Target Health Blog

New Clues to Niemann-Pick type C1

July 24, 2017

Orphan Disease

Niemann-Pick type C1 (NPC1) a rare, lysosomal storage disease, occurs when a faulty gene fails to remove cholesterol and other lipids from cells. The disease is characterized by too much accumulation of 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 NPC1, a gene mutation blocks the transport of fats like cholesterol out of the lysosome, causing them to pile up. Elevated cholesterol and other fats thus accumulate in the spleen, liver and brain, which are hallmarks associated with severe neurological problems The lipids accumulation results in impaired movement, slurred speech, seizures and dementia. Patients with NPC1 typically die in their teens, though a late-onset form of the disease affects young adults.


According to an article published in the journal Autophagy (17 July 2017), it has been demonstrated how an investigational drug works against NPC1. The study found that a closely related compound can activate an enzyme, AMPK, thus triggering a cellular “recycling“ system that helps reduce elevated cholesterol and other accumulated fats in the brains and livers of NPC1 patients. Autophagy is what cells use to recycle their trash. This process malfunctions in NPC1 and a number of neurodegenerative diseases, thus making the AMPK enzyme a potential target for future drugs. The research was led by scientists at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health, and their colleagues. 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.


An investigational drug, called 2-hydroxypropyl-beta-cyclodextrin, is being tested in a Phase 3 clinical trial in patients with NPC1. Pre-clinical studies, including those at NCATS, and previous testing in patients showed the potential drug reduced cholesterol and other lipids in patient cells, delaying disease onset and lessening some disease symptoms. However, investigators were unsure of how the drug worked. To find out, the authors turned to a similar, more potent compound named methyl-?-cyclodextrin. In several pre-clinical experiments using cells from NPC1 patients, the authors determined that the compound could bind to AMPK, turning on its activity and the autophagy process, resulting in a drop in accumulated cholesterol in NPC1 cells. When they blocked AMPK activity, preventing methyl-beta-cyclodextrin from turning on the enzyme, there was no reduction in cholesterol in NPC1 cells. In addition, the authors found that other compounds that also turned on AMPK had similar effects in reducing cholesterol in NPC1 cells, suggesting that AMPK is a potential target for the design of new drugs to treat NPC1 patients.

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