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