Efficacy and mechanism of action of cyclodextrin in the treatment of Niemann-Pick type C disease

Abstract

Niemann-Pick type C (NPC) disease is a rare, inherited metabolic disorder caused by a mutation in one of two genes, NPC1 or NPC2. The two proteins encoded by these genes, NPC1 and NPC2, function in the same metabolic pathway where they likely facilitate efflux of cholesterol and glycolipids from late endosomal/lysosomal compartments. Defects in either protein lead to widespread intracellular accumulation of the aforementioned metabolites resulting in severe neurological dysfunction. As there is no cure for NPC disease, research has been focused on developing therapies to arrest disease progression. One promising approach is substrate reduction therapy (SRT), wherein the underlying goal is to ease cellular burden by limiting or reducing stored metabolites.;Our lab serendipitously discovered that cyclodextrin, a cyclic sugar compound originally used as a vehicle for drug delivery, provides benefit to NPC mutant mice when administered alone. Cyclodextrin-treated mice show delayed clinical progression, significant increase in lifespan, and reduction of stored metabolites. Our studies administering cyclodextrin to other mouse models of lysosomal disease indicate that its effects are unique to NPC disease. In additional studies, we show that effectiveness of metabolite reduction depends on the specific cyclodextrin administered. Furthermore, in vitro complexation assays between the different cyclodextrins tested in vivo and NPC-related substrates of interest indicate that the mechanism of action for cyclodextrin is not fully explained by an interaction between cyclodextrin and cholesterol alone.;Based in part on our work, an NIH-sponsored FDA phase 1 clinical trial is now underway for cyclodextrin in children and young adults with NPC disease. Since many NPC patients already take miglustat, another SRT discovered by our laboratory, a clear understanding of possible clinical effects due to drug interactions between cyclodextrin and miglustat has been of the utmost importance. We have tested this combination in NPC1 mutant mice and found some evidence of synergism without deleterious effects. Although cyclodextrin is currently in clinical trial, determining precisely how it ameliorates NPC disease remains a key question that must be answered, for its therapeutic value may well extend beyond that of NPC disease into other non-lysosomal, more common neurological disorders.