The potential of histone deacetylase inhibitors in N iemann – P ick type C disease

Niemann– P ick type C ( NPC ) disease is a fatal complex neurodegenerative lysosomal storage disorder caused by genetic mutations in the proteins NPC 1 (95% of patients) or NPC 2 that decrease intracellular cholesterol trafficking, resulting in accumulation of unesterified cholesterol and sphingolipids in lysosomal storage organelles. Unfortunately, treatment options for NPC disease are still very limited, although miglustat, which inhibits glucosylceramide synthase, thus limiting ganglioside accumulation, has been approved for treatment of NPC disease. Here we discuss advances in the understanding of NPC 1 and its functions, and several new strategies for interfering with cholesterol and sphingolipid accumulation in NPC 1‐null mice. We also describe several recent studies demonstrating that histone deacetylase inhibitors may correct cholesterol‐storage defects in human NPC 1 mutant fibroblasts by increasing expression of the low‐transport‐activity NPC 1 mutant protein. These studies may lead to development of new therapeutic approaches for treatment of NPC disease.