Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins increases safety margin in treatment of Niemann-Pick disease type C

Background and Purpose Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), a cyclic octasaccharide with a larger cavity than HP-beta-CD, as a candidate drug to treat NPC. However, the molecular target of HP-gamma-CD with respect to NPC and its potential for clinical application are still unclear. Experimental Approach We investigated the mode of interaction between HP-gamma-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-gamma-CD compared with HP-beta-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted. Key Results HP-gamma-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-beta-CD. In vitro, HP-gamma-CD and HP-beta-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-beta-CD shifted to the highly soluble 2:1 complex whereas that of HP-gamma-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-gamma-CD conferred it with significantly reduced toxicity compared with HP-beta-CD, but equal efficacy in treating a mouse model of NPC. Conclusions and Implications HP-gamma-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-beta-CD in terms of ototoxicity and pulmonary toxicity.

Automated summary

The study showed that HP-gamma-CD forms a stable 1:1 inclusion complex with cholesterol, and has almost equivalent therapeutic effects in treating NPC compared to HP-beta-CD. HP-gamma-CD has lower toxicity than HP-beta-CD, and demonstrates the same efficacy in treating NPC models.