NIH scientists find rare disease clues in cell’s recycling system


The work could lead to a new generation of potential therapies for NPC1 and other similar disorders, as well as neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The scientists reported their findings online on July 17, 2017 in the journal Autophagy.

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





"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 Marugan, who is acting branch chief of the NCATS Chemical Genomics Center.

"This work is a great illustration of the bi-directional nature of translation – certainly basic science insights can lead to new interventions, but the reverse is equally true," said NCATS Director Christopher P. Austin, M.D., who is also a publication co-author. "Rather than building on the basic science studies to develop a therapy, in this case, we're taking an experimental drug in clinical testing and picking apart how it works."

NPC1 is a lysosomal storage disease, characterized by too much cholesterol and other lipids in the cell's lysosomes, which are sacs of enzymes that break apart proteins, fats and other materials for recycling. In the disease, a gene mutation blocks the transport of fats like cholesterol out of the lysosome, causing them to pile up. In many such diseases, there's also a breakdown in the recycling process, likely due to the cholesterol buildup.

"Malfunctions in the autophagy process have been reported in other lysosomal storage diseases, in addition to diseases such as Parkinson's and Alzheimer's diseases," Zheng said. "Understanding how the drug works may enable us to develop a new generation of anti-NPC1 drugs, and perhaps new drugs against other lysosomal storage and neurodegenerative diseases."


While the current study showed how methyl-β-cyclodextrin can work in NPC1, more research remains to show if the investigational drug, 2-hydroxypropyl-β-cyclodextrin, works in a comparable way, he noted. NCATS supported the research in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Neurological Disorders and Stroke (NINDS), grant NS081985.





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