1. Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins increases safety margin in treatment of Niemann-Pick disease type C.
- Author
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Yamada, Yusei, Ishitsuka, Yoichi, Kondo, Yuki, Nakahara, Shuichi, Nishiyama, Asami, Takeo, Toru, Nakagata, Naomi, Motoyama, Keiichi, Higashi, Taishi, Arima, Hidetoshi, Kamei, Shunsuke, Shuto, Tsuyoshi, Kai, Hirofumi, Hayashino, Yuji, Sugita, Masatake, Kikuchi, Takeshi, Hirata, Fumio, Miwa, Toru, Takeda, Hiroki, and Orita, Yorihisa
- Subjects
NIEMANN-Pick diseases ,MOLECULAR spectroscopy ,HAPTOGLOBINS ,MOLECULAR dynamics ,CHOLESTEROL ,CYCLODEXTRIN derivatives ,THERAPEUTICS ,BIOLOGICAL models ,RESEARCH ,GLUCANS ,ANIMAL experimentation ,RESEARCH methodology ,MEDICAL cooperation ,EVALUATION research ,COMPARATIVE studies ,RESEARCH funding ,MICE - Abstract
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), 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.Experimental Approach: 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.Key Results: 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.Conclusions and Implications: 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. [ABSTRACT FROM AUTHOR]- Published
- 2021
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