A compound that’s effective for cats with a version of Niemann Pick Disease, or NPC, is safe enough to be tested in children with the disease, say researchers.
Niemann Pick Disease type C, often referred to as “childhood Alzheimer’s” because of the progressive mental and physical decline seen in the children it afflicts, affects only one person in 150,000. There is no specific, FDA-approved treatment—only drugs to treat the symptoms.
But, new research reports that cats with NPC show vast improvements when treated with a compound called cyclodextrin. While NPC typically results in inexorable neurological decline, administering cyclodextrin into the fluid around the cats’ brains largely halted the progression of disease.
‘A horrible disease’
NPC type c is caused by a mutation in one of two genes, resulting in problems in how a person’s cells process cholesterol in structures called lysosomes.
Researchers still don’t fully understand how this cholesterol-processing dysfunction leads to the suite of symptoms seen in NPC patients, including abnormal motor function and loss of cognitive function.
Some patients don’t develop symptoms until adulthood and can live with the disease for many years, but when NPC arises in childhood, it is usually fatal relatively quickly.
“It’s a horrible disease,” says lead author Charles Vite, associate professor of veterinary neurology at University of Pennsylvania. “Unlike a lot of other genetic diseases, there’s no hint that there’s anything wrong when the child is born.
“These are beautiful, normal kids until they reach school age. Then they start to have trouble with learning, some of them develop motor disturbances, some can’t talk well, some of them develop psychosis and seizures. Death usually occurs by 20.”
Cats, dogs, and people
NPC is naturally occurring in cats and their disease progression is very similar to that seen in children.
“Large animal models of human disease, like cats, are really helpful for determining what’s going to happen in a child when you’re treating them,” Vite says. “By using these natural models, the ultimate goal is to find something that helps your cat and your dog population and your human population, too.”
Though no approved FDA therapies exist specifically for NPC, several years ago two labs, headed by John Dietschy of the University of Texas Southwestern Medical Center and Steven Walkley of Albert Einstein College of Medicine, independently identified a compound with promise.
“The discovery was totally serendipitous,” says Walkley, a coauthor of the study that is published in Science Translational Medicine. “We were at the time repeating published studies that had found that a certain drug dissolved in 2-hydroxypropyl-beta-cyclodextrin, or HPβCD, was beneficial in the mouse model of NPC disease.
“Turns out, carefully controlled studies revealed it wasn’t the drug having the benefit at all but rather what it was dissolved in, namely the HPβCD. Our studies in NPC mice clearly showed that this compound had the ability to dramatically ameliorate the lysosomal pathology in the brain.”
Neurologically normal cats
HPβCD, which is the active ingredient in the odor-fighting household product Febreze, had previously been shown in cell culture to remove cholesterol from cells.
In the current study, researchers administered HPβCD subcutaneously to cats with NPC at various concentrations, as had been done in mice, but found that the dose needed to achieve neurological benefits caused the cats to develop serious lung disease.
To see if they could avoid the negative impact on the lungs while still being effective at treating neurological symptoms, the researchers then tried to give the compound directly into the fluid surrounding the brain, starting when the cats were three weeks old and repeating the dose every two weeks.
The cats, remarkably, were neurologically normal at six months and had only mild symptoms at 18 months. Their brains reflected this as well: There was a large reduction in cholesterol storage in the brain and their Purkinje cells, neurons responsible for motor coordination that are destroyed in large number in NPC, remained intact.
“The cats that were untreated die at six months of age, but the cats who were being treated looked normal at six months of age,” Vite says. “It was a pretty astonishing finding.”
Some of the cats treated with the highest dose have survived past three years of age and have gone on to have kittens.
Even starting the treatment after cats began to show symptoms was helpful. Cats that received HPβCD treatment beginning at 16 weeks lived significantly longer than untreated cats, 43.5 weeks on average.
The research did identify negative side effects to the treatment. Whether given subcutaneously or directly into the brain, the treatment caused hearing loss.
“We went through a study of trying to decrease the dose to see what dose improved signs of disease but didn’t cause deafness,” Vite says. “The bottom line was we didn’t find a good cutoff; if the dose was going to be efficacious you were going to lose some hearing.”
Vite and colleagues will continue looking for other compounds that could have a similar benefit to HPβCD without the negative side effects. His lab will also continue working to understand why the build up of cholesterol causes neurons to die and how HPβCD is able to remove cholesterol from cells.
The Phase 1 clinical trial in children, to identify a safe dose and take note of side effects, began last year and is headed by Forbes D. Porter at the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Phase 2, intended to determine whether the drug is effective in a larger population, will likely begin later this year.
The Phase 2/3 trials will be sponsored by Vtesse, a new biotech company that was formed
specifically to evaluate the safety and efficacy of cyclodextrin for the treatment of NPC and ultimately obtain FDA labeling if the drug is effective.
“It doesn’t get any better than finding something that treats animals and then will go on to treat kids,” Vite says. “That’s the holy grail. That’s what keeps us going. And we are really excited about it.”
The Ara Parseghian Medical Research Foundation and Dana’s Angels Research Trust formed by parents with children with NPC disease were the first to support the work with cats.
Researchers from Washington University in St. Louis, Janssen Research and Development, and the Institut National de la Santé et de la Recherche Médicale contributed to the study. The National Institutes of Health, the Hide and Seek Foundation, the Race for Adam Foundation, members of SOAR-NPC, the National Niemann-Pick Disease Foundation, and Johnson and Johnson supported the work.
Source: University of Pennsylvania