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Macroglossia, Motor Neuron Pathology, and Airway Malacia Contribute to Respiratory Insufficiency in Pompe Disease: A Commentary on Molecular Pathways and Respiratory Involvement in Lysosomal Storage Diseases
Article

In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C

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
Program for Leading Graduate Schools “HIGO (Health life science: Interdisciplinary and Glocal Oriented) Program”, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
3
Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan
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Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
5
Institute Biosciences, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan
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Laboratory of Physical Pharmaceutics, Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
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Division of Functional Genomics, Research Center for Bioscience and Technology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan
8
Sanin Rosai Hospital, 1-8-1, Kaikeshinden, Yonago 683-8605, Japan
9
Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(5), 1152; https://doi.org/10.3390/ijms20051152
Received: 8 February 2019 / Revised: 27 February 2019 / Accepted: 28 February 2019 / Published: 6 March 2019
(This article belongs to the Special Issue Molecular Features of Lysosomal Storage Disorders)
Niemann-Pick disease Type C (NPC) is a rare lysosomal storage disease characterized by the dysfunction of intracellular cholesterol trafficking with progressive neurodegeneration and hepatomegaly. We evaluated the potential of 6-O-α-maltosyl-β-cyclodextrin (G2-β-CD) as a drug candidate against NPC. The physicochemical properties of G2-β-CD as an injectable agent were assessed, and molecular interactions between G2-β-CD and free cholesterol were studied by solubility analysis and two-dimensional proton nuclear magnetic resonance spectroscopy. The efficacy of G2-β-CD against NPC was evaluated using Npc1 deficient Chinese hamster ovary (CHO) cells and Npc1 deficient mice. G2-β-CD in aqueous solution showed relatively low viscosity and surface activity; characteristics suitable for developing injectable formulations. G2-β-CD formed higher-order inclusion complexes with free cholesterol. G2-β-CD attenuated dysfunction of intercellular cholesterol trafficking and lysosome volume in Npc1 deficient CHO cells in a concentration dependent manner. Weekly subcutaneous injections of G2-β-CD (2.9 mmol/kg) ameliorated abnormal cholesterol metabolism, hepatocytomegaly, and elevated serum transaminases in Npc1 deficient mice. In addition, a single cerebroventricular injection of G2-β-CD (21.4 μmol/kg) prevented Purkinje cell loss in the cerebellum, body weight loss, and motor dysfunction in Npc1 deficient mice. In summary, G2-β-CD possesses characteristics favorable for injectable formulations and has therapeutic potential against in vitro and in vivo NPC models. View Full-Text
Keywords: Niemann-Pick disease type C; cyclodextrin; 6-O-α-maltosyl-β-cyclodextrin; 2-hydroxypropyl-β-cyclodextrin Niemann-Pick disease type C; cyclodextrin; 6-O-α-maltosyl-β-cyclodextrin; 2-hydroxypropyl-β-cyclodextrin
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MDPI and ACS Style

Yasmin, N.; Ishitsuka, Y.; Fukaura, M.; Yamada, Y.; Nakahara, S.; Ishii, A.; Kondo, Y.; Takeo, T.; Nakagata, N.; Motoyama, K.; Higashi, T.; Okada, Y.; Nishikawa, J.; Ichikawa, A.; Iohara, D.; Hirayama, F.; Higaki, K.; Ohno, K.; Matsuo, M.; Irie, T. In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C. Int. J. Mol. Sci. 2019, 20, 1152. https://doi.org/10.3390/ijms20051152

AMA Style

Yasmin N, Ishitsuka Y, Fukaura M, Yamada Y, Nakahara S, Ishii A, Kondo Y, Takeo T, Nakagata N, Motoyama K, Higashi T, Okada Y, Nishikawa J, Ichikawa A, Iohara D, Hirayama F, Higaki K, Ohno K, Matsuo M, Irie T. In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C. International Journal of Molecular Sciences. 2019; 20(5):1152. https://doi.org/10.3390/ijms20051152

Chicago/Turabian Style

Yasmin, Nushrat; Ishitsuka, Yoichi; Fukaura, Madoka; Yamada, Yusei; Nakahara, Shuichi; Ishii, Akira; Kondo, Yuki; Takeo, Toru; Nakagata, Naomi; Motoyama, Keiichi; Higashi, Taishi; Okada, Yasuyo; Nishikawa, Junichi; Ichikawa, Atsushi; Iohara, Daisuke; Hirayama, Fumitoshi; Higaki, Katsumi; Ohno, Kousaku; Matsuo, Muneaki; Irie, Tetsumi. 2019. "In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C" Int. J. Mol. Sci. 20, no. 5: 1152. https://doi.org/10.3390/ijms20051152

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