Arimoclomol

Lysosomes play a critical role in degrading macromolecules, including cholesterol, within the cell. Niemann-Pick disease, type C (NPC), is an inherited lysosomal storage disease associated with mutations in the NPC1 or NPC2 proteins, which regulate cholesterol content within membranes. NPC1 and NPC2 cause cholesterol efflux from late lysosomal and endosomal compartments, and dysfunction of these proteins leads to impaired lysosomal function and the accumulation of multiple lipid species, causing perturbed cellular function and cell death. NPC leads to severe systemic and central nervous system symptoms, such as cognitive impairment, cerebellar ataxia, dysarthria, cataplexy, and seizures.

The mechanism by which arimoclomol exerts its clinical effects in patients with NPC has not been fully elucidated; however, it is believed to modulate heat shock proteins (HSPs), which are involved in an important cellular defence mechanism against cellular stress such as metabolic or lysosomal stress. HSPs, particularly HSP70, are molecular chaperones responsible for the correct processing and folding of damaged or mutated proteins. HSPs increase the activity of sphingolipid‐degrading enzymes, stabilize lysosomal membranes, and exert neuroprotective effects against cell death. Arimoclomol is an HSP70 co-inducer that can cross the blood-brain barrier. It is proposed to clear protein aggregates. Arimoclomol is not believed to directly induce HSP or stress cells; instead, it is reported to stabilize the interaction of Heat Shock Factor 1 (HSF1) with Heat Shock Elements (HSEs), which are transcriptional elements that regulate HSP production.