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.

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."

Who loves ya.
Tom

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