Rare disease clues found in cell’s recycling system — ScienceDaily

Scientists have demonstrated how an investigational drug works against a rare, fatal genetic disease, Niemann-Pick type C1 (NPC1). They found that a closely related compound will activate an enzyme, AMPK, triggering a cellular “recycling” system that helps reduce elevated cholesterol and other accumulated fats in the brains and livers of NPC1 patients, which are hallmarks associated with severe neurological problems. 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. 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.”

NPC1 occurs when a faulty gene fails to remove cholesterol and other lipids from cells. The lipids accumulate in the spleen, liver and brain, impairing movement and leading to slurred speech, seizures and dementia. Patients with NPC1 typically die in their teens, though a late-onset form of the disease affects young adults.

An investigational drug, called 2-hydroxypropyl-β-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…

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