NIH Study May Lead to New Therapies for Neurodegenerative Diseases

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Researchers have demonstrated how an investigational drug currently in testing works against Niemann-Pick type C1, which may lead to treatments for other similar disorders.

On July 17, 2017, the National Institutes of Health (NIH) announced that researchers have demonstrated how the investigational drug 2-hydroxypropyl-β-cyclodextrin, which is currently in Phase III clinical trials, works against Niemann-Pick type C (NPC1), a rare, fatal genetic disease. According to NIH, the research could lead to new treatments for NPC1, similar disorders, and neurodegenerative diseases such as Parkinson’s and Alzheimer’s. The findings were published online on July 17, 2017 in Autophagy.

NPC1, a lysosomal storage disease, is caused by a faulty gene that fails to remove cholesterol and other lipids in cells. The lipids then accumulate in the spleen, liver, and brain, which causes impaired movement. Patients with NPC1 experience slurred speech, seizures, and dementia and typically die in their teens. Pre-clinical studies of the investigational drug, 2-hydroxypropyl-β-cyclodextrin, showed “the potential drug reduced cholesterol and other lipids in patient cells, delaying disease onset and lessening some disease symptoms.”

To find out how the drug worked, researchers at NIH’s National Center for Advancing Translational Sciences (NCATS) and Washington University School of Medicine in St. Louis used a compound named methyl-β-cyclodextrin on cells from NPC1 patients. They found that the compound could bind to the AMPK enzyme, which would turn on its activity and the autophagy process. This activity would result in a drop in accumulated cholesterol in NPC1 cells. Other compounds that turned on AMPK had similar effects on reducing cholesterol. When AMPK activity was blocked, methyl-β-cyclodextrin was prevented from turning on the enzyme and there was no reduction in cholesterol in NPC1 cells. The findings led researchers to believe that AMPK is a potential target for designing new drugs to treat NPC1 patients.

“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, PhD, scientist, NCATS Therapeutics for Rare and Neglected Diseases program, Division of Pre-Clinical Innovation, 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.”


“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, PhD, acting branch chief of the NCATS Chemical Genomics Center, in the release. 

Source: NIH