Rare disease clues found in cell's recycling system

Niemann-Pick type C1 is a rare, fatal genetic disease that causes impaired movement, slurred speech, seizures and dementia.
By Amy Wallace  |  July 17, 2017 at 3:24 PM
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July 17 (UPI) -- Researchers with the National Institutes of Health uncovered a compound in a cell's recycling system that could lead to a treatment for a rare genetic disease.

Niemann-Pick type C1, or NPC1, is a rare, fatal genetic disease that occurs when a faulty gene prevents the removal of cholesterol and other lipids from cells causing them to accumulate in the spleen, liver and brain. NPC1 causes impaired movement, slurred speech, seizures and dementia, and patients with the disease often die in their teens.

The study, published July 17 in Autophagy, found that a closely-related compound can activate an enzyme called AMPK to trigger a cellular recycling system to help reduce elevated cholesterol and other fats from accumulating in the brains and livers of NPC1 patients.

Researchers are testing the investigational drug 2-hydroxypropyl-β-cyclodextrin in a Phase 3 clinical trial of patients with NPC-1. Previous research suggests the drug has the potential to reduce cholesterol and other lipids in cells, which delays the onset of the disease and lessens some symptoms.

"We've shown that a compound very similar to the repurposed drug currently in clinical testing in patients actually turns on an enzyme that jump starts the cell's waste disposal system to reduce cholesterol in cells," Wei Zheng, scientist, NCATS Therapeutics for Rare and Neglected Diseases program, Division of Pre-Clinical Innovation, said in a press release.

"This process, called autophagy, is what cells use to recycle their trash. The process malfunctions in NPC1 and a number of neurodegenerative diseases, making the AMPK enzyme a potential target for future drugs."

In pre-clinical tests of cells from NPC1 patients, researchers found the compound could bind to AMPK to turn on its activity and the autophagy process reducing the amount of accumulated cholesterol in NPC1 cells.

"Our findings provide important new insights into the mechanism of action by which cyclodextrin reduces cholesterol buildup in NPC1 cells and eventually restores a balance," said Juan Marugan, acting branch chief of the NCATS Chemical Genomics Center.

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