Lysosomal storage diseases (LSDs) are a group of more than 70 rare monogenic disorders, the majority of which follow a neurodegenerative clinical course. They result from inherited mutations in genes encoding proteins required for lysosomal function. The accumulated substrates in LSDs are biochemically diverse, and the pathogenic cascades they trigger are highly complex. Although significant translational progress has been achieved, most LSDs remain without disease-modifying therapies and are therefore managed symptomatically. A central question in the field concerns the extent to which pathogenic cascades converge across different LSDs, and whether therapies developed for one subgroup may have therapeutic utility in others.
This presentation will focus on Niemann–Pick disease type C (NPC), an LSD caused by mutations in the NPC1 or NPC2 genes. The NPC1 and NPC2 proteins act cooperatively within the NPC pathway, which we have found regulates organelle crosstalk, lipid homeostasis, and lysosomal Ca²⁺ signalling. I will review recent advances in our understanding of the cell biology of NPC and highlight progress in the development and approval of small-molecule therapies. Finally, I will consider the potential of these therapeutics to be of clinical benefit in other LSDs, including the neuronal ceroid lipofuscinoses (NCLs).