Rare Disease Report

NCATS Researchers Discover New Clues On Treating Niemann-Pick type C1

JULY 17, 2017
Mathew Shanley
Research published by the National Institutes of Health (NIH) this morning explained how methyl-β-cyclodextrin, which is very similar to a drug begin tested in a phase 3 study (2-hydroxypropyl-β-cyclodextrin), could work against Niemann-Pick type C1 (NPC1). It is not yet fully understood how 2-hydroxypropyl-β-cyclodextrin works.
The data, provided by scientists from the National Center for Advancing Translational Sciences (NCATS), could potentially lead to the next generation of therapies for and clues about the pathophysiology of the rare, fatal genetic disorder and others like it. The findings could additionally lead to treatment for neurodegenerative diseases like Parkinson’s and Alzheimer’s.
NPC1, a lysosomal storage disease, is classified by the excess of cholesterol and other lipids in the lysosomes – sacs of enzymes that break apart proteins, fats and other materials for recycling – of a cell. In NPC1, a genetic mutation prevents the transportation of fats, like cholesterol, out of the lysosome and results in a buildup. Symptoms vary in each patient but, in many cases, the more concerning symptoms are neurological. Children with NPC1 often have severe neurological problems due to dystonia and catapexy to seizers and demetia.
2-hydroxypropyl-β-cyclodextrin is currently being tested in a Phase 3 clinical trial in patients with NPC1. Pre-clinical studies and previous testing in patients displayed results like reduced cholesterol and other lipids in patient cells, a delay in disease onset and a lessening of some symptoms, however, it was never clear to investigators how the drug worked.
To find out, co-corresponding authors Wei Zheng, Ph.D., scientist, NCATS Therapeutics for Rare and Neglected Diseases program, Division of Pre-Clinical Innovation, Juan Marugan, Ph.D. at NCATS and Daniel ORY, M.D, at Washington University School of Medicine in St. Louis, turned to a more potent, but similar compound named methyl-β-cyclodextrin.
“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 Zheng. “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.”
While the current study showed the operation and activity of methyl-β-cyclodextrin in NPC1 patients, further research still needs to be done to see if the investigational 2-hydroxypropyl-β-cyclodextrin works in a similar way.
“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,” said Zheng. “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.”
For more about preclinical trials and potential treatment options for NPC1 and other rare diseases, follow Rare Disease Report on Facebook and Twitter.

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