Hope For A Rare Disease
Solubilizing agent reverses Niemann-Pick C disorder in mice
Stuart A. Borman

A FORM of the common organic solubilizing agent β-cyclodextrin reverses NiemannPick C (NPC) disease in mice. The finding could point the way to a treatment for the human form of the disease, which is fatal. NPC disease is a rare disorder in children, with approximately 500 cases currently diagnosed worldwide, according to the National Niemann-Pick Disease Foundation.
NPC sufferers cannot process cholesterol properly. Cholesterol is used to build cell membranes and for other cell functions. It is processed in lysosomes, and the protein NPC1 then transports it into the cytosol for active use. 
In NPC, one of about 40 rare lysosomal- storage diseases, cholesterol gets stuck in lysosomes. The condition is set off by a mutation in the gene for NPC1 and causes spleen and liver problems, brain damage, difficulty in walking and swallowing, vision and hearing loss, and eventually death. 
Professor of internal medicine John M. Dietschy and coworkers at the University of Texas Southwestern Medical Center now find that when NPC mice are injected with 2-hydroxypropyl-β-cyclodextrin, they process cholesterol normally and their health improves (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0810895106). The treatment results in a reduction of cholesterol levels to a normal range, improved liver function, decreased neurodegeneration, and significantly longer life spans. 
Dietschy and coworkers discovered β-cyclodextrin's potential as an NPC medication serendipitously. In an earlier study, a neurosteroid dissolved in β-cyclodextrin showed activity against NPC in mice. But surprisingly, they recently found that the solvent and not the neurosteroid was the active agent. 
They have now tested 2-hydroxypropyl-β-cyclodextrin in animals and found it to be effective. "We postulate, but have not yet proven, that β-cyclodextrin is getting into the lysosomal compartment of cells and overcoming the mutation in NPC1 in some manner," Dietschy says. He and his coworkers believe β-cyclodextrin might aid cholesterol transport because it has a hydrophobic binding pocket similar to NPC1's. The group now hopes to study the compound's mechanism of action. 
"β-Cyclodextrin is a pretty generic, nontoxic solvent for many molecules, so it could suffer from lack of specificity" when used as an NPC therapeutic, comments William E. Balch, a membrane transport expert at Scripps Research Institute, in La Jolla, Calif. Therefore, "β-cyclodextrin would probably not be a drug of choice" for NPC, but the new findings nevertheless "point our nose in a new direction," he says. 
Peter G. Pentchev of Metabolic Modeling Services, in West Lafayette, Ind., leader of the team that discovered the NPC1 mutation in 1997, says he is "very cautious at this time to label these findings as a major medical breakthrough that can now readily be applied to human NPC patients," but "sometimes great journeys begin with small steps." β-Cyclodextrin is "an important new experimental tool to further study intracellular cholesterol metabolism that bears much promise," he concludes.