by around 2.9 points per year on average. However, in those treated with cyclodextrin, scores actually increased by an average of 1.2 points per year.

"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," explained Daniel S Ory, first author of the study and Alan A and Edith L Wolff Professor of Cardiology at WUSM. "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."

"Some of the patients began this trial without the ability to speak, and now they speak," he continued. "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, use of the drug was found to accelerate the deterioration of hearing in patients, something the researchers expected following their trials in animal models.

"Before beginning the trial, we discussed this issue extensively with patients and families in the NPC community, as well as with the Food and Drug Administration," Ory said. "A therapy that causes hearing loss is not ideal. But since the disease itself causes hearing loss, we felt that this side effect may be a reasonable trade-off, given the alternative decline and death that the disease also causes."

Ory also noted that patients were able to maintain quality of life through the use of a hearing aid. Phase 3 trials, utilising randomised and controlled groups, is already underway.