A compound used to solubilize drugs surprisingly improves the symptoms of a rare genetic disorder, Niemann-Pick type C, and a new study in PNAS provides some clues as to how.
Researchers at the University of Texas Southwestern Medical School in Dallas fed NPC mice a form of cyclodextrin, a doughnut-shaped chemical with a water-soluble ring and a fat-soluble hole that enables the compound to solubilize an otherwise insoluble molecule, such as a drug.
The hallmark of NPC is disrupted cholesterol trafficking inside cells, causing the substance to accumulate and leading to problems in the liver and brain. When the researchers, led by John Dietschy, administered one dose of cyclodextrin to young NPC mice, the amount of accumulated cholesterol in cells decreased markedly, liver function and neural function improved, and the mice lived longer than untreated NPC mice.
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| Chemical structure of beta-cyclodextrin |
“There are major biochemical shifts, very suddenly,” Dietschy told The Scientist. “This was very surprising. We’ve never seen this with any other compound.”
Previous research has shown that cyclodextrin can improve NPC. What makes this study exciting, said Charles Vite, who was not involved in the study but is trying cyclodextrin in cats with NPC at the University of Pennsylvania in Philadelphia, is that it shows why cyclodextrin works. Specifically, it enters cells and causes cholesterol to move to where it can be processed, either within the cytosol or outside, perhaps excreted into bile. “I don’t think anybody had a clue how” cyclodextrin was working in NPC, Vite told The Scientist. The paper shows that cyclodextrin is “returning the cell back to its normal function,” he said. “It seems really exciting.”
Dietschy added that he hopes cyclodextrin will help reveal even more clues about how cholesterol moves inside cells. “We view cyclodextrin as merely a tool to view this process,” which remains largely a mystery, Dietschy said. “There’s a big black box inside the cell.”
Currently, patients with NPC (a disorder profiled in our November issue) have few treatment options. The only prescription drug available, an inhibitor of glycosphingolipid synthesis, normally treats another lysosomal storage disorder, and is prohibitively expensive (one family, the subject of the November story, spends up to $160,000 per year to treat two children with the medication, called Zavesca). Unfortunately, the drug simply delays progression, and children with NPC inevitably develop liver problems and dementia, before dying prematurely.
Cyclodextrin fell within NPC researchers’ radars after an experiment that showed a steroid hormone solubilized with cyclodextrin had an effect on the disease. Gradually, scientists began to realize it was the solubilizer, and not the drug, that was doing the work.
In the current study, Dietschy and his team gave one dose of a form of cyclodextrin to 7-day-old mice with NPC, and observed its effect inside cells. The researchers saw changes in tissues within a few hours after giving the mice the drug, Dietschy said, adding that he and his team now have data on hour-by-hour changes inside cells following a dose of cyclodextrin, and are testing the effects of repeated doses.
Thomas Ohm, who studies NPC at Charité – University Medicine Berlin and was not involved in the study, cautioned that although the treated mice lived longer than untreated mice, they did not live nearly as long as mice without NPC. And cyclodextrin did not appear to lengthen lifespan any more than other experimental drugs for NPC, he added in an email.
“It is intriguing that all kinds of different approaches in our endeavors to find a safe treatment lead only to a very limited magnitude in improvements,” Ohm wrote, “though the effects are most often highly statistically significant.”
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