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

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