Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann-Pick Type C disease models

Yuta Tanaka; Yoichi Ishitsuka; Yusei Yamada; Yuki Kondo; Toru Takeo; Naomi Nakagata; Taishi Higashi; Keiichi Motoyama; Hidetoshi Arima; Muneaki Matsuo; Katsumi Higaki; Kousaku Ohno; Tetsumi Irie

doi:10.1016/j.ymgmr.2013.12.003

Influence of Npc1 genotype on the toxicity of hydroxypropyl-β-cyclodextrin, a potentially therapeutic agent, in Niemann-Pick Type C disease models

Mol Genet Metab Rep. 2014 Jan 11:1:19-30. doi: 10.1016/j.ymgmr.2013.12.003. eCollection 2014.

Authors

Affiliations

¹ Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
² Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, 2-2-1 Honjo Kumamoto 860-0811, Japan.
³ Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.
⁴ Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1, Nabeshima, Saga, 849-8501, Saga, Japan.
⁵ Division of Functional Genomics, Research Center for Bioscience and Technology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan.
⁶ Department of Child Neurology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, 36-1, Nishi-cho, Yonago, 683-8504, Japan.

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 in Npc1-deficient mice. When treated with HPBCD (20,000 mg/kg, subcutaneously), over half of the wild-type (Npc1^+/+) or Npc1^+/- mice died by 72 h after the injection. In contrast, all of the Npc1^-/- 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 in Npc1^+/+ or Npc1^+/- mice. However, these pathophysiological changes were significantly alleviated in Npc1^-/- mice. In addition, in vitro analysis showed that the Npc1 gene deficiency and treatment with U18666A, an Npc1 inhibitor, remarkably attenuated the cytotoxicity of HPBCD in Chinese hamster ovary cells. These results suggest that the NPC1 genotype exacerbates the cytotoxicity of HPBCD and Npc1^-/- mice have substantial resistance to the lethality and the organ injury induced by HPBCD injection compared with Npc1^+/+ or Npc1^+/- mice. We suggest that the Npc1 genotype should be considered in the safety evaluation of HPBCD using experimental animals and cells.

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.