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DALLAS—In a development that may give hope to children who suffer from fatal Niemann-Pick type C (NP-C) disease and their parents, scientists at the University of Texas Southwestern Medical Center have successfully tested a compound that frees cell-bound cholesterol that has accumulated to excessive levels.
The compound, a cyclodextrin called CYCLO, is a cylindrical hydrocarbon polymer comprised of a hydrophilic exterior and a lypophilic core. Far from exotic, it has been used for many years in solubilizing applications in industry.
NP-C is a unique inherited disease, notes team leader Dr. John Dietschy, professor of internal medicine at UT Southwestern. It causes normal lipoprotein uptake to be trapped in the liposomal compartment of cells throughout the body. The liver and spleen become enlarged, and later—generally between ages 10 and 12—the disease becomes neurological, leading to neuron degeneration and death. Although late onset of neurological symptoms can indicate longer life spans, few people diagnosed with NP-C reach age 40. The vast majority of children die before they are 20 and many before age 10.
Using seven-day-old mice that carry the NP-C mutation, the UT researchers injected a single dose of cholesterol-binding CYCLO and found that, shortly afterwards, the mice began to process cholesterol just as their healthy counterparts did. After seven weeks, the mice treated with a single injection continued to show substantially lower tissue cholesterol levels than the untreated mice, as well as improved liver function and decreased neurodegeneration.
"What we've shown is that very quickly after administration of this compound, the huge pool of cholesterol that has just been accumulating in the cells is suddenly released and metabolized normally," Dr. Dietschy says. "Interestingly," he adds, "treatment with CYCLO did nothing in normal animals."
In vitro, he notes, cells create more cholesterol when treated, but this rebound effect was not seen in normal animal models.
Dietschy is cautious about immediate therapeutic implications of the UT findings.
Although the discovery sheds light on how cholesterol is transported through the cells of the body, "the findings in no way represent a Niemann-Pick disease cure," he says. No dose-response data have been developed, for example, although kidney toxicity has been shown, Dietschy points out.
Dietschy's group is pursuing a number of next steps to determine if repeat administration will normalize the defect and extend the animal's life. Is dose-response linear or might a 10-fold difference in dose be necessary to find where the effect first appears? And there's the challenge of directly demonstrating that CYCLO actually gets into the cells. In addition, there are about 40 other lysosomal storage diseases, Dietschy notes. As one example, ganglioside mouse models exist that could be used to determine if CYCLO's effect is non-specific. "We view it as a tool to dissect the chemistry that may lead to a therapy," he says.
Finally, Dietschy understands that the parents of children afflicted with NP-C are desperate, which may lead to clinical studies—or even unauthorized trial—in humans. He notes that no one knows what dose might be effective, or even how best to administer the compound, and he urges caution.