Pharmacological BET Protein Inhibition Reverts Niemann-Pick Type C Disease-Associated Changes in Human iPSC-Derived Cortical Neurons

Niemann-Pick type C1 (NPC1) disease is a fatal lysosomal disorder caused by impaired intracellular cholesterol trafficking, leading to progressive neurodegeneration and premature death. Despite advances in disease modelling, therapeutic development remains limited, partly due to the lack of human neuronal systems that accurately recapitulate disease-relevant phenotypes.

Here, we generated a patient-specific neuronal model by differentiating induced pluripotent stem cells (iPSCs) homozygous for the most common NPC1 c.3182T>C (p.I1061T) variant into cortical neurons. These cells exhibited hallmarks of neuronal pathology associated with NPC1 disease. Using this experimental model, we explored the effects of pharmacological inhibition of bromodomain and extraterminal (BET) proteins. Treatment with the BET inhibitor JQ1 attenuated disease-associated endophenotypes, improving neuronal viability and modulating intracellular cholesterol accumulation. Overall, our findings identify BET inhibition as a novel strategy to ameliorate NPC1-associated neuronal pathology, uncover a previously underexplored link between epigenetic regulation and cholesterol homeostasis, and highlight the use of iPSC-derived neurons as a powerful platform for therapeutic discovery.