# Exploration of Bromodomain Proteins as Drug Targets for Niemann–Pick Type C Disease

## TL;DR

This study explores bromodomain proteins as potential drug targets for Niemann–Pick Type C Disease, a fatal disorder involving cholesterol metabolism issues in lysosomes.

## Contribution

The study identifies bromodomain and extra-terminal domain (BET) proteins as novel therapeutic targets for Niemann–Pick Type C Disease (NPCD).

## Key findings

- Treatment with JQ1, a BET protein inhibitor, increased NPC1 protein levels and reduced lysosomal cholesterol accumulation.
- JQ1 induced extracellular release of lysosomal components in a dose- and patient-dependent manner.
- JQ1 modulated cholesterol accumulation caused by NPC1 inhibition and histone deacetylase activity.

## Abstract

Defects in lysosomal cholesterol handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann–Pick type C disease (NPCD), where cholesterol export from the endosomal–lysosomal system is impaired due to variants of either NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2). Therapeutic options for NPCD are limited to palliative care and disease-modifying drugs, and there is a need for new treatments. Here, we explored bromodomain and extra-terminal domain (BET) proteins as new drug targets for NPCD using patient-derived skin fibroblasts. Treatment with JQ1, a prototype BET protein inhibitor, raised the level of NPC1 protein, diminished lysosomal expansion and cholesterol accumulation, and induced extracellular release of lysosomal components in a dose-, time-, and patient-dependent manner. Lastly, JQ1 enhanced and reduced cholesterol accumulation induced by pharmacologic inhibition of NPC1 and of histone deacetylase (HDAC) activity, respectively. Taken together, bromodomain proteins should be further explored as therapeutic drug targets for lysosomal diseases like NPCD, and as new components regulating lysosomal function and cholesterol metabolism.