Major hurdle crossed in rare disease

Researchers have pinpointed two compounds in blood that together act as reliable biomarkers for Niemann-Pick Type C disease -- a step that could make it easier to screen new therapies and diagnose the disease early, when treatment will help most.

Normal lysosomes (pink) and
those that lack NPC1 (purple,
because they are full of cholesterol).
Image: Washington University in St. Louis

"We've found markers that are, on average, increased nearly ten-fold relative to normal counterparts," last author linkurl:Daniel Ory;http://dbbs.wustl.edu/rib/oryDANS of Washington University School of Medicine told The Scientist. "That's huge."The biomarkers distinguished NPC, a fatal disease that disrupts cholesterol trafficking, from other phenotypically similar diseases. "We've identified correctly every NPC1 case that's been sent to us." Moreover, the markers were detectable before symptoms appeared in mice, and, in humans, were correlated with both severity and how long people had exhibited symptoms.As a result, researchers may be able to quantify the effectiveness of new compounds by tracking levels of these biomarkers, Ory said. "This is really, I think, going to be quite useful," predicted linkurl:John Dietschy;http://www.utsouthwestern.edu/findfac/professional/0,,11822,00.html of the University of Texas Southwestern Medical Center, who did not participate in the study.The disease is caused by mutations to the NPC1 gene that render cells unable to traffic cholesterol, resulting in its accumulation. At the same time, there is a marked increase in the amount of free radicals (for as-yet unknown reasons, Ory said) -- a unique combination of events, which does not seem to occur with any other disease process, Ory explained. He and his colleagues thus reasoned that the free cholesterol might react with these excess free radicals to create unique oxidized forms of cholesterol, or oxysterols, that diffuse into the blood.Sure enough, the researchers found that 2 oxysterols -- 3beta,5alpha,6beta-triol and 7-KC -- were increased by a factor of 10 in human patients, versus healthy controls, according to a recent report in Science Translational Medicine. Turing to mouse models of the disease, the team further found that these oxysterols increased weeks before they typically show any symptoms of the disease. And in linkurl:cats with NPC,;http://www.the-scientist.com/2008/11/1/32/100/ oxysterols decreased after treatment with beta-cyclodextrin, a compound that appears to linkurl:help cells process cholesterol,;http://www.the-scientist.com/blog/display/55377/ now being studied for NPC. Interestingly, people who carried only 1 copy of the mutated NPC1 gene, who typically show no symptoms of NPC, had nearly twice as many oxysterols as normal controls, suggesting they, too, have excess free radicals and trouble processing cholesterol. The findings are "puzzling," Dietschy said, because previous research has found mutated NPC1 carriers don't have excess cholesterol in their tissues. But it could mean, Ory added, that people heterozygous for the mutation -- who likely number in the "millions," he estimated -- may be at increased risk of diseases associated with oxidation, such as diabetes, heart disease, or Alzheimer's. Researchers have already developed a diagnostic test based on these two oxysterols, which will be ready "hopefully within a matter of months," Ory said. (He and one of his co-authors have filed for a patent covering the use of these oxysterols as diagnostics or biomarkers for NPC.)Traditionally, people with NPC have been diagnosed via an invasive skin biopsy, which checks if fibroblasts are accumulating cholesterol -- but is not very sensitive, Ory said, and provides qualitative, not quantitative data. Genotyping is difficult, because there are many different mutations that can disrupt NPC1. This diagnostic test needs only a drop of blood, so could be used for any patient worldwide suspected of NPC, or even general screening of newborns, he said. So far, his team has found the diagnostic misses only 3 cases out of 100, and has no false positives. Chris Hempel, whose twin girls Addi and Cassi both have NPC, said her entire family contributed blood samples for the study, and they are very excited by the results. "When Addi and Cassi were first diagnosed [three years ago], we didn't really even have any biomarkers," Hempel said. "Now, as we do various clinical trials, we have something to measure against." (linkurl:Click here to read more;http://www.the-scientist.com/2008/11/1/32/1/ about Addi and Cassi.)Recently, Hempel received approval from the US Food and Drug Administration to give her girls 6 injections of cyclodextrin into their spine, to ensure it reaches the brain. After just a few infusions, she said the girls were likely better than they would be without the treatment, but the disease is progressing. "They're still declining neurologically," she said. But it's early in the process, Hempel added. "We're still a little bit in wait-and-see mode," she said. "We feel that we're on the right path."To see a video about the story behind the discovery of NPC biomarkers, linkurl:click here.;http://blog.the-scientist.com/2010/12/08/video-new-npc-biomarkers/ (Video will begin to play automatically.)F.D. Porter et al, "Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease," linkurl:Sci Transl Med,;http://stm.sciencemag.org/content/2/56/56ra81.abstract Nov 3;2(56):56ra81, 2010.
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