Effects of bromodomain protein inhibition in a mouse model of Niemann-Pick type C disease

Abstract

Defects in lysosomal lipid handling provoke fatal disorders presenting neurovisceral symptoms with variable onset and life spans. A prime example is Niemann-Pick type C disease (NPCD), where export of cholesterol and other lipids 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 an unmet need for new treatments. Based on positive effects in patient-derived fibroblasts in vitro, we explored here how inhibition of bromodomain and extra-terminal domain (BET) proteins, a family of histone acetylation readers, affects a well-established mouse model bearing the frequent I1061T variant of NPC1. To this end, we used employed intraperitoneal administration of the blood-brain-barrier penetrating drug JQ1 or vehicle (dimethylsulfoxide), and gauged drug effects based on weight, biomarker levels and quantitative assessment of motor coordination.Treatment of mice with JQ1 induced beneficial effects on some outcome measures, notably a transient increase in weight, reduction of liver cholesterol, and improvements in the footprint test, but these effects occurred only in male but not in female mice. Our results indicate bromodomain proteins as potential therapeutic drug target for NPCD and reveal sex-dependent BET protein signaling in mice.