Progress Made Towards Treatment for Neimann-Pick Disease


Investigational treatment may reduce lipid build-up in patients with Neimann-Pick type C1.

In a new study, researchers discovered how an experimental drug can be used to treat Neimann-Pick type C1 (NPC1), a rare and fatal genetic disease.

A compound similar to the investigational drug was observed to activate the AMPK enzyme, which results in the initiation of a cellular recycling system. This system reduces elevated cholesterol and fats in the brain and livers of patients with NPC1, the hallmark of neurological problems, according to a study published by Autophagy.

The authors believe that these findings could lead to novel therapies for patients with NPC1 and neurodegenerative conditions, such as Parkinson’s disease and Alzheimer’s disease.

“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. “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 dysfunctional gene does not remove cholesterol and lipids from cells. The lipids then collect in the spleen, liver, and brain, which results in impaired movement, slurred speech, seizures, and dementia, according to the study. These patients typically do not survive past their teenage years.

The experimental drug, 2-hydroxypropyl-β-cyclodextrin, is being evaluated in a phase 3 clinical trial in patients with NPC1.

Preclinical trials and previous patient testing indicate that the drug can reduce cholesterol and lipids in patient cells, according to the authors. While this action delays disease onset and reduces symptoms, investigators were uncertain of how the drug worked.

To determine how the novel treatment cleared lipid build-up, the authors explored methyl-β-cyclodextrin, a more potent compound. The team previously found that the compound binds to AMPK and turns on its autophagy process, which resulted in a drop cholesterol in NPC1 cells, according to the study.

When AMPK was inhibited, the investigators did not discover a reduction in cholesterol in the cells. They also found that compounds that turned on AMPK effectively reduced cholesterol in the cells, which suggests that the enzyme could be a targeted treatment for NPC1, according to the study.

“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 National Center for Advancing Translational Sciences’ Chemical Genomics Center.

While the current findings indicated how methyl-β-cyclodextrin works to reduce lipid build-up in NPC1, additional studies are needed to determine if 2-hydroxypropyl-β-cyclodextrin works in a similar way, according to the study.

“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,” Dr Zheng concluded. “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.”

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