Discovery of Autophagy Modulators that Increase I1061T NPC1 Expression and Promote Cholesterol Efflux in Niemann-Pick Type C Patient-Derived Fibroblasts

Two compounds were identified that induced autophagy and reduced unesterified cholesterol accumulation in patient-derived cells.

• Autophagy is implicated as a potential therapeutic target in Niemann-Pick Type C (NPC) disease.
• The compounds identified reduced cholesterol levels to a degree similar to that achieved by a known treatment.
• Treatment with the compounds led to a significant reduction in lysosomal hydrolase levels in patient-derived fibroblasts.
• The NPC1 protein is necessary for the compounds to effectively reduce cholesterol accumulation.
• The compounds increase the expression of the mutant NPC1 protein without broadly inhibiting proteasomal activity or worsening endoplasmic reticulum stress.

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