title: Influence ofNpc1genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann-Pick Type C disease models.
abstract: Hydroxypropyl-β-cyclodextrin (HPBCD) is an attractive drug candidate against Niemann-Pick Type C (NPC) disease. However, the safety of HPBCD treatment for NPC patients remains to be elucidated. In this study, we examined the acute toxicity of HPBCD inNpc1-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1+/+) orNpc1+/-mice died by 72 h after the injection. In contrast, all of theNpc1-/-mice survived. Marked pathophysiological changes, such as an elevation in serum transaminase and creatinine levels, hepatocellular necrosis, renal tubular damage, interstitial thickening, and hemorrhages in lungs, were induced by the HPBCD treatment inNpc1+/+orNpc1+/-mice. However, these pathophysiological changes were significantly alleviated inNpc1-/-mice. In addition,in vitroanalysis showed that theNpc1gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that theNPC1genotype exacerbates the cytotoxicity of HPBCD andNpc1-/-mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared withNpc1+/+orNpc1+/-mice. We suggest that theNpc1genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishitsuka
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yusei
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, 2-2-1 Honjo Kumamoto 860-0811, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takeo
authors.affiliation: Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, 2-2-1 Honjo Kumamoto 860-0811, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.affiliation: Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1, Nabeshima, Saga, 849-8501, Saga, Japan.
authors.forename: Muneaki
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.affiliation: Department of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1, Nishi-cho, Yonago, 683-8504, Japan.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
keywords: ALT, Alanine aminotransferase; Autosomal recessive disorder; CHO, Chinese hamster ovary; HPBCD, Hydroxypropyl-β-cyclodextrin; Hydroxypropyl-β-cyclodextrin; Lysosomal storage disease; NPC, Niemann–Pick Type C disease; Niemann–Pick Type C; Npc1-deficient mice; U18666A