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Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann-Pick disease type C without hearing loss. Yamada, Yusei Miwa, Toru Nakashima, Masaki Shirakawa, Aina Ishii, Akira Namba, Nanami Kondo, Yuki Takeo, Toru Nakagata, Naomi Motoyama, Keiichi Higashi, Taishi Arima, Hidetoshi Kurauchi, Yuki Seki, Takahiro Katsuki, Hiroshi Okada, Yasuyo Ichikawa, Atsushi Higaki, Katsumi Hayashi, Ken Minami, Kentaro Yoshikawa, Naoki 50398278 池田, 龍二 イケダ, リュウジ Ikeda, Ryuji 池田 イケダ Ikeda 龍二 リュウジ Ryuji 宮崎大学 University of Miyazaki Ishikawa, Yoshihide Kajii, Tomohito Tachii, Kyoko Takeda, Hiroki Orita, Yorihisa Matsuo, Muneaki Irie, Tetsumi Ishitsuka, Yoichi © 2022 The Authors. Published by Elsevier Masson SAS. Cholesterol Cyclodextrin Niemann–Pick disease type C Ototoxicity Physicochemical property Solubilization application/pdf Niemann-Pick disease type C （NPC） is a fatal disorder with abnormal intracellular cholesterol trafficking resulting in neurodegeneration and hepatosplenomegaly. A cyclic heptasaccharide with different degrees of substitution of 2-hydroxypropyl groups, 2-hydroxypropyl-β-cyclodextrin （HP-β-CD）, acts as a strong cholesterol solubilizer and is under investigation for treating this disease in clinical trials, but its physicochemical properties and ototoxicity remain a concern. Here, we evaluated the potential of mono-6-O-α-maltosyl-γ-CD （G2-γ-CD）, a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, for treating NPC. We identified that G2-γ-CD ameliorated NPC manifestations in model mice and showed lower ototoxicity in mice than HP-β-CD. To investigate the molecular mechanisms of action behind the differential ototoxicity of these CDs, we performed cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modeling, and estimated that the cholesterol inclusion mode of G2-γ-CD maintained solely the 1:1 inclusion complex, whereas that of HP-β-CD shifted to the highly-soluble 2:1 complex at higher concentrations. We predicted the associations of these differential complexations of CDs with cholesterol with the profile of disease attenuation and of the auditory cell toxicity using specific cell models. We proposed that G2-γ-CD can serve as a fine-tuned cholesterol solubilizer for treating NPC, being highly biocompatible and physicochemically suitable for clinical application. Elsevier 2022-09-16 eng journal article VoR http://hdl.handle.net/10458/00010420 https://miyazaki-u.repo.nii.ac.jp/records/6568 36116252 https://doi.org/10.1016/j.biopha.2022.113698 1950-6007 Biomedicine & pharmacotherapy 155 113698 https://miyazaki-u.repo.nii.ac.jp/record/6568/files/1-s2.0-S0753332222010873-main.pdf application/pdf 8.8 MB 2022-10-17