Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins

Abstract

AbstractNiemann-Pick type C disease (NPCD) is a lysosomal disorder whith patients presenting highly variable onset, neurovisceral symptoms and life spans due to defective lipid homeostasis. At present, therapeutic options are limited to palliative and disease-modifying drugs, and there is a continued need for new approaches. Here, we explored bromodomain and extraterminal (BET) proteins as new drug target for NPCD using patient-derived fibroblasts. Treatment of cells with JQ1, a prototype BET inhibitor, enhanced the level of NPC1 protein and increased its presence in lysosomes, diminished lysosomal expansion and cholesterol accumulation and induced extracellular release of lysosomal components in a time- and dose-dependent manner. The reversal of pathologic changes in an established cell model suggest inhibition of BET protein as new therapeutic approach for NPCD.